|
1
|
Gasparello J, Ceccon C, Angerilli V, Comunello T, Sabbadin M, D'Almeida Costa F, Antico A, Luchini C, Parente P, Bergamo F, Lonardi S, Fassan M. Liquid biopsy in gastric cancer: A snapshot of the current state of the art. THE JOURNAL OF LIQUID BIOPSY 2025; 7:100288. [PMID: 40027230 PMCID: PMC11863821 DOI: 10.1016/j.jlb.2025.100288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/15/2025] [Accepted: 01/15/2025] [Indexed: 03/05/2025]
Abstract
Circulating tumor DNA (ctDNA) is nowadays considered a robust source to search for druggable tumoral genetic alterations, and in some specific settings liquid biopsy (LB) is already part of the diagnostics scenario and it has successfully implemented in the everyday practice. Three strengths make LB an extraordinary tool: i) to represent the complex molecular mosaicism that characterizes spatially heterogeneous malignancies; ii) to monitor in real-time the tumoral molecular landscape (i.e. to depict the longitudinal/temporal tumor evolution); iii) to ensure molecular profiling even in those cases in which tissue sampling is not feasible or not adequate. This review provides a snapshot of the current state of the art concerning ctDNA assay utility in gastric cancer (GC), testing its robustness as marker and seeking to understand the reasons for the delay in its application in clinical practice.
Collapse
Affiliation(s)
| | - Carlotta Ceccon
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Valentina Angerilli
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Department of Surgical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Pathology, Nijmegen, the Netherlands
| | - Tatiane Comunello
- Department of Pathology, A.C. Camargo Cancer Center, Sao Paulo, Brazil
| | - Marianna Sabbadin
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Department of Surgical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | | | - Antonio Antico
- Department of Clinical Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | | | - Sara Lonardi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padova, Padova, Italy
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| |
Collapse
|
|
2
|
Nixon AB, Navarro FCP, Zhou KI, Abbott C, McDaniel L, Howard L, Brady JC, Liu Y, Jia J, Niedzwiecki D, Strickler J, Boyle SM, Chen RO, Uronis H. Ultra-sensitive, tumor-informed ctDNA profiling in pembrolizumab-treated esophagogastric cancer patients predicts clinical responses. RESEARCH SQUARE 2024:rs.3.rs-5349536. [PMID: 39764133 PMCID: PMC11702795 DOI: 10.21203/rs.3.rs-5349536/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2025]
Abstract
To explore whether ultra-sensitive circulating tumor DNA (ctDNA) profiling enables early prediction of treatment response and early detection of disease progression, we applied NeXT Personal, an ultra-sensitive bespoke tumor-informed liquid biopsy platform, to profile tumor samples from the KeyLargo study, a phase II trial in which metastatic esophagogastric cancer (mEGC) patients received capecitabine, oxaliplatin, and pembrolizumab. All 25 patients evaluated were ctDNA-positive at baseline. Minimal residual disease (MRD) events varied from 406,067 down to 1.5 parts per million (PPM) of ctDNA with a median limit of detection of 2.03 PPM. ctDNA dynamics were highly correlated with changes in tumor size (ρ = 0.59, p = 7.3×10-9). Lack of early molecular response (lack of ctDNA decrease) was associated with worse overall survival (OS) (HR 6.6, 95% CI 1.8-24.1, p = 0.005) and progression-free survival (PFS) (HR 15.4, 95% CI 2.7-87.0, p = 0.002). Lack of molecular clearance of ctDNA was associated with worse OS (HR 6.9, 95% CI 1.5-30.8, p = 0.012) and PFS (HR 19.2, 95% CI 2.4-152.8, p = 0.005). Molecular progression (ctDNA increase) preceded imaging-derived progression by a median lead time of 65 days. These results suggest that ultra-sensitive liquid biopsy approaches could improve treatment decision-making for mEGC patients receiving chemotherapy and immunotherapy.
Collapse
|
|
3
|
Battaglin F, Lenz HJ. Clinical Applications of Circulating Tumor DNA Profiling in GI Cancers. JCO Oncol Pract 2024; 20:1481-1490. [PMID: 39531845 PMCID: PMC11567053 DOI: 10.1200/op.24.00167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/11/2024] [Accepted: 05/01/2024] [Indexed: 11/16/2024] Open
Abstract
Over the next few years, the analysis of circulating tumor DNA (ctDNA) through liquid biopsy is expected to enter clinical practice and revolutionize the approach to biomarker testing and treatment selection in GI cancers. In fact, growing evidence support the use of ctDNA testing as a noninvasive, effective, and highly specific tool for molecular profiling in GI cancers. Analysis of blood ctDNA has been investigated in multiple settings including early tumor detection, minimal residual disease evaluation, tumor diagnosis and evaluation of prognostic/predictive biomarkers for targeted treatment selection, longitudinal monitoring of treatment response, and identification of resistance mechanisms. Here, we review the clinical applications, advantages, and limitations of ctDNA profiling for precision oncology in GI cancers.
Collapse
Affiliation(s)
- Francesca Battaglin
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| | - Heinz-Josef Lenz
- Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
| |
Collapse
|
|
4
|
Saikia J, Malik PS, Kumar S, Jain D, Madan K, Bharati SJ, Deo S, Kumar S. Can cell-free DNA (cfDNA) in pleural lavage serve as a predictive and prognostic biomarker among surgically treated Stage I-III a nonsmall cell lung cancer (NSCLC)? A pilot study. J Surg Oncol 2024; 129:1224-1234. [PMID: 38436618 DOI: 10.1002/jso.27610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 01/16/2024] [Accepted: 02/11/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND AND OBJECTIVES The role of cell-free DNA (cfDNA) in operable nonsmall cell lung cancer (NSCLC) is unclear. This study was aimed to evaluate the feasibility for identification of cfDNA in pleural lavage fluid and its correlation with plasma in resectable NSCLCs. METHODS Consecutively resected NSCLCs were evaluated for cfDNA levels in preoperative plasma (PLS1), intraoperative pleural-lavage (PLV) and postoperative (at 1 month) plasma sample (PLS2). CfDNA was isolated and measured quantitatively by qPCR in a TaqMan probe-detection approach using the human β-actin gene as the amplifying target. RESULTS All (n = 34) except one were negative for malignant cells in PLV cytology. CfDNA could be isolated from all the three samples (PLS1, PLV, and PLS2) successfully in each patient. The median cfDNA levels in PLS1, PLV and PLS2 were 118 ng/mL (IQR 61-158), 167 ng/mL (IQR 59.9-179.9) and 103 ng/mL (IQR 66.5-125.4) respectively. The median follow-up was 34.1 months (IQR 25.2-41.6). A significant overall-survival (OS) and disease-free survival (DFS) were recorded for patients with cfDNA level cut-offs at 125, 170, and 100 ng/mL, respectively for PLS1, PLV, and PLS2. Patients with raised cfDNA in PLS1 (>125 ng/mL) and PLV (>170 ng/mL) had significantly poorer 2-year OS, p = 0.005 and p = 0.012, respectively. The hazards (OS) were also higher for those with raised cfDNA in PLV (HR = 5.779, 95% CI = 1.162-28.745, p = 0.032). PLV (>170 ng/mL) had increased pleural recurrences (p = 0.021) and correlated significantly with poorer DFS at 2-years (p = 0.001) with increased hazards (HR = 9.767, 95% CI = 2.098-45.451, p = 0.004). Multivariable analysis suggested higher cfDNA in PLV as a poor prognostic factor for both OS and DFS. CONCLUSIONS Among patients with operable NSCLC, it is feasible to identify cfDNA in pleural lavage and correlate PLV cfDNA with pleural recurrences and outcomes.
Collapse
Affiliation(s)
- Jyoutishman Saikia
- Department of Surgical Oncology, DR.BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Prabhat S Malik
- Department of Medical Oncology, DR.BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Sachin Kumar
- Department of Medical Oncology, DR.BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Deepali Jain
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Karan Madan
- Department of Pulmonary Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Sachidanand Jee Bharati
- Department of Oncoanaesthesia, DR.BRA IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Suryanarayana Deo
- Department of Surgical Oncology, DR.BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Sunil Kumar
- Department of Surgical Oncology, DR.BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
5
|
Hashimoto T, Nakamura Y, Oki E, Kobayashi S, Yuda J, Shibuki T, Bando H, Yoshino T. Bridging horizons beyond CIRCULATE-Japan: a new paradigm in molecular residual disease detection via whole genome sequencing-based circulating tumor DNA assay. Int J Clin Oncol 2024; 29:495-511. [PMID: 38551727 PMCID: PMC11043144 DOI: 10.1007/s10147-024-02493-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 02/16/2024] [Indexed: 04/26/2024]
Abstract
Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer. Notably, the project underscores the prognostic significance of the ctDNA status at 4 weeks post-surgery and its correlation to adjuvant therapy efficacy at interim analysis. This substantiates the hypothesis that MRD is a critical prognostic indicator of relapse in patients with colorectal cancer. Despite remarkable advancements, challenges endure, primarily attributable to the exceedingly low ctDNA concentration in peripheral blood, particularly in scenarios involving low tumor shedding and the intrinsic error rates of current sequencing technologies. These complications necessitate more sensitive and sophisticated assays to verify the clinical utility of MRD across all solid tumors. Whole genome sequencing (WGS)-based tumor-informed MRD assays have recently demonstrated the ability to detect ctDNA in the parts-per-million range. This review delineates the current landscape of MRD assays, highlighting WGS-based approaches as the forefront technique in ctDNA analysis. Additionally, it introduces our upcoming endeavor, WGS-based pan-cancer MRD detection via ctDNA, in our forthcoming project, SCRUM-Japan MONSTAR-SCREEN-3.
Collapse
Affiliation(s)
- Tadayoshi Hashimoto
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yoshiaki Nakamura
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shin Kobayashi
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Junichiro Yuda
- Department of Hematology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Taro Shibuki
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideaki Bando
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
| |
Collapse
|
|
6
|
Díaz del Arco C, Fernández Aceñero MJ, Ortega Medina L. Liquid biopsy for gastric cancer: Techniques, applications, and future directions. World J Gastroenterol 2024; 30:1680-1705. [PMID: 38617733 PMCID: PMC11008373 DOI: 10.3748/wjg.v30.i12.1680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/01/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024] Open
Abstract
After the study of circulating tumor cells in blood through liquid biopsy (LB), this technique has evolved to encompass the analysis of multiple materials originating from the tumor, such as nucleic acids, extracellular vesicles, tumor-educated platelets, and other metabolites. Additionally, research has extended to include the examination of samples other than blood or plasma, such as saliva, gastric juice, urine, or stool. LB techniques are diverse, intricate, and variable. They must be highly sensitive, and pre-analytical, patient, and tumor-related factors significantly influence the detection threshold, diagnostic method selection, and potential results. Consequently, the implementation of LB in clinical practice still faces several challenges. The potential applications of LB range from early cancer detection to guiding targeted therapy or immunotherapy in both early and advanced cancer cases, monitoring treatment response, early identification of relapses, or assessing patient risk. On the other hand, gastric cancer (GC) is a disease often diagnosed at advanced stages. Despite recent advances in molecular understanding, the currently available treatment options have not substantially improved the prognosis for many of these patients. The application of LB in GC could be highly valuable as a non-invasive method for early diagnosis and for enhancing the management and outcomes of these patients. In this comprehensive review, from a pathologist's perspective, we provide an overview of the main options available in LB, delve into the fundamental principles of the most studied techniques, explore the potential utility of LB application in the context of GC, and address the obstacles that need to be overcome in the future to make this innovative technique a game-changer in cancer diagnosis and treatment within clinical practice.
Collapse
Affiliation(s)
- Cristina Díaz del Arco
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - M Jesús Fernández Aceñero
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| | - Luis Ortega Medina
- Department of Surgical Pathology, Health Research Institute of the Hospital Clínico San Carlos, Hospital Clínico San Carlos, Madrid 28040, Spain
- Department of Legal Medicine, Psychiatry and Pathology, Universidad Complutense de Madrid, Madrid 28040, Spain
| |
Collapse
|
|
7
|
Cheung KS, Chan AOO, Yu Wong BC. Intestinal‐type Gastric Cancer. GASTROINTESTINAL ONCOLOGY ‐ A CRITICAL MULTIDISCIPLINARY TEAM APPROACH 2E 2024:120-138. [DOI: 10.1002/9781119756422.ch7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
8
|
Li JH, Zhang DY, Zhu JM, Dong L. Clinical applications and perspectives of circulating tumor DNA in gastric cancer. Cancer Cell Int 2024; 24:13. [PMID: 38184573 PMCID: PMC10770949 DOI: 10.1186/s12935-024-03209-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 01/02/2024] [Indexed: 01/08/2024] Open
Abstract
Gastric cancer remains a leading cause of cancer-related death worldwide, largely due to inadequate screening methods, late diagnosis, and limited treatment options. Liquid biopsy has emerged as a promising non-invasive approach for cancer screening and prognosis by detecting circulating tumor components like circulating tumor DNA (ctDNA) in the blood. Numerous gastric cancer-specific ctDNA biomarkers have now been identified. CtDNA analysis provides insight into genetic and epigenetic alterations in tumors, holding promise for predicting treatment response and prognosis in gastric cancer patients. This review summarizes current research on ctDNA biology and detection technologies, while highlighting clinical applications of ctDNA for gastric cancer diagnosis, prognosis, and guiding treatment decisions. Current challenges and future perspectives for ctDNA analysis are also discussed.
Collapse
Affiliation(s)
- Jing-Han Li
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Dan-Ying Zhang
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Ji-Min Zhu
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Ling Dong
- Department of Gastroenterology and Hepatology and Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| |
Collapse
|
|
9
|
Han HS, Lee KW. Liquid Biopsy: An Emerging Diagnostic, Prognostic, and Predictive Tool in Gastric Cancer. J Gastric Cancer 2024; 24:4-28. [PMID: 38225764 PMCID: PMC10774753 DOI: 10.5230/jgc.2024.24.e5] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 01/17/2024] Open
Abstract
Liquid biopsy, a minimally invasive procedure that causes minimal pain and complication risks to patients, has been extensively studied for cancer diagnosis and treatment. Moreover, it facilitates comprehensive quantification and serial assessment of the whole-body tumor burden. Several biosources obtained through liquid biopsy have been studied as important biomarkers for establishing early diagnosis, monitoring minimal residual disease, and predicting the prognosis and response to treatment in patients with cancer. Although the clinical application of liquid biopsy in gastric cancer is not as robust as that in other cancers, biomarker studies using liquid biopsy are being actively conducted in patients with gastric cancer. Herein, we aimed to review the role of various biosources that can be obtained from patients with gastric cancer through liquid biopsies, such as blood, saliva, gastric juice, urine, stool, peritoneal lavage fluid, and ascites, by dividing them into cellular and acellular components. In addition, we reviewed previous studies on the diagnostic, prognostic, and predictive biomarkers for gastric cancer using liquid biopsy and discussed the limitations of liquid biopsy and the challenges to overcome these limitations in patients with gastric cancer.
Collapse
Affiliation(s)
- Hye Sook Han
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
| |
Collapse
|
|
10
|
Seo SH, Park YS, Nam SK, Lee HS, Park DJ, Park KU. Concordance of circulating tumor DNA and matched formalin-fixed paraffin-embedded tumor tissue in gastric cancer as a predictor of recurrence. KOREAN JOURNAL OF CLINICAL ONCOLOGY 2023; 19:45-51. [PMID: 38229488 DOI: 10.14216/kjco.23009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 10/24/2023] [Indexed: 01/18/2024]
Abstract
PURPOSE Combined analysis of the variant composition of circulating tumor DNA (ctDNA) from cell-free plasma and DNA from tumor tissue could provide insight into the implications of the genetic alterations responsible for the intratumoral and intertumoral heterogeneity of gastric cancer. We aimed to evaluate the usefulness of this approach in these patients. METHODS Cell-free plasma and formalin-fixed paraffin-embedded tumor tissue samples from 46 patients with gastric cancer were examined. Targeted deep sequencing was performed using a commercially available kit. RESULTS The cell-free DNA (cfDNA) concentration was higher in stage II-IV versus stage I patients and in larger versus smaller tumors. Only 12 of the 36 (33.3%) alterations in the tumor tissue samples were in concordance with those in the ctDNA samples. Two variants were in concordance in stage I samples and 10 in stage II-IV samples. Actionable variants that were detected in concordance were in the stage II-IV samples. Preoperative ctDNA positivity of actionable variants was significantly associated with cfDNA concentration, lymphatic invasion, N stage, and TNM stage. Cancer recurrence was significantly associated with tumor size, lymphatic/vascular invasion, TNM stage, and ctDNA-tumor tissue variant concordance. CONCLUSION Preoperative ctDNA genetic analysis using a multigene panel offers substantial clinical benefits when performed in conjunction with targeted deep sequencing of tumor tissue. Concordance between preoperative ctDNA and tumor tissue mutations may serve as a prognostic indicator in patients with gastric cancer.
Collapse
Affiliation(s)
- Soo Hyun Seo
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Young Suk Park
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Soo Kyung Nam
- Department of Interdisciplinary Program in Cancer Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Kyoung Un Park
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| |
Collapse
|
|
11
|
Mi J, Wang R, Han X, Ma R, Li H. Circulating tumor DNA predicts recurrence and assesses prognosis in operable gastric cancer: A systematic review and meta-analysis. Medicine (Baltimore) 2023; 102:e36228. [PMID: 38050202 PMCID: PMC10695564 DOI: 10.1097/md.0000000000036228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 10/30/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Selecting the appropriate patient for further treatment after surgery for gastric cancer can improve the patient prognosis. Circulating tumor DNA (ctDNA) has the potential to predict recurrence and prognosis after gastric cancer surgery, but the results are still inconclusive. As the completed studies had small sample sizes and were inconsistent, a meta-analysis was conducted to assess the effect of ctDNA on recurrence and prognosis after gastric cancer surgery. METHODS PubMed, Embase, Scopus, and the Web of Science were searched for potentially eligible studies published up to April 7, 2023. Pooled relative risk (RR) and pooled hazard ratio (HR) were calculated to evaluate recurrence, recurrence-free survival (RFS), and overall survival (OS) following gastric cancer surgery. RESULTS A pooled analysis revealed that patients who were ctDNA positive before and after surgery were at a high risk of gastric cancer recurrence (RR = 1.79, 95% CI: 1.19-2.71; RR = 3.17, 95% CI: 2.36-4.25). The pooled data revealed that ctDNA-positive patients had a poorer RFS and OS (HR = 6.37, 95% CI: 2.70-15.01; HR = 4.58, 95% CI: 1.68-12.49). CONCLUSIONS ctDNA-positive patients were at a high risk of recurrence after gastric cancer surgery and had a poorer prognosis. Hence, ctDNA-positive patients needed close follow-up and further treatment.
Collapse
Affiliation(s)
- Junjie Mi
- Department of Gastroenterology, Shanxi Provincial People’s Hospital (The Fifth Hospital of Shanxi Medical University), Taiyuan, China
| | - Rong Wang
- Department of Gastroenterology, Shanxi Provincial People’s Hospital (The Fifth Hospital of Shanxi Medical University), Taiyuan, China
| | - Xiaofang Han
- Core Laboratory, Shanxi Provincial People’s Hospital (The Fifth Hospital of Shanxi Medical University), Taiyuan, China
| | - Ruijun Ma
- Department of Gastroenterology, Shanxi Provincial People’s Hospital (The Fifth Hospital of Shanxi Medical University), Taiyuan, China
| | - Huiying Li
- Fenyang College of Shanxi Medical University, Fenyang, China
| |
Collapse
|
|
12
|
Han Y, Wei J, Wang W, Gao R, Shen N, Song X, Ni Y, Li Y, Xu LD, Chen W, Li X. Multidimensional Analysis of a Cell-Free DNA Whole Methylome Sequencing Assay for Early Detection of Gastric Cancer: Protocol for an Observational Case-Control Study. JMIR Res Protoc 2023; 12:e48247. [PMID: 37728978 PMCID: PMC10551793 DOI: 10.2196/48247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 08/17/2023] [Accepted: 08/18/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Commonly used noninvasive serological indicators serve as a step before endoscope diagnosis and help identify the high-risk gastric cancer (GC) population. However, they are associated with high false positives and high false negatives. Alternative noninvasive approaches, such as cancer-related features in cell-free DNA (cfDNA) fragments, have been gradually identified and play essential roles in early cancer detection. The integrated analysis of multiple cfDNA features has enhanced detection sensitivity compared to individual features. OBJECTIVE This study aimed to develop and validate an assay based on assessing genomic-scale methylation and fragmentation profiles of plasma cfDNA for early cancer detection, thereby facilitating the early diagnosis of GC. The primary objective is to evaluate the overall specificity and sensitivity of the assay in predicting GC within the entire cohort, and subsequently within each clinical stage of GC. The secondary objective involved investigating the specificity and sensitivity of the assay in combination with possible serological indicators. METHODS This is an observational case-control study. Blood samples will be prospectively collected before gastroscopy from 180 patients with GC and 180 nonmalignant control subjects (healthy or with benign gastric diseases). Cases and controls will be randomly divided into a training and a testing data set at a ratio of 2:1. Plasma cfDNA will be isolated and extracted, followed by bisulfite-free low-depth whole methylome sequencing. A multidimensional model named Thorough Epigenetic Marker Integration Solution (THEMIS) will be constructed in the training data set. The model includes features such as the methylated fragment ratio, chromosomal aneuploidy of featured fragments, fragment size index, and fragment end motif. The performance of the model in distinguishing between patients with cancer and noncancer controls will then be evaluated in the testing data set. Furthermore, GC-related biomarkers, such as pepsinogen, gastrin-17, and Helicobacter pylori, will be measured for each patient, and their predictive accuracy will be assessed both independently and in combination with the THEMIS model. RESULTS Recruitment began in November 2022 and will be ended in April 2024. As of August 2022,250 patients have been enrolled. The final data analysis is anticipated to be completed by September 2024. CONCLUSIONS This is the first registered case-control study designed to investigate a stacked ensemble model integrating several cfDNA features generated from a bisulfite-free whole methylome sequencing assay. These features include methylation patterns, fragmentation profiles, and chromosomal copy number changes, with the aim of identifying the GC population. This study will determine whether multidimensional analysis of cfDNA will prove to be an effective strategy for distinguishing patients with GC from nonmalignant individuals within the Chinese population. We anticipate the THEMIS model will complement the standard-of-care screening and aid in identifying high-risk patients for further diagnosis. TRIAL REGISTRATION ClinicalTrial.gov NCT05668910; https://www.clinicaltrials.gov/study/NCT05668910. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/48247.
Collapse
Affiliation(s)
- Yongjun Han
- Department of General Surgery, First Hospital of Yulin, Yulin, China
| | - Jiangpeng Wei
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Weidong Wang
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Ruiqi Gao
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Ning Shen
- Genecast Biotechnology Co, Ltd, Wuxi, China
| | | | - Yang Ni
- Genecast Biotechnology Co, Ltd, Wuxi, China
| | - Yulong Li
- Genecast Biotechnology Co, Ltd, Wuxi, China
| | - Li-Di Xu
- Genecast Biotechnology Co, Ltd, Wuxi, China
| | | | - Xiaohua Li
- Department of Gastrointestinal Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| |
Collapse
|
|
13
|
Shyr BS, Chen SC, Shyr YM, Wang SE, Shyr BU. Cell-free DNA as a prognostic and predictive biomarker in resectable distal common bile duct cancer. J Chin Med Assoc 2023; 86:835-841. [PMID: 36998178 DOI: 10.1097/jcma.0000000000000923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/01/2023] Open
Abstract
BACKGROUND Cell-free DNA (cfDNA) as an oncological biomarker has drawn much attention in recent years, but very limited effort has been made to investigate the prognostic values of cfDNA in distal common bile duct (CBD) cancer. METHODS Plasma cfDNA was measured in 67 patients with resectable distal CBD cancer. Survival outcomes and the correlation of cfDNA with other conventional prognostic factors were determined. RESULTS cfDNA levels were significantly higher in female patients, and those with poor tumor differentiation, abnormal serum carcinoembryonic antigen (CEA) level, and stage III cancer. The significant prognostic factors included a high cfDNA level (>8955 copies/mL), abnormal serum CEA level, stage III cancer, and positive resection margins. Compared with patients with high cfDNA level, those with lower cfDNA level (≤8955 copies/mL) had significantly better overall survival outcomes (74.4% vs 100% and 19.2% vs 52.6%, for 1- and 5-year survival rates, respectively, p = 0.001). The cfDNA level, perineural invasion, CEA level, and radicality were identified as independent prognostic factors for distal CBD cancer after multivariate analysis. CONCLUSION Circulating cfDNA levels play a significant role in predicting the prognosis and survival outcome for resectable distal CBD cancer. Furthermore, acting as a promising liquid biopsy, cfDNA could serve as a prognostic and predictive biomarker in combination with current conventional markers to improve diagnostic and prognostic efficacy.
Collapse
Affiliation(s)
- Bor-Shiuan Shyr
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, and National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | | | | | | | | |
Collapse
|
|
14
|
Zhu L, Xu R, Yang L, Shi W, Zhang Y, Liu J, Li X, Zhou J, Bing P. Minimal residual disease (MRD) detection in solid tumors using circulating tumor DNA: a systematic review. Front Genet 2023; 14:1172108. [PMID: 37636270 PMCID: PMC10448395 DOI: 10.3389/fgene.2023.1172108] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/20/2023] [Indexed: 08/29/2023] Open
Abstract
Minimal residual disease (MRD) refers to a very small number of residual tumor cells in the body during or after treatment, representing the persistence of the tumor and the possibility of clinical progress. Circulating tumor DNA (ctDNA) is a DNA fragment actively secreted by tumor cells or released into the circulatory system during the process of apoptosis or necrosis of tumor cells, which emerging as a non-invasive biomarker to dynamically monitor the therapeutic effect and prediction of recurrence. The feasibility of ctDNA as MRD detection and the revolution in ctDNA-based liquid biopsies provides a potential method for cancer monitoring. In this review, we summarized the main methods of ctDNA detection (PCR-based Sequencing and Next-Generation Sequencing) and their advantages and disadvantages. Additionally, we reviewed the significance of ctDNA analysis to guide the adjuvant therapy and predict the relapse of lung, breast and colon cancer et al. Finally, there are still many challenges of MRD detection, such as lack of standardization, false-negatives or false-positives results make misleading, and the requirement of validation using large independent cohorts to improve clinical outcomes.
Collapse
Affiliation(s)
- Lemei Zhu
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha, China
- Academician Workstation, Changsha Medical University, Changsha, China
- School of Public Health, Changsha Medical University, Changsha, China
| | - Ran Xu
- Geneis Beijing Co., Ltd., Beijing, China
| | | | - Wei Shi
- Geneis Beijing Co., Ltd., Beijing, China
| | - Yuan Zhang
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha, China
- Academician Workstation, Changsha Medical University, Changsha, China
- School of Public Health, Changsha Medical University, Changsha, China
| | - Juan Liu
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha, China
- Academician Workstation, Changsha Medical University, Changsha, China
- School of Public Health, Changsha Medical University, Changsha, China
| | - Xi Li
- Department of Orthopedics, Xiangya Hospital Central South University, Changsha, China
| | - Jun Zhou
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha, China
- Academician Workstation, Changsha Medical University, Changsha, China
| | - Pingping Bing
- Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha, China
- Academician Workstation, Changsha Medical University, Changsha, China
| |
Collapse
|
|
15
|
Kung CY, Fang WL, Hung YP, Huang KH, Chen MH, Chao Y, Lin SC, Li AFY, Lo SS, Wu CW. Comparison of the mutation patterns between tumor tissue and cell-free DNA in stage IV gastric cancer. Aging (Albany NY) 2023; 15:777-790. [PMID: 36779847 PMCID: PMC9970310 DOI: 10.18632/aging.204512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 02/01/2023] [Indexed: 02/12/2023]
Abstract
Compared to stage I-III gastric cancer (GC), the level of cell-free DNA (cfDNA) was significantly higher in stage IV GC. The mutation patterns of different metastatic patterns between cfDNA and tumor DNA in stage IV GC have not yet been reported. We used next-generation sequencing (NGS) to analyze cfDNA and tumor DNA in 56 stage IV GC patients. Tumor DNA and cfDNA were analyzed using a 29-gene NGS panel. In tumor samples, the most commonly mutated gene was TP53 (64%), followed by ARID1A (62%), KMT2C (60%) and KMT2D (58%). In cfDNA samples, the most commonly mutated genes were FAT4 (19%) and MACF1 (19%), followed by KMT2D (18%), ARID1A (14%) and LRP1B (14%). The concordance of mutation patterns in these 29 genes was 42.0% between cfDNA and tumor DNA. A specificity of 100% was found when using the mutation status of cfDNA to predict mutations in tumor samples. The sensitivity of the mutation status of cfDNA to predict mutation in tumor samples was highest in FAT4 (88.9%), followed by MACF1 (80%), CDH1 (75%) and PLB1 (75%). For cfDNA with PLB1 mutations, patients were more likely to develop distant lymphatic metastasis than peritoneal metastasis. Patients with multiple-site metastases had significantly more mutated spots than patients with single-site metastasis. Due to the high sensitivity and specificity of some genes in the prediction of mutation in tumor samples, monitoring the mutation pattern of cfDNA may be useful in the stage IV GC treatment.
Collapse
Affiliation(s)
- Ching-Yun Kung
- Department of Surgery, Division of General Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wen-Liang Fang
- Department of Surgery, Division of General Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Ping Hung
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,Department of Oncology, Center of Immuno-Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Kuo-Hung Huang
- Department of Surgery, Division of General Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Huang Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,Department of Oncology, Center of Immuno-Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yee Chao
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,Department of Oncology, Center of Immuno-Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shih-Chieh Lin
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Anna Fen-Yau Li
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,Department of Anatomical Pathology, Cheng Hsin General Hospital, Taipei, Taiwan
| | - Su-Shun Lo
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan,National Yang Ming Chiao Tung University Hospital, Yilan, Taiwan
| | - Chew-Wun Wu
- Department of Surgery, Division of General Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| |
Collapse
|
|
16
|
Ma S, Zhou M, Xu Y, Gu X, Zou M, Abudushalamu G, Yao Y, Fan X, Wu G. Clinical application and detection techniques of liquid biopsy in gastric cancer. Mol Cancer 2023; 22:7. [PMID: 36627698 PMCID: PMC9832643 DOI: 10.1186/s12943-023-01715-z] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 01/02/2023] [Indexed: 01/12/2023] Open
Abstract
Gastric cancer (GC) is one of the most common tumors worldwide and the leading cause of tumor-related mortality. Endoscopy and serological tumor marker testing are currently the main methods of GC screening, and treatment relies on surgical resection or chemotherapy. However, traditional examination and treatment methods are more harmful to patients and less sensitive and accurate. A minimally invasive method to respond to GC early screening, prognosis monitoring, treatment efficacy, and drug resistance situations is urgently needed. As a result, liquid biopsy techniques have received much attention in the clinical application of GC. The non-invasive liquid biopsy technique requires fewer samples, is reproducible, and can guide individualized patient treatment by monitoring patients' molecular-level changes in real-time. In this review, we introduced the clinical applications of circulating tumor cells, circulating free DNA, circulating tumor DNA, non-coding RNAs, exosomes, and proteins, which are the primary markers in liquid biopsy technology in GC. We also discuss the current limitations and future trends of liquid biopsy technology as applied to early clinical biopsy technology.
Collapse
Affiliation(s)
- Shuo Ma
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Meiling Zhou
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Yanhua Xu
- grid.452743.30000 0004 1788 4869Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, 225000 Jiangsu China
| | - Xinliang Gu
- grid.440642.00000 0004 0644 5481Department of Laboratory Medicine, Medical School, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001 Jiangsu China
| | - Mingyuan Zou
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Gulinaizhaer Abudushalamu
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Yuming Yao
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Xiaobo Fan
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Guoqiu Wu
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University, Nanjing, 210009 Jiangsu China
| |
Collapse
|
|
17
|
Chen MC, Su HY, Su YH, Huang KH, Fang WL, Lin CW, Chen MH, Chao Y, Lo SS, Fen-Yau Li A, Wu CW. The clinicopathological and genetic differences among gastric cancer patients with no recurrence, early recurrence, and late recurrence after curative surgery. J Chin Med Assoc 2023; 86:57-64. [PMID: 36374529 DOI: 10.1097/jcma.0000000000000846] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND To date, few reports have investigated the genetic alterations and clinicopathological features among gastric cancer (GC) patients with no tumor recurrence, early recurrence, and late recurrence following curative surgery. METHODS A total of 473 GC patients undergoing curative surgery were included. The clinicopathological characteristics, patient prognosis, recurrence patterns, and genetic alterations were compared between GC patients with early recurrence and late recurrence. RESULTS Among the 473 GC patients, 119 had early recurrence (<2 years) and 45 had late recurrence (≥2 years). Patients with early recurrence had tumor size larger than 5 cm, fewer superficial-type tumors, more lymphovascular invasion, more advanced pathological T and N categories and Tumor, Node, Metastasis (TNM) stages, and worse 5-year overall survival than patients with late recurrence and no recurrence. For intestinal-type GC, patients with no tumor recurrence had more Helicobacter pylori infection than patients with early recurrence and late recurrence; for diffuse-type GC patients, the frequency of PIK3CA amplification was the highest in early recurrence, followed by late recurrence and no recurrence. GC patients with single-site recurrence had more ARID1A mutations than those with multiple-site recurrence. Multivariate analysis demonstrated that age, tumor recurrence, and pathological N categories were independent prognostic factors. CONCLUSION PIK3CA amplifications were more common in diffuse-type GC with early recurrence, whereas ARID1A mutations were more common in patients with single-site recurrence. Targeted therapy and immunotherapy might be helpful for these patients.
Collapse
Affiliation(s)
- Meng-Chao Chen
- Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan, ROC
- Department of Neurosurgery, China Medical University Hospital, Taipei Branch, Taipei, Taiwan, ROC
| | - Hsuan-Yu Su
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yen-Hao Su
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
- Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, ROC
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan, ROC
| | - Kuo-Hung Huang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Gastric Cancer Medical Center, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Wen-Liang Fang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Gastric Cancer Medical Center, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chii-Wann Lin
- Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan, ROC
| | - Ming-Huang Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yee Chao
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Su-Shun Lo
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Surgery, National Yang Ming Chiao Tung University Hospital, Yilan, Taiwan, ROC
| | - Anna Fen-Yau Li
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chew-Wun Wu
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| |
Collapse
|
|
18
|
Haque E, Esmail A, Muhsen I, Salah H, Abdelrahim M. Recent Trends and Advancements in the Diagnosis and Management of Gastric Cancer. Cancers (Basel) 2022; 14:5615. [PMID: 36428707 PMCID: PMC9688354 DOI: 10.3390/cancers14225615] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/10/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer is an enigmatic malignancy that has recently been shown to be increasing in incidence globally. There has been recent progress in emerging technologies for the diagnosis and treatment of the disease. Improvements in non-invasive diagnostic techniques with serological tests and biomarkers have led to decreased use of invasive procedures such as endoscopy. A multidisciplinary approach is used to treat gastric cancer, with recent significant advancements in systemic therapies used in combination with cytotoxic chemotherapies. New therapeutic targets have been identified and clinical trials are taking place to assess their efficacy and safety. In this review, we provide an overview of the current and emerging treatment strategies and diagnostic techniques for gastric cancer.
Collapse
Affiliation(s)
- Emaan Haque
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Abdullah Esmail
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
| | - Ibrahim Muhsen
- Section of Hematology and Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Haneen Salah
- Department of Pathology, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA
- Cockrell Center for Advanced Therapeutic Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA
| |
Collapse
|
|
19
|
Bacterial Involvement in Progression and Metastasis of Adenocarcinoma of the Stomach. Cancers (Basel) 2022; 14:cancers14194886. [PMID: 36230809 PMCID: PMC9562638 DOI: 10.3390/cancers14194886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/26/2022] [Accepted: 10/03/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Infectious bacteria influence primary gastric carcinogenesis, organotropism, and metastatic progression by altering the microenvironment at the primary and secondary tumors. Key species include Helicobacter pylori (H. pylori) and Mycoplasma hyorhinis (M. hyorhinis). Inflammation caused by H. pylori virulence factors, such as CagA, VacA, and oipA, disrupt epithelial integrity, which allows the primary tumor to progress through the metastatic process. Evidence supports the activation of aquaporin-5 by CagA-positive H. pylori infection, promoting epithelial–mesenchymal transition via the extracellular signal-regulated kinase/mitogen-activated protein kinase (MEK/ERK) pathway, thus laying the foundation for metastatic disease. M. hyorhinis has also been implicated in gastric neoplasia via β-catenin stabilization and subsequent activation of the WNT-signaling pathway, promoting gastric cancer cell motility and inciting cancer progression. Abstract Gastric cancer metastasis is a process in which the tumor microenvironment may carry significant influence. Helicobacter pylori (H. pylori) infection is well-established as a contributor to gastric carcinoma. However, the role that these bacteria and others may play in gastric carcinoma metastasis is a current focus of study. A review of the literature was conducted to elucidate the process by which gastric adenocarcinoma metastasizes, including its ability to utilize both the lymphatic system and the venous system to disseminate. Studies that investigate the tumor microenvironment at both the primary and secondary sites were assessed in detail. H. pylori and Mycoplasma hyorhinis (M. hyorhinis) were found to be important drivers of the pathogenesis of gastric adenocarcinoma by modifying various steps in cell metastasis, including epithelial–mesenchymal transition, cell migration, and cell invasion. H. pylori is also a known driver of MALT lymphoma, which is often reversible simply with the eradication of infection. M. hyorhinis has been implicated in gastric neoplasia via β-catenin stabilization and subsequent activation of the WNT-signaling pathway, promoting gastric cancer cell motility and inciting cancer progression. Fusobacterium nucleatum (F. nucleatum) and its association with worse prognosis in diffuse-type gastric adenocarcinoma are also reviewed. Recognition of the roles that bacteria play within the metastatic cascade is vital in gastrointestinal adenocarcinoma treatment and potential reoccurrence. Further investigation is needed to establish potential treatment for metastatic gastric carcinoma by targeting the tumor microenvironment.
Collapse
|
|
20
|
Pan X, Xu C, Cheng G, Chen Z, Liu M, Mei Y. High-Performance Circulating Tumor DNA Liquid Biopsy Based on Graphitic Carbon Nitride Nanosheet for Monitoring Gastric Cancer-Related Gene Mutations. J Biomed Nanotechnol 2022. [DOI: 10.1166/jbn.2022.3417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Early diagnosis and timely monitoring of cancer progression are the most effective ways to improve the cure rate of cancer patients. And it is essential to create convenient, sensitive, accurate, as well as noninvasive or minimally invasive tests for better respecting patients’
wishes and optimizing diagnosis. The fluorescent biosensor discovered in our study on the basis of graphitic carbon nitride nanosheet (CNNS) could be used to detect the gastric cancer-associated circulating tumor DNA (ctDNA) in human blood by highly specific binding to fluorescein-labeled
single-stranded DNA detection probes. The ssDNA detection probe was adsorbed on the surface of CNNS through weak Π–Π stacking, thereby obtaining efficient fluorescence quenching. With the presence of the target DNA, the ssDNA probe showed weak affinity for CNNS and restored
fluorescence by base complementary pairing with target ssDNA through strong hydrogen bonds. The results show that the nanometer detection is a convenient, low-cost and high-efficiency technology, which is promising in biological detection and analysis.
Collapse
Affiliation(s)
- Xiaoming Pan
- Department of Gastrointestinal Surgery, Lishui People’s Hospital, Lishui, Zhejiang, 323000, China
| | - Chaobo Xu
- Department of Gastrointestinal Surgery, Lishui People’s Hospital, Lishui, Zhejiang, 323000, China
| | - Guoxiong Cheng
- Department of Gastrointestinal Surgery, Lishui People’s Hospital, Lishui, Zhejiang, 323000, China
| | - Zhengwei Chen
- Department of Gastrointestinal Surgery, Lishui People’s Hospital, Lishui, Zhejiang, 323000, China
| | - Ming Liu
- Department of Gastrointestinal Surgery, Lishui People’s Hospital, Lishui, Zhejiang, 323000, China
| | - Yijun Mei
- Department of Gastrointestinal Surgery, Lishui People’s Hospital, Lishui, Zhejiang, 323000, China
| |
Collapse
|
|
21
|
Boisteau E, François E, Aparicio T, Le Malicot K, Boulahssass R, Lecomte T, Laurent-Puig P, Guiu B, Paillaud E, Galais MP, Lopez-Trabada Ataz D, Tougeron D, Dourthe LM, Guimbaud R, Samalin E, Moreau M, Louvet C, Lepage C, Lièvre A. SOCRATE-PRODIGE 55 trial: A randomized phase II study to evaluate second-line ramucirumab alone or with paclitaxel in older patients with advanced gastric cancer. Dig Liver Dis 2022; 54:747-754. [PMID: 35351371 DOI: 10.1016/j.dld.2022.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Patients ≥ 70 years old constitute 40% of patients with advanced gastric cancer (GC). Ramucirumab plus Paclitaxel is a therapeutic option validated in the second-line treatment of advanced GC, but as older patients are at higher risk of severe toxicity, due to comorbidities and/or frailty, we aimed to evaluate second-line Ramucirumab alone or combined with Paclitaxel in terms of overall survival (OS) and quality of life (QoL) in patients ≥ 70 years-old with advanced GC. METHODS In this multicenter, randomized, open-label, non-comparative, prospective phase II clinical trial, the main inclusion criteria are: patients ≥ 70 years old, with advanced GC having progressed after first-line chemotherapy or in the six months following the last administration of adjuvant chemotherapy, with WHO performance status <2. They are randomized to receive either ramucirumab alone (arm A) or ramucirumab plus Paclitaxel (arm B). The primary endpoint is 6-month OS and QoL evaluated with the EORTC QLQ-ELD14 questionnaire. The secondary endpoints include other parameters of QoL, time to definitive deterioration (TTDD) in QoL and TTDD in autonomy, treatment toxicities, other parameters of survival and disease control, identification of geriatric and nutritional prognostic scores and predictive factors of treatment safety and efficacy. OS of 60% is expected at 6 months (H0:40%). Using a Simon-minimax design, with one-sided α risk of 2% and 80% power for OS, and considering 5% lost to follow-up, it is necessary to randomize 56 patients in each arm. PERSPECTIVES As older patients are at higher risk of chemotherapy toxicity, ramucirumab alone could be an interesting alternative to Paclitaxel plus ramucirumab, as a second-line therapy for patients ≥ 70 years old with advanced GC, and needs to be evaluated.
Collapse
Affiliation(s)
- Emeric Boisteau
- Service des Maladies de l'Appareil Digestif, INSERM U1242, CHU de Rennes, CHU Pontchaillou, Université de Rennes 1, Rennes Cedex9 35033, France
| | - Eric François
- Service d'Oncologie, Center Antoine Lacassagne, Nice, France
| | - Thomas Aparicio
- Service de Gastroentérologie, Hôpital Saint Louis, APHP, Université de Paris, Paris, France
| | - Karine Le Malicot
- FFCD EPICAD INSERM LNC-UMR 1231, Université de Bourgogne Franche-Comté Dijon, France
| | | | - Thierry Lecomte
- Service d'Hépato-Gastroentérologie, CHU de Tours, Tours, France; INSERM UMR 1069, "Nutrition, Croissance et Cancer", Université de Tours, France
| | - Pierre Laurent-Puig
- INSERM U 775 - Faculté des Sciences Fondamentales et Biomédicales, Center Universitaire des Saints-Pères, Université des Saints Pères, Paris Descartes, Paris, France
| | - Boris Guiu
- Département de Radiologie, CHU St-Eloi, Montpellier, France
| | - Elena Paillaud
- Hôpital Européen Georges Pompidou, Service de Gériatrie, APHP, Paris Cancer Institute CARPEM, Paris 75015, France
| | | | | | - David Tougeron
- Service d'Hépato-gastroentérologie, CHU de Poitiers, La Milétrie, et l'Université de Poitiers, Poitiers, France
| | | | - Rosine Guimbaud
- Département d'Oncologie Médicale, Pôle Digestif, CHU Toulouse, Toulouse, France
| | - Emmanuelle Samalin
- Département d'Oncologie Médicale, Institut du Cancer de Montpellier, Université de Montpellier, Montpellier, France
| | - Marie Moreau
- Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France
| | - Christophe Louvet
- Service d'Oncologie Médicale, Institut Mutualiste Montsouris, Paris, France
| | - Côme Lepage
- Service d'Hépato-gastroentérologie, CHU de Dijon, Dijon, France
| | - Astrid Lièvre
- Service des Maladies de l'Appareil Digestif, INSERM U1242, CHU de Rennes, CHU Pontchaillou, Université de Rennes 1, Rennes Cedex9 35033, France.
| |
Collapse
|
|
22
|
Zhang C, Xie M, Zhang Y, Zhang X, Feng C, Wu Z, Feng Y, Yang Y, Xu H, Ma T. Determination of Survival of Gastric Cancer Patients With Distant Lymph Node Metastasis Using Prealbumin Level and Prothrombin Time: Contour Plots Based on Random Survival Forest Algorithm on High-Dimensionality Clinical and Laboratory Datasets. J Gastric Cancer 2022; 22:120-134. [PMID: 35534449 PMCID: PMC9091455 DOI: 10.5230/jgc.2022.22.e12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/17/2022] [Accepted: 03/17/2022] [Indexed: 11/20/2022] Open
Affiliation(s)
- Cheng Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China
- Anhui Provincial Cancer Institute/Anhui Provincial Office for Cancer Prevention and Control, Hefei, People’s Republic of China
| | - Minmin Xie
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China
| | - Yi Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China
| | - Xiaopeng Zhang
- Department of Noncommunicable Diseases and Health Education, Hefei Center for Disease Prevention and Control, Hefei, People’s Republic of China
| | - Chong Feng
- Department of Noncommunicable Diseases and Health Education, Hefei Center for Disease Prevention and Control, Hefei, People’s Republic of China
| | - Zhijun Wu
- Department of Oncology, Ma’anshan Municipal People’s Hospital, Ma’anshan, People’s Republic of China
| | - Ying Feng
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China
| | - Yahui Yang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China
| | - Hui Xu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China
- Anhui Provincial Cancer Institute/Anhui Provincial Office for Cancer Prevention and Control, Hefei, People’s Republic of China
| | - Tai Ma
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China
| |
Collapse
|
|
23
|
Varkalaite G, Forster M, Franke A, Kupcinskas J, Skieceviciene J. Liquid Biopsy in Gastric Cancer: Analysis of Somatic Cancer Tissue Mutations in Plasma Cell-Free DNA for Predicting Disease State and Patient Survival. Clin Transl Gastroenterol 2021; 12:e00403. [PMID: 34644276 PMCID: PMC8462609 DOI: 10.14309/ctg.0000000000000403] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/05/2021] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Gastric cancer (GC) diagnosis in late stages and high mortality rates are the main issues that require new noninvasive molecular tools. We aimed to assess somatic mutational profiles in GC tissue and plasma cell-free DNA (cfDNA), evaluate their concordance rate, and analyze the role of multilayer molecular profiling to predict disease state and prognosis. METHODS Treatment-naive GC patient group (n = 29) was selected. Whole exome sequencing (WES) of GC tissue was performed, and a unique 38-gene panel for deep targeted sequencing of plasma cfDNA was developed. Oncoproteins were measured by enzyme-linked immunosorbent assay, and other variables such as tumor mutational burden and microsatellite instability were evaluated using WES data. RESULTS The yield of cfDNA was increased 43.6-fold; the integrity of fragments was decreased in GC compared with controls. WES analysis of cancerous tissue and plasma cfDNA (targeted sequencing) mutational profiles revealed 47.8% concordance. The increased quantity of GC tissue-derived alterations detected in cfDNA was associated with worse patients' survival. Analysis of importance of multilayer variables and receiver operating characteristic curve showed that combination of 2 analytes: (i) quantity of tissue matching alterations and (ii) presence of any somatic alteration in plasma cfDNA resulted in area under curve 0.744 when discriminating patients with or without distant metastasis. Furthermore, cfDNA sequence alterations derived from tumor tissue were detected in patients who had even relatively small GC tumors (T1-T2). DISCUSSION Our results indicate that quantitative and qualitative cfDNA mutational profile analysis is a promising tool for evaluating GC disease status or poorer prognosis.
Collapse
Affiliation(s)
- Greta Varkalaite
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania;
| | - Michael Forster
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany;
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany;
| | - Juozas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania;
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania;
| |
Collapse
|
|
24
|
Salati M, Venetis K, Fassan M, Malapelle U, Pagni F, Sajjadi E, Fusco N, Ghidini M. ctDNA analysis in the personalized clinical management of gastroesophageal adenocarcinoma: turning hope into reality. Future Oncol 2021; 17:4607-4618. [PMID: 34406032 DOI: 10.2217/fon-2021-0228] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Gastroesophageal adenocarcinoma (GEA) is a global health issue with a high fatality-to-case ratio and a 5-year overall survival that has only slightly improved. High-throughput molecular profiling has uncovered a profound complexity and heterogeneity in GEA biology, which limits considerably the treatment advances. Liquid biopsy with circulating tumor (ct)DNA analysis could elucidate GEA molecular heterogeneity and provide diagnostic, prognostic and predictive information to guide clinical decision-making. However, only a handful of studies have shown positive results for the application of ctDNA analysis in GEA clinical management. As a result, no comprehensive information is available to date on this continuously evolving topic. Here, we discuss the current state of knowledge, along with promises and challenges related to ctDNA analysis in GEA.
Collapse
Affiliation(s)
- Massimiliano Salati
- Division of Oncology, Oncology and Hematology Department, University of Modena and Reggio Emilia, Modena, Italy.,Ph.D. Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Konstantinos Venetis
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy.,Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan 20141, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Italy
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Fabio Pagni
- Department of Medicine and Surgery, Pathology, University Milan Bicocca, Milan 20126, Italy
| | - Elham Sajjadi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy.,Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan 20141, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology, University of Milan, Milan 20122, Italy.,Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan 20141, Italy
| | - Michele Ghidini
- Division of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
| |
Collapse
|
|
25
|
MSI Analysis in Solid and Liquid Biopsies of Gastroesophageal Adenocarcinoma Patients: A Molecular Approach. Int J Mol Sci 2021; 22:ijms22147244. [PMID: 34298864 PMCID: PMC8303574 DOI: 10.3390/ijms22147244] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/22/2021] [Accepted: 06/30/2021] [Indexed: 12/24/2022] Open
Abstract
Gastroesophageal adenocarcinoma (GEA) patients with the microsatellite instability (MSI) subtype emerged as optimal candidates for immunotherapy. To date, immunohistochemistry (IHC) is the gold standard for MSI assessment in formalin-fixed paraffin-embedded (FFPE) specimens. However, IHC, although useful for diagnostic typing, cannot be used to analyze cell-free DNA (cfDNA) in liquid biopsy, a tool that could overcome tumor heterogeneity and enable longitudinal monitoring. In order to find an alternative diagnostic method to IHC, we analyzed 86 retrospective GEAs FFPE samples with multiplex PCR. Moreover, to verify the feasibility of MSI detection in liquid biopsy, cfDNA samples of five patients that resulted in having MSI in a prospective cohort of 35 patients were evaluated by multiplex PCR, real-time PCR and droplet digital PCR (ddPCR). Analysis of FFPE showed 100% concordance between multiplex PCR and IHC (Cohen’s Kappa agreement = 1). On the contrary, only ddPCR was able to detect MSI in cfDNAs of T3/T4 GEA patients. In conclusion, data highlight the molecular analysis as an optimal alternative to IHC for the diagnostic typing and suggest that the ddPCR assay can be considered as the most reliable and promising molecular approach to detect MSI in the cfDNA of GEA patients.
Collapse
|
|
26
|
Pai SM, Huang KH, Chen MH, Fang WL, Chao Y, Lo SS, Li AFY, Wu CW, Shyr YM. Cardia Gastric Cancer Is Associated With Increased PIK3CA Amplifications and HER2 Expression Than Noncardia Gastric Cancer According to Lauren Classification. Front Oncol 2021; 11:632609. [PMID: 34168977 PMCID: PMC8217656 DOI: 10.3389/fonc.2021.632609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 05/17/2021] [Indexed: 12/02/2022] Open
Abstract
Background To date, few reports have investigated genetic alterations and clinicopathological features in cardia and noncardia gastric cancer (GC). Methods In total, 435 GC patients receiving curative surgery were included. The clinicopathological features, recurrence patterns, prognoses and genetic alterations were compared between cardia and noncardia GC patients. Results Among the 435 enrolled patients, 47 (10.8%) had cardia GC. Compared with noncardia GC, cardia GC was associated with more intestinal-type tumors and similar initial recurrence patterns and 5-year overall survival (OS; 50.8% vs. 50.5%, P = 0.480) and disease-free survival (DFS; 48.6% vs. 48.9%, P = 0.392) rates. For both intestinal-type GC and diffuse-type GC, the clinicopathological features and 5-year OS and DFS rates were not significantly different between the cardia and noncardia GC patients. Multivariable analysis showed that cardia GC was not an independent prognostic factor. Compared with noncardia GC, cardia GC was associated with increased PIK3CA amplification than in patients with intestinal-type GC and was associated with increased HER2 expression in patients with diffuse-type GC. Conclusions Cardia GC is not an independent prognostic factor. In cardia GC patients with intestinal-type GC, PIK3CA amplification was more common, and in those with diffuse-type GC, HER2 expression was more common. Targeted therapy may be beneficial for these patient subgroups.
Collapse
Affiliation(s)
- Shih-Min Pai
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Kuo-Hung Huang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Huang Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wen-Liang Fang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yee Chao
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Su-Shun Lo
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Surgery, National Yang Ming Chiao Tung University Hospital, Yilan, Taiwan
| | - Anna Fen-Yau Li
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chew-Wun Wu
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-Ming Shyr
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| |
Collapse
|
|
27
|
Circulating Cell-Free DNA as a Prognostic Biomarker in Resectable Ampullary Cancer. Cancers (Basel) 2021; 13:cancers13102313. [PMID: 34065893 PMCID: PMC8151754 DOI: 10.3390/cancers13102313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/09/2021] [Accepted: 05/10/2021] [Indexed: 01/05/2023] Open
Abstract
Simple Summary Circulating cell-free DNA (cfDNA) in patients with ampullary cancer was measured to clarify the correlation between cfDNA and clinicopathological factors and the impact of cfDNA on survival outcomes. The level of cfDNA was significantly higher in patients with lymph node involvement, lymphovascular invasion, abnormal serum carcinoembryonic antigen level, and stage II and III cancer. The 1- and 5-year survival rates were 92.0% and 66.5%, respectively, for patients with low cfDNA levels ≤ 6687 copies/mL as compared with 84.0% and 49.9%, respectively, for patients with high cfDNA levels > 6687 copies/mL (p < 0.001). After multivariate analysis, only the cfDNA level and cancer stage were independent factors in determining the prognosis of the ampullary cancer. The cfDNA level could act as a surrogate marker of both disease extent and biological aggressiveness of ampullary cancer. Moreover, cfDNA plays a significant role in determining the prognosis of resectable ampullary cancer. Abstract Circulating cell-free DNA (cfDNA) in ampullary cancer patients was measured to clarify the correlation between cfDNA and clinicopathological factors and the impact of cfDNA on survival outcomes. Patients with ampullary cancer undergoing pancreaticoduodenectomy were included. Correlations between cfDNA and clinicopathological and prognostic factors were determined. The cfDNA levels in patients ranged from 1282 to 21,674 copies/mL, with a median of 6687 copies/mL. The cfDNA level was significantly higher in patients with lymph node involvement, lymphovascular invasion, abnormal serum carcinoembryonic antigen (CEA) level, and stage II and III cancer. Poor prognostic factors for ampullary cancer included high cfDNA > 6687 copies/mL, lymph node involvement, abnormal serum CEA > 5 ng/mL, and advanced stage II and III cancer. The 1- and 5-year survival rates were 92.0% and 66.5%, respectively, for patients with low cfDNA < 6687 copies/mL and 84.0% and 49.9%, respectively, for patients with high cfDNA > 6687 copies/mL (p < 0.001). After multivariate analysis, only the cfDNA level and stage were independent prognostic factors of ampullary cancer. Thus, the cfDNA level could act as a surrogate marker of both disease extent and biological aggressiveness of ampullary cancer. Moreover, cfDNA plays a significant role in the prognosis of resectable ampullary cancer.
Collapse
|
|
28
|
Sun J, Wang X, Zhang Z, Zeng Z, Ouyang S, Kang W. The Sensitivity Prediction of Neoadjuvant Chemotherapy for Gastric Cancer. Front Oncol 2021; 11:641304. [PMID: 33937042 PMCID: PMC8085495 DOI: 10.3389/fonc.2021.641304] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/22/2021] [Indexed: 12/24/2022] Open
Abstract
The overall efficacy of neoadjuvant chemoradiotherapy (NACT) for locally advanced gastric cancer (LAGC) has been recognized. However, the response rate of NACT is limited due to tumor heterogeneity. For patients who are resistant to NACT, not only the operation timing will be postponed, patients will also suffer from the side effects of it. Thus, it is important to develop a comprehensive strategy and screen out patients who may be sensitive to NACT. This article summarizes the related research progress on the sensitivity prediction of NACT for GC in the following aspects: microRNAs, metabolic enzymes, exosomes, other biomarkers; inflammatory indicators, and imageological assessments. The results showed that there were many studies on biomarkers, but no unified conclusion has been drawn. The inflammatory indicators are related to the survival and prognosis of patients under NACT. For imageological assessments such as CT, MRI, and PET, with careful integration and optimization, they will have unique advantages in early screening for patients who are sensitive to NACT.
Collapse
Affiliation(s)
- Juan Sun
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Xianze Wang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Zimu Zhang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Ziyang Zeng
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Siwen Ouyang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Peking Union Medical College Hospital (CAMS), Beijing, China
| | - Weiming Kang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of General Surgery, Peking Union Medical College Hospital (CAMS), Beijing, China
| |
Collapse
|
|
29
|
Jonaitis P, Kiudelis V, Streleckiene G, Gedgaudas R, Skieceviciene J, Kupcinskas J. Novel Biomarkers in the Diagnosis of Benign and Malignant Gastrointestinal Diseases. Dig Dis 2021; 40:1-13. [PMID: 33647906 DOI: 10.1159/000515522] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/26/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Various noninvasive biomarkers have been used in the diagnosis, prognosis, and treatment of different gastrointestinal (GI) diseases for years. Novel technological developments and profound perception of molecular processes related to GI diseases over the last decade have allowed researchers to evaluate genetic, epigenetic, and many other potential molecular biomarkers in different diseases and clinical settings. Here, we present a review of recent and most relevant articles in order to summarize major findings on novel biomarkers in the diagnosis of benign and malignant GI diseases. SUMMARY Genetic variations, noncoding RNAs (ncRNAs), cell-free DNA (cfDNA), and microbiome-based biomarkers have been extensively analyzed as potential biomarkers in benign and malignant GI diseases. Multiple single-nucleotide polymorphisms have been linked with a number of GI diseases, and these observations are further being used to build up disease-specific genetic risk scores. Micro-RNAs and long ncRNAs have a large potential as noninvasive biomarkers in the management of inflammatory bowel diseases and GI tumors. Altered microbiome profiles were observed in multiple GI diseases, but most of the findings still lack translational clinical application. As of today, cfDNA appears to be the most potent biomarker for early detection and screening of GI cancers. Key Messages: Novel noninvasive molecular biomarkers show huge potential as useful tools in the diagnostics and management of different GI diseases. However, the use of these biomarkers in real-life clinical practice still remains limited, and further large studies are needed to elucidate the ultimate role of these potential noninvasive clinical tools.
Collapse
Affiliation(s)
- Paulius Jonaitis
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Vytautas Kiudelis
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Greta Streleckiene
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Rolandas Gedgaudas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Jurgita Skieceviciene
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Juozas Kupcinskas
- Department of Gastroenterology and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| |
Collapse
|
|
30
|
Wallander K, Eisfeldt J, Lindblad M, Nilsson D, Billiau K, Foroughi H, Nordenskjöld M, Liedén A, Tham E. Cell-free tumour DNA analysis detects copy number alterations in gastro-oesophageal cancer patients. PLoS One 2021; 16:e0245488. [PMID: 33539436 PMCID: PMC7861431 DOI: 10.1371/journal.pone.0245488] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 12/30/2020] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Analysis of cell-free tumour DNA, a liquid biopsy, is a promising biomarker for cancer. We have performed a proof-of principle study to test the applicability in the clinical setting, analysing copy number alterations (CNAs) in plasma and tumour tissue from 44 patients with gastro-oesophageal cancer. METHODS DNA was isolated from blood plasma and a tissue sample from each patient. Array-CGH was applied to the tissue DNA. The cell-free plasma DNA was sequenced by low-coverage whole-genome sequencing using a clinical pipeline for non-invasive prenatal testing. WISECONDOR and ichorCNA, two bioinformatic tools, were used to process the output data and were compared to each other. RESULTS Cancer-associated CNAs could be seen in 59% (26/44) of the tissue biopsies. In the plasma samples, a targeted approach analysing 61 regions of special interest in gastro-oesophageal cancer detected cancer-associated CNAs with a z-score >5 in 11 patients. Broadening the analysis to a whole-genome view, 17/44 patients (39%) had cancer-associated CNAs using WISECONDOR and 13 (30%) using ichorCNA. Of the 26 patients with tissue-verified cancer-associated CNAs, 14 (54%) had corresponding CNAs in plasma. Potentially clinically actionable amplifications overlapping the genes VEGFA, EGFR and FGFR2 were detected in the plasma from three patients. CONCLUSIONS We conclude that low-coverage whole-genome sequencing without prior knowledge of the tumour alterations could become a useful tool for cell-free tumour DNA analysis of total CNAs in plasma from patients with gastro-oesophageal cancer.
Collapse
Affiliation(s)
- Karin Wallander
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Jesper Eisfeldt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Mats Lindblad
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Daniel Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Kenny Billiau
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Hassan Foroughi
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Nordenskjöld
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Agne Liedén
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Emma Tham
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
31
|
Chen W, Yan H, Li X, Ge K, Wu J. Circulating tumor DNA detection and its application status in gastric cancer: a narrative review. Transl Cancer Res 2021; 10:529-536. [PMID: 35116282 PMCID: PMC8797971 DOI: 10.21037/tcr-20-2856] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/20/2020] [Indexed: 12/30/2022]
Abstract
Circulating tumor DNA (ctDNA) is the small genomic fragment released by tumor cells into the circulating system, which carries the gene variation features, such as mutation, insertion, deletion, rearrangement, copy number variation (CNV) and methylation, rendering it an important biomarker. It can be used not only to diagnose certain types of solid tumors, but also to monitor the therapeutic response and explore the minimal residual disease (MRD) and resistant mutation of targeted therapy. Therefore, ctDNA detection may become the preferred non-invasive tumor screening method. For patients who cannot receive further gene detection due to insufficient or restricted sample collection with the defined pathological diagnosis, ctDNA detection can be carried out to determine the gene mutation type, with no need for repeated sampling. Gastric cancer (GC) is a malignancy with extremely high morbidity and mortality, and its genesis and development are the consequence of interactions of multiple factors, including environment, diet, heredity, helicobacter pylori infection, chronic inflammatory infiltration, and precancerous lesion. As the research on GC moves forward, the existing research mainly focuses on genetic and epigenetic changes, including DNA methylation, histone modification, non-coding RNA changes, gene mutation, gene heterozygosity loss and microsatellite instability. This paper aimed to summarize the contents of ctDNA detection, its application status in GC and clinical significance.
Collapse
Affiliation(s)
- Wenyu Chen
- Department of Oncology, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Haijiao Yan
- Department of Oncology, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiaodong Li
- Department of Oncology, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Kele Ge
- Department of Oncology, Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jun Wu
- Department of Oncology, Third Affiliated Hospital of Soochow University, Changzhou, China
| |
Collapse
|
|
32
|
Hsu LW, Huang KH, Chen MH, Fang WL, Chao Y, Lo SS, Li AFY, Wu CW, Shyr YM. Genetic alterations in gastric cancer patients according to sex. Aging (Albany NY) 2020; 13:376-388. [PMID: 33288737 PMCID: PMC7835020 DOI: 10.18632/aging.202142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 10/09/2020] [Indexed: 02/06/2023]
Abstract
To date, few reports have investigated the genetic alterations and clinicopathological features in gastric cancer (GC) according to sex. In total, 2673 GC patients receiving curative surgery were enrolled. Among the 2673 GC patients, 1979 (74.0%) patients were male. After propensity-score matching, 846 patients were enrolled for the analysis, including 423 males and 423 females. There was no significant difference in the clinicopathological features between the sexes. Regarding the initial recurrence pattern, the males were more likely to develop tumor recurrence and liver metastasis than the females, especially in stage III GC. Regarding the molecular analysis, the males had higher PD-L1 expression than the females, especially in stage III GC. In addition, the patients aged ≥ 65 years had higher PD-L1 expression than the patients younger than 65 years. The multivariate analysis demonstrated that sex was among the independent prognostic factors affecting overall survival (OS) and disease-free survival (DFS). Among the patients with liver metastases, PD-L1 expression was more common among the aged male patients. The males were associated with more tumor recurrence and higher PD-L1 expression than the females, especially in stage III GC. For GC patients with liver metastases, PD-L1 testing is recommended, especially among aged male patients.
Collapse
Affiliation(s)
- Li-Wen Hsu
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Kuo-Hung Huang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Huang Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wen-Liang Fang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yee Chao
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Su-Shun Lo
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,National Yang-Ming University Hospital, Yilan, Taiwan
| | - Anna Fen-Yau Li
- School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chew-Wun Wu
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yi-Ming Shyr
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| |
Collapse
|
|
33
|
Zhang C, Chen Z, Chong X, Chen Y, Wang Z, Yu R, Sun T, Chen X, Shao Y, Zhang X, Gao J, Shen L. Clinical implications of plasma ctDNA features and dynamics in gastric cancer treated with HER2-targeted therapies. Clin Transl Med 2020; 10:e254. [PMID: 33377634 PMCID: PMC7737756 DOI: 10.1002/ctm2.254] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/25/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is confronted with limited options for precision medicine. Human epidermal growth factor receptor 2 (HER2) is the principal druggable target of GC, yet proper biomarkers for response/resistance prediction remain unveiled. METHODS From 40 GC patients received HER2-targeted therapy, a total of 327 peripheral blood plasma specimens was collected including baseline and treatment time points. Circulating tumor DNA (ctDNA) was extracted and sequenced with a target panel of 425 genes. Experimental validation of resistant mutations was carried out in NIH-3T3 cell line. RESULTS Genomic features, including ERBB2 copy number variation (CNV), total copy number load, and tumor mutation burdens (TMBs), dynamically changed along with the treatment process and correlated with disease progression. Plasma ctDNA-based diagnosis was more sensitive than conventional computed tomography scanning in 40% of investigated patients, gaining additional time for clinical management. Compared to baseline, new gene alterations were emerged in 12 patients who developed drug resistance during treatment. ERBB2 mutations potentially related to Pyrotinib resistance were identified in plasma ctDNA of one patient and functional analysis of their downstream signaling pathways was carried out in NIH-3T3 cell line. TMB exhibited more power than ERBB2 CNV in predicting treatment responses and prognosis for HER2-targeted therapy in GC patients. Interestingly, survival analysis indicated that patients harboring both HER2 (ERBB2) positivity and high TMB might gain more therapeutic benefits from immune checkpoint inhibitors instead of HER2-targeted regimens that required further studies and validations CONCLUSIONS: Our work showed that the dynamic surveillance of plasma ctDNA genomic features provided instructive information for the precision medication of GC patients.
Collapse
Affiliation(s)
- Cheng Zhang
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Zuhua Chen
- Department of OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoyi Chong
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Yang Chen
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Zhenghang Wang
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Ruoying Yu
- Translational Medicine Research InstituteGeneseeq Technology IncTorontoOntarioCanada
| | | | - Xiaoxi Chen
- Translational Medicine Research InstituteGeneseeq Technology IncTorontoOntarioCanada
| | - Yang Shao
- Nanjing Geneseeq Technology IncNanjingChina
| | - Xiaotian Zhang
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Jing Gao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenChina
| | - Lin Shen
- Department of Gastrointestinal OncologyKey laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| |
Collapse
|
|
34
|
The clinicopathological characteristics and genetic alterations of gastric cancer patients according to the Lauren classification. Int Surg 2020. [DOI: 10.9738/intsurg-d-20-00022.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
ObjectiveThe Lauren classification is an important histological classification of gastric cancer (GC) with different biological behaviors between histological types.BackgroundTo date, there are few reports on the genetic alterations and survival differences between different histological types according to the Lauren classification.MethodsIn total, 433 GC patients undergoing surgery were enrolled. The clinicopathological features, prognoses, and genetic alterations of the different Lauren types were compared.ResultsDiffuse-type GC was associated with a younger age, female predominance, more Borrmann type 3 and 4 tumors, more advanced pathological tumor (T) and node (N) categories, more tumor recurrences (especially peritoneal recurrence), and worse 5-year overall survival and disease-free survival rates than intestinal-type GC and mixed-type GC. Regarding genetic alterations, mixed-type GC was associated with more TP53 mutations than intestinal-type GC and diffuse-type GC. Multivariate analysis demonstrated the following independent prognostic factors: age, Lauren classification, and pathological T and N categories. Regarding mixed-type GC, diffuse-type major tumors were associated with more lymphovascular invasion, a more advanced N category and TNM stage, and fewer PI3K/AKT pathway mutations than intestinal-type major tumors.ConclusionsDiffuse-type GC had unfavorable clinicopathological features and a worse prognosis than intestinal-type GC. For mixed-type GC, the clinicopathological features and genetic alterations were different between intestinal-type major tumors and diffuse-type major tumors.
Collapse
|
|
35
|
Sasaki N, Iwaya T, Chiba T, Fujita M, Ju Z, Endo F, Yaegashi M, Hachiya T, Sugimoto R, Sugai T, Siwak DR, Liotta LA, Lu Y, Mills GB, Nakagawa H, Nishizuka SS. Analysis of mutational and proteomic heterogeneity of gastric cancer suggests an effective pipeline to monitor post-treatment tumor burden using circulating tumor DNA. PLoS One 2020; 15:e0239966. [PMID: 33027286 PMCID: PMC7540850 DOI: 10.1371/journal.pone.0239966] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 09/16/2020] [Indexed: 12/22/2022] Open
Abstract
Circulating tumor DNA (ctDNA) is released from tumor cells into blood in advanced cancer patients. Although gene mutations in individual tumors can be diverse and heterogenous, ctDNA has the potential to provide comprehensive biomarker information. Here, we performed multi-region sampling (three sites) per resected specimen from 10 gastric cancer patients followed by targeted sequencing and proteomic profiling using reverse-phase protein arrays. A total of 126 non-synonymous mutations were identified from 30 samples from 10 tumors. Of these, 16 (12.7%) were present in all three regions and were designated as founder mutations. Variant allele frequencies (VAFs) of founder mutations were significantly higher than those of non-founder mutations. Phylogenetic analysis also demonstrated a good concordance between founder and truncal mutations, defined as mutations shared by all simulated clones at the trunk of the tumor phylogenetic tree. These findings led us to prioritize founder mutations for quantitative ctDNA monitoring by digital PCR with individually-designed primer/probe sets. In preoperative plasma, the average ctDNA VAF of founder mutations was significantly higher than that of non-founder mutations (p = 0.039). Proteomic heterogeneity was present across the tumor regions both within and between patients independent of mutational status. Our results suggest that, in practice, mutations having high VAF identified without multi-regional sequencing may be immediately useful for quantitative ctDNA monitoring but do not provide sufficient information to predict the proteomic composition of tumors.
Collapse
Affiliation(s)
- Noriyuki Sasaki
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Japan
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Japan
- Division of Biomedical Research and Development, Iwate Medical University Institute of Biomedical Sciences, Yahaba, Japan
| | - Takeshi Iwaya
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Japan
- Molecular Therapeutics Laboratory, Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Takehiro Chiba
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Masashi Fujita
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Science, Yokohama, Japan
| | - Zhenlin Ju
- Department of Bioinformatics and Computational Biology, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Fumitaka Endo
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Mizunori Yaegashi
- Department of Surgery, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Tsuyoshi Hachiya
- Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Yahaba, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Yahaba, Japan
| | - Doris R. Siwak
- Department of Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Lance A. Liotta
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, Virginia, United States of America
| | - Yiling Lu
- Department of Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Gordon B. Mills
- Department of Genomic Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States of America
- Department of Cell, Development & Cancer Biology, Knight Cancer Institute, Oregon Health Science University School of Medicine, Portland, Oregon, United States of America
| | - Hidewaki Nakagawa
- Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Science, Yokohama, Japan
| | - Satoshi S. Nishizuka
- Division of Biomedical Research and Development, Iwate Medical University Institute of Biomedical Sciences, Yahaba, Japan
- * E-mail:
| |
Collapse
|
|
36
|
Wu CW, Chen MH, Huang KH, Chang SC, Fang WL, Lin CH, Chao Y, Lo SS, Li AFY, Shyr YM. The clinicopathological characteristics and genetic alterations between younger and older gastric cancer patients with curative surgery. Aging (Albany NY) 2020; 12:18137-18150. [PMID: 32961530 PMCID: PMC7585087 DOI: 10.18632/aging.103627] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 06/22/2020] [Indexed: 01/24/2023]
Abstract
Few reports have investigated different genetic alterations according to age in various cancers. In total, 1749 GC patients receiving curative surgery were enrolled. The clinicopathological features, and prognoses were compared between younger (<65 years) and older (≥65 years) patients. Genetic mutations were analyzed using mass spectrometric single nucleotide polymorphism genotyping technology, including 68 validated mutations within eight genes (TP53, ARID1A, BRAF, and the PI3K/AKT pathway) previously reported in relation to age. Younger patients were more likely to be female and have poor cell differentiation, diffuse-type tumors, less lymphovascular invasion, fewer liver metastases, and better 5-year overall survival (OS) (68.0% vs. 54.6%, P<0.001) and disease-free survival (DFS) (65.4% vs. 53.0%, P<0.001) rates than older patients. Regarding the genetic alterations, older patients had more microsatellite instability-high (MSI-H) tumors and more ARID1A mutations than younger patients. Younger patients had significantly better OS and DFS rates than older patients for each pathological Tumor, Node, Metastasis (TNM) stage. Older patients had a significantly higher non-cancer related death rate than younger patients (36.2% vs. 12.3%, P<0.001). Age was an independent prognostic factor in GC. In conclusion, age was associated with different clinicopathological features and genetic alterations in GC with curative surgery.
Collapse
Affiliation(s)
- Chew-Wun Wu
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Huang Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Kuo-Hung Huang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shih-Ching Chang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wen-Liang Fang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chien-Hsing Lin
- Genome Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Yee Chao
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Su-Shun Lo
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,National Yang-Ming University Hospital, Yilan, Taiwan
| | - Anna Fen-Yau Li
- School of Medicine, National Yang-Ming University, Taipei, Taiwan,Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Ming Shyr
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan,School of Medicine, National Yang-Ming University, Taipei, Taiwan
| |
Collapse
|
|
37
|
The Clinicopathological Characteristics And Genetic Alterations of Signet-ring Cell Carcinoma in Gastric Cancer. Cancers (Basel) 2020; 12:cancers12082318. [PMID: 32824568 PMCID: PMC7463705 DOI: 10.3390/cancers12082318] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 08/04/2020] [Accepted: 08/12/2020] [Indexed: 02/08/2023] Open
Abstract
Signet-ring cell carcinoma (SRC) in advanced gastric cancer (GC) is often associated with more invasiveness and a worse prognosis than other cell types. The genetic alterations associated with gastric carcinogenesis in SRC are still unclear. In this study, 441 GC patients receiving curative surgery for GC between 2005 and 2013 were enrolled. The clinicopathological characteristics and genetic alterations of GC patients with and without SRC were compared. Among the 441 GC patients, 181 had SRC. For early GC, patients with SRC had more tumors located in the middle and lower stomach, more infiltrating tumors and better overall survival (OS) rates than those without SRC. For advanced GC, patients with SRC had more scirrhous type tumors, more PIK3CA amplifications, fewer microsatellite instability-high (MSI-H) tumors, more peritoneal recurrences and worse 5-year OS rates than those without SRC. For advanced GC with SRC, patients with peritoneal recurrence tended to have PD-L1 expression. For advanced GC without SRC, patients with liver metastasis tended to have PD-L1 expression, PI3K/AKT pathway mutations, TP53 mutations and MSI-H tumors. For advanced GC, PD-L1 expression was associated with peritoneal recurrence in SRC tumors, while non-SRC tumors with liver metastasis were likely to have PI3K/AKT pathway mutations, TP53 mutations and PD-L1 expression; immunotherapy and targeted therapy may be beneficial for these patients.
Collapse
|
|
38
|
Zhang X, Zhan D, Li Y, Wang H, Cheng C, Yao Y, Jia J. Glutathione Peroxidase 8 as a Prognostic Biomarker of Gastric Cancer: An Analysis of The Cancer Genome Atlas (TCGA) Data. Med Sci Monit 2020; 26:e921775. [PMID: 32392186 PMCID: PMC7241213 DOI: 10.12659/msm.921775] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Glutathione peroxidase 8 (GPX8) has previously been shown to play a role in Keshan disease. In the present study, we explored the prognostic relevance of GPX8 expression in patients with gastric cancer (GC) based upon The Cancer Genome Atlas (TCGA) data. Material/Methods We assessed the relationship between the expression of GPX8 and clinicopathological findings in GC patients via logistic regression analyses, Kruskal-Wallis tests, and Wilcoxon signed-rank tests. We further assessed the prognostic relevance of specific variables using Kaplan-Meier and Cox regression analyses. We lastly conducted gene set enrichment analyses (GSEA). Results We detected a significant association between elevated GPX8 levels and more advanced GC tumor stage (OR=5.92 for I vs. IV), as well as more advanced T (OR=22.91 for T1 vs. T4) and N classification (OR=1.82 for N0 vs. N3). We found worse prognosis in patients expressing high levels of GPX8 relative to those with lower expression of this gene (P=0.021). In a univariate analysis, we found high GPX8 expression was strongly correlated with worse OS (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 1.01–1.08; P=0.018), and multivariate analysis confirmed that GPX8 expression independently predicts GC patient OS (HR: 1.04; CI: 1.00–1.08, P=0.041). GSEA revealed that elevated GPX8 expression was associated with enrichment of pathways consistent with MAPK signaling, JAK/STAT signaling, TGF-β signaling, melanoma, and basal cell carcinoma. Conclusions The expression of GPX8 may have prognostic relevance, being positively associated with worse OS in GC patients.
Collapse
Affiliation(s)
- Xinxin Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| | - Dankai Zhan
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| | - Yingying Li
- School of Pharmacy, Bengbu Medical College, Anhui Engineering Technology Research Center of Biochemical Pharmaceuticals, Bengbu, Anhui, China (mainland)
| | - Hui Wang
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| | - Chen Cheng
- Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| | - Yue Yao
- Department of Urology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| | - Jianguang Jia
- Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China (mainland)
| |
Collapse
|
|
39
|
Identification of Somatic Mutations in Thirty-year-old Serum Cell-free DNA From Patients With Breast Cancer: A Feasibility Study. Clin Breast Cancer 2020; 20:413-421.e1. [PMID: 32650988 DOI: 10.1016/j.clbc.2020.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 01/05/2023]
Abstract
INTRODUCTION The aim of this study was to assess the feasibility of cell-free DNA (cfDNA) extraction and circulating tumor DNA sequencing in 30-year-old serum samples. MATERIALS AND METHODS We evaluated serum samples from 52 patients with breast cancer, which were collected between 1983 and 1991, with correlating clinicopathologic data. cfDNA was extracted by using the QIAamp Circulating Nucleic Acid Extraction Kit (Qiagen). Of these 52 cfDNA samples, 10 were randomly selected and sequenced with the Oncomine Breast cfDNA Assay (A31183). In a second step, high-depth targeted sequencing of 15 additional cfDNA samples was performed using a custom Ampliseq Ion Torrent panel targeting breast cancer-related genes. RESULTS cfDNA extraction was successful in 52 (100%) of 52 patients with a total concentration of 0.2 to 54 ng/uL. A total of 24 cancer-specific mutations were found in 22 (88%) of the 25 samples undergoing sequencing. Of the 52 patients, 32 (62%) had died from breast cancer after a median follow-up of 7.9 years (interquartile range, 3.7-15.5 years). CONCLUSION The present study shows that current next generation sequencing technology is sufficiently robust and specific to analyze 30-year-old serum. Therefore, longitudinal studies can be designed with storage of serum samples over many years, thereby obviating the need for timely and continuous cfDNA extraction and sequencing. The samples can be pooled and processed at once with the most modern technology available at the end of the study, when accumulation of events allows correlation of clinical outcomes with adequate power.
Collapse
|
|
40
|
Gastric Cancer with Radiographically Occult Metastatic Disease: Biology, Challenges, and Diagnostic Approaches. Cancers (Basel) 2020; 12:cancers12030592. [PMID: 32150838 PMCID: PMC7139817 DOI: 10.3390/cancers12030592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 02/13/2020] [Accepted: 03/02/2020] [Indexed: 12/20/2022] Open
Abstract
Gastric adenocarcinoma is an aggressive cancer that demonstrates heterogeneous biology depending on patient ethnicity, tumor location, tumor type, and genetic profile. It remains the third leading cause of cancer deaths worldwide and was estimated to result in 782,000 deaths in 2018. Challenges exist in accurately assessing the disease burden, as available radiological staging often underestimates metastatic disease. This diagnostic handicap, along with the poor understanding of the heterogeneous biology of gastric cancer, has hindered the development of effective therapeutic solutions and thus halted improvement in patient outcomes over the last few decades. The management of occult peritoneal disease is complicated, as most patients are understaged by standard imaging studies and therefore thought to have local diseases. In this article, we systematically review recent literature on the limitations that are associated with standard radiographic staging, discuss recent molecular biology advances to better identify and diagnose occult peritoneal disease, and propose possible management strategies to approach this complicated clinical problem.
Collapse
|
|
41
|
Abstract
Gastric cancer is an active topic of clinical and basic research due to high morbidity and mortality. To date, gastrectomy and chemotherapy are the only therapeutic options for gastric cancer patients, but drug resistance, either acquired or primary, is the main cause for treatment failure. Differences in development and response to cancer treatments have been observed among ethnically diverse GC patient populations. In spite of major incidence, GC Asian patients have a significantly better prognosis and response to treatments than Caucasian ones due to genetic discordances between the two populations. Gene therapy could be an alternative strategy to overcome such issues and especially CRISPR/Cas9 represents one of the most intriguing gene-editing system. Thus, in this review article, we want to provide an update on the currently used therapies for the treatment of advanced GC. Graphical abstract.
Collapse
|
|
42
|
Tseng CH, Fang WL, Huang KH, Chen MH, Chao Y, Lo SS, Li AFY, Wu CW, Shyr YM. The clinicopathological characteristics and genetic alterations of mucinous carcinoma of the stomach. J Chin Med Assoc 2020; 83:141-147. [PMID: 32015267 DOI: 10.1097/jcma.0000000000000232] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Mucinous gastric carcinoma (MGC) is rare and often associated with an advanced stage. The clinicopathological features and prognosis of MGC and non-MGC (NMGC) are controversial. METHODS In total, 2637 gastric cancer (GC) patients receiving curative surgery were enrolled. The clinicopathological features and genetic alterations were compared between patients with MGC and NMGC. RESULTS Among the 2637 GC patients, 92 (3.5%) had MGC. After propensity score matching, compared to patients with NMGC, patients with MGC had more poorly differentiated tumors, medullary stromal reaction-type tumors, tumors with infiltrating Ming's classification, diffuse-type tumors, more abnormal preoperative serum carbohydrate antigen 19-9 levels, and more advanced T categories. After propensity score matching, there were no significant differences between MGC and NMGC regarding the initial recurrence patterns, 5-year overall survival (OS), and disease-free survival (DFS) rates. Multivariate analysis demonstrated that the MGC cell type is not an independent prognostic factor of OS and DFS. No significant differences in microsatellite instability status, Epstein-Barr virus infection, Helicobacter pylori infection, or genetic mutations were observed between MGC and NMGC. The expression of programmed death-ligand 1 (PD-L1) was significantly higher in MGC than that in NMGC. MGC was diagnosed at a more advanced stage compared with NMGC. CONCLUSION MGC itself was not an independent prognostic factor of worse survival. MGC was correlated with higher PD-L1 expression than NMGC, which may have a clinical impact on the treatment of MGC in the future.
Collapse
Affiliation(s)
- Chien-Hsun Tseng
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Wen-Liang Fang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Kuo-Hung Huang
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Ming-Huang Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yee Chao
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Su-Shun Lo
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- National Yang-Ming University Hospital, Yilan, Taiwan, ROC
| | - Anna Fen-Yau Li
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chew-Wun Wu
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Yi-Ming Shyr
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| |
Collapse
|
|
43
|
Said R, Guibert N, Oxnard GR, Tsimberidou AM. Circulating tumor DNA analysis in the era of precision oncology. Oncotarget 2020; 11:188-211. [PMID: 32010431 PMCID: PMC6968778 DOI: 10.18632/oncotarget.27418] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022] Open
Abstract
The spatial and temporal genomic heterogeneity of various tumor types and advances in technology have stimulated the development of circulating tumor DNA (ctDNA) genotyping. ctDNA was developed as a non-invasive, cost-effective alternative to tumor biopsy when such biopsy is associated with significant risk, when tumor tissue is insufficient or inaccessible, and/or when repeated assessment of tumor molecular abnormalities is needed to optimize treatment. The role of ctDNA is now well established in the clinical decision in certain alterations and tumors, such as the epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer and the v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in colorectal cancer. The role of ctDNA analysis in other tumor types remains to be validated. Evolving data indicate the association of ctDNA level with tumor burden, and the usefulness of ctDNA analysis in assessing minimal residual disease, in understanding mechanisms of resistance to treatment, and in dynamically guiding therapy. ctDNA analysis is increasingly used to select therapy. Carefully designed clinical trials that use ctDNA analysis will increase the rate of patients who receive targeted therapy, will elucidate our understanding of evolution of tumor biology and will accelerate drug development and implementation of precision medicine. In this article we provide a critical overview of clinical trials and evolving data of ctDNA analysis in specific tumors and across tumor types.
Collapse
Affiliation(s)
- Rabih Said
- Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Oncology, St. George Hospital University Medical Center, University of Balamand, Beirut, Lebanon
- Co-authorship
| | - Nicolas Guibert
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Thoracic Oncology, Toulouse University Hospital, Toulouse, France
- Co-authorship
| | - Geoffrey R. Oxnard
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Apostolia M. Tsimberidou
- Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
44
|
Fang WL, Wu CH, Tseng CH, Huang KH, Chen MH, Li AY, Wu CW. The clinical significance of ARID1A mutations in gastric cancer patients. FORMOSAN JOURNAL OF SURGERY 2020. [DOI: 10.4103/fjs.fjs_66_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
45
|
Gao Y, Xi H, Wei B, Cui J, Zhang K, Li H, Cai A, Shen W, Li J, Rosell R, Chao J, Chen T, Klempner S, Qiao Z, Chen L. Association Between Liquid Biopsy and Prognosis of Gastric Cancer Patients: A Systematic Review and Meta-Analysis. Front Oncol 2019; 9:1222. [PMID: 31850190 PMCID: PMC6901923 DOI: 10.3389/fonc.2019.01222] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 10/25/2019] [Indexed: 12/24/2022] Open
Abstract
Background: Reports regarding liquid biopsy and gastric cancer (GC) have emerged rapidly in recent decades, yet their prognostic value still remains controversial. This study was aimed to assess the impact of liquid biopsy, including circulating tumor cells (CTCs) and cell-free nucleic acids, on GC patients' prognosis. Methods: PubMed, Medline, EMBASE, and ClinicalTrial.gov databases were searched for studies that report GC patient survival data stratified by CTC/circulating tumor DNA (ctDNA)/circulating miRNAs' status. The hazard ratios (HRs) and their 95% confidence intervals (CIs) for patients' overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS) were recorded or calculated depending on circulating target status. Results: We initially identified 4,221 studies, from which 43 were eligible for further analysis, comprising 3,814 GC patients. Pooled analyses showed that detection of certain CTCs, ctDNA, and circulating miRNA was associated with poorer OS (CTCs: HR = 1.84, 95%CI 1.50–2.26, p < 0.001; ctDNA: HR = 1.78, 95%CI 1.36–2.34, p < 0.001; circulating miRNA: HR = 1.74, 95%CI 1.13–2.69, p < 0.001) and DFS/PFS (CTCs: HR = 3.39, 95%CI 2.21–5.20, p < 0.001; ctDNA: HR = 2.38, 95%CI 1.31–4.32, p = 0.004; circulating miRNA: HR = 3.30, 95%CI 2.39–4.55, p < 0.001) of GC patients, regardless of disease stage and time point at which sample is taken (at baseline or post-treatment). Conclusions: The presence of CTCs and/or cellular components identifies a group of GC with poorer prognosis. Among circulating markers, CTCs demonstrated a stronger and more stable predictive value for late-stage disease and among Mongolian populations with GC. Less data are available for ctDNA and miRNA; however, their presence may also reflect aggressive biology and warrants further prospective study.
Collapse
Affiliation(s)
- Yunhe Gao
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China.,General Surgery Institute, Chinese PLA General Hospital, Beijing, China
| | - Hongqing Xi
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Bo Wei
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China.,General Surgery Institute, Chinese PLA General Hospital, Beijing, China
| | - Jianxin Cui
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Kecheng Zhang
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Hua Li
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Aizhen Cai
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China.,General Surgery Institute, Chinese PLA General Hospital, Beijing, China
| | - Weishen Shen
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China.,Nanjing General Hospital of Nanjing Military Command, Nanjing, China
| | - Jiyang Li
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China.,General Surgery Institute, Chinese PLA General Hospital, Beijing, China
| | - Rafael Rosell
- Catalan Institute of Oncology, Germans Trias i Pujol Health Science Institute and Hospital, Barcelona, Spain
| | - Joseph Chao
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Tianhui Chen
- Department of Cancer Prevention, Institute of Cancer and Basic Medicine (ICBM), Zhejiang Provincial Office for Cancer Prevention and Control, Cancer Hospital of the University of CAS, Chinese Academy of Sciences (CAS), Hangzhou, China
| | - Samuel Klempner
- The Angeles Clinic and Research Institute, Los Angeles, CA, United States.,Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Zhi Qiao
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Lin Chen
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China.,General Surgery Institute, Chinese PLA General Hospital, Beijing, China
| |
Collapse
|
|
46
|
Wang Y, Chen S, Tian W, Zhang Q, Jiang C, Qian L, Liu Y. High-Expression HBO1 Predicts Poor Prognosis in Gastric Cancer. Am J Clin Pathol 2019; 152:517-526. [PMID: 31247063 DOI: 10.1093/ajcp/aqz065] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES Our goal was to assess the expression of histone acetyltransferase binding to origin recognition complex 1 (HBO1) in gastric cancer and the effect on prognosis for the patients. METHODS We used quantitative reverse transcription polymerase chain reaction, Western blot, and tissue microarray immunohistochemistry to investigate the expressions of HBO1 messenger RNA (mRNA) and protein in gastric cancer tissues. Online resources, including Oncomine and Kaplan-Meier Plotter, were used to further assess the correlation between HBO1 expression and the prognosis of the patients with gastric cancer. RESULTS HBO1 mRNA and protein expressions in gastric cancer tissues were both significantly higher than those in normal tissues. The correlations between high HBO1 expression and differentiation, invasive depth (T), lymph node metastasis (N), distant metastasis (M), TNM staging, and serum carcinoembryonic antigen levels were positive. High HBO1 expression was negatively correlated with survival time in patients with gastric cancer. CONCLUSIONS HBO1 might be a valuable biomarker to evaluate the prognosis of patients with gastric cancer.
Collapse
Affiliation(s)
- Yan Wang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Sufang Chen
- Department of Medical Imaging and Laboratory, Xiangnan University, Chenzhou, China
| | - Wei Tian
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Qing Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Chunyi Jiang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Li Qian
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| | - Ying Liu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, China
| |
Collapse
|
|
47
|
Du WB, Lin CH, Chen WB. High expression of APC is an unfavorable prognostic biomarker in T4 gastric cancer patients. World J Gastroenterol 2019; 25:4452-4467. [PMID: 31496624 PMCID: PMC6710185 DOI: 10.3748/wjg.v25.i31.4452] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 07/18/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Adenoma polyposis coli (APC) mutation is associated with tumorigenesis via the Wnt signaling pathway. AIM To investigate the clinical features and mechanism of APC expression in gastric cancer (GC). METHODS Based on APC expression profile, the related genome-wide mRNA expression, microRNA (miRNA) expression, and methylation profile in GC, the relationship between APC and GC, as well as the prognostic significance of APC were systematically analyzed by multi-dimensional methods. RESULTS We found that high expression of APC (APC high) was significantly associated with adverse outcomes of T4 GC patients. Genome-wide gene expression analysis revealed that varying APC expression levels in GC were associated with some important oncogenes, and corresponding cellular functional pathways. Genome-wide miRNA expression analysis indicated that most of miRNAs associated with high APC expression were downregulated. The mRNA-miRNA regulatory network analysis revealed that down-regulated miRNAs affected their inhibitory effect on tumor genes. Genome-wide methylation profiles associated with APC expression showed that there was differential methylation between the APC high and APC low groups. The number of hypermethylation sites was larger than that of hypomethylation sites, and most of hypermethylation sites were enriched in CpG islands. CONCLUSION Our research demonstrated that high APC expression is an unfavorable prognostic factor for T4 GC patients and may be used as a novel biomarker for pathogenesis research, diagnosis, and treatment of GC.
Collapse
Affiliation(s)
- Wei-Bo Du
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Chen-Hong Lin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Wen-Biao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| |
Collapse
|
|
48
|
Zubarayev M, Min EK, Son T. Clinical and molecular prognostic markers of survival after surgery for gastric cancer: tumor-node-metastasis staging system and beyond. Transl Gastroenterol Hepatol 2019; 4:59. [PMID: 31559340 DOI: 10.21037/tgh.2019.08.05] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 07/30/2019] [Indexed: 12/12/2022] Open
Abstract
For accurately predicting prognosis and for effectively describing cancer states at a certain point during treatment to other care providers and patients, various staging systems have been utilized in gastric cancer. Among these, the UICC/AJCC tumor-node-metastasis (TNM) staging system is most widely used. However, even within the same substage, gastric cancers can vary substantially in regards to prognosis after treatment. For more accurate and individualized prognostication, staging systems have been found to benefit from including molecular markers and genomic subtypes, in addition to clinicopathological parameters, such as age, sex, tumor size, tumor location, Lauren classification, number of lymph nodes resected, extent of surgical resection, lymphovascular invasion, and adjuvant chemotherapy. In this review article, we review and summarize relevant biomarkers for gastric cancer that can be incorporated into the current anatomy-based TNM staging system, as well as results from validation studies thereof.
Collapse
Affiliation(s)
- Mykola Zubarayev
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.,GI laparoscopic & Robotic Surgery, National Cancer Institute, Kiev, Ukraine
| | - Eun-Ki Min
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Taeil Son
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.,Gastric Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea
| |
Collapse
|
|
49
|
Cervena K, Vodicka P, Vymetalkova V. Diagnostic and prognostic impact of cell-free DNA in human cancers: Systematic review. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:100-129. [PMID: 31416571 DOI: 10.1016/j.mrrev.2019.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
|
|
50
|
Davidson M, Barber LJ, Woolston A, Cafferkey C, Mansukhani S, Griffiths B, Moorcraft SY, Rana I, Begum R, Assiotis I, Matthews N, Rao S, Watkins D, Chau I, Cunningham D, Starling N, Gerlinger M. Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma. Cancers (Basel) 2019; 11:E736. [PMID: 31137920 PMCID: PMC6563045 DOI: 10.3390/cancers11050736] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 05/20/2019] [Accepted: 05/23/2019] [Indexed: 12/24/2022] Open
Abstract
DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing (lcWGS) of ctDNA from 30 patients with advanced OGA prior to first-line chemotherapy and on progression. SCNA profiles were detectable pretreatment in 23/30 (76.7%) patients. The presence of liver metastases, primary tumour in situ, or of oesophageal or junctional tumour location predicted for a high ctDNA fraction. A low ctDNA concentration associated with significantly longer overall survival. Neither chromosomal instability metrics nor ploidy correlated with chemotherapy outcome. Chromosome 2q and 8p gains before treatment were associated with chemotherapy responses. lcWGS identified all amplifications found by prior targeted tumour tissue sequencing in cases with detectable ctDNA as well as finding additional changes. SCNA profiles changed during chemotherapy, indicating that cancer cell populations evolved during treatment; however, no recurrent SCNA changes were acquired at progression. Tracking the evolution of OGA cancer cell populations in ctDNA is feasible during chemotherapy. The observation of genetic evolution warrants investigation in larger series and with higher resolution techniques to reveal potential genetic predictors of response and drivers of chemotherapy resistance. The presence of liver metastasis is a potential biomarker for the selection of patients with high ctDNA content for such studies.
Collapse
Affiliation(s)
- Michael Davidson
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - Louise J Barber
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
| | - Andrew Woolston
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
| | - Catherine Cafferkey
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - Sonia Mansukhani
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
| | - Beatrice Griffiths
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
| | - Sing-Yu Moorcraft
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - Isma Rana
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - Ruwaida Begum
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - Ioannis Assiotis
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
| | - Nik Matthews
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
| | - Sheela Rao
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - David Watkins
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - Ian Chau
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - David Cunningham
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - Naureen Starling
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
| | - Marco Gerlinger
- Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, Sutton, London SM2 5PT, UK.
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
| |
Collapse
|