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Yang L, Yang J, Kleppe A, Danielsen HE, Kerr DJ. Personalizing adjuvant therapy for patients with colorectal cancer. Nat Rev Clin Oncol 2024; 21:67-79. [PMID: 38001356 DOI: 10.1038/s41571-023-00834-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2023] [Indexed: 11/26/2023]
Abstract
The current standard-of-care adjuvant treatment for patients with colorectal cancer (CRC) comprises a fluoropyrimidine (5-fluorouracil or capecitabine) as a single agent or in combination with oxaliplatin, for either 3 or 6 months. Selection of therapy depends on conventional histopathological staging procedures, which constitute a blunt tool for patient stratification. Given the relatively marginal survival benefits that patients can derive from adjuvant treatment, improving the safety of chemotherapy regimens and identifying patients most likely to benefit from them is an area of unmet need. Patient stratification should enable distinguishing those at low risk of recurrence and a high chance of cure by surgery from those at higher risk of recurrence who would derive greater absolute benefits from chemotherapy. To this end, genetic analyses have led to the discovery of germline determinants of toxicity from fluoropyrimidines, the identification of patients at high risk of life-threatening toxicity, and enabling dose modulation to improve safety. Thus far, results from analyses of resected tissue to identify mutational or transcriptomic signatures with value as prognostic biomarkers have been rather disappointing. In the past few years, the application of artificial intelligence-driven models to digital images of resected tissue has identified potentially useful algorithms that stratify patients into distinct prognostic groups. Similarly, liquid biopsy approaches involving measurements of circulating tumour DNA after surgery are additionally useful tools to identify patients at high and low risk of tumour recurrence. In this Perspective, we provide an overview of the current landscape of adjuvant therapy for patients with CRC and discuss how new technologies will enable better personalization of therapy in this setting.
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Affiliation(s)
- Li Yang
- Department of Gastroenterology, Sichuan University, Chengdu, China
| | - Jinlin Yang
- Department of Gastroenterology, Sichuan University, Chengdu, China
| | - Andreas Kleppe
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
- Department of Informatics, University of Oslo, Oslo, Norway
- Centre for Research-based Innovation Visual Intelligence, UiT The Arctic University of Norway, Tromsø, Norway
| | - Håvard E Danielsen
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
- Radcliffe Department of Medicine, Oxford University, Oxford, UK
| | - David J Kerr
- Radcliffe Department of Medicine, Oxford University, Oxford, UK.
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Rajarajan S, C E A, Jose B, Correa M, Sengupta S, Prabhu JS. Identification of colorectal cancers with defective DNA damage repair by immunohistochemical profiling of mismatch repair proteins, CDX2 and BRCA1. Mol Clin Oncol 2020; 13:57. [PMID: 32953111 PMCID: PMC7484731 DOI: 10.3892/mco.2020.2128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 07/09/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is a complex disease as shown by consensus classification. The present study attempted to identify subtypes with known prognostic markers for better clinical management. A total of 72 CRC tumors were examined for the expression of mismatch repair (MMR) proteins, along with caudal-type homeobox protein 2 (CDX2) and BRCA1, by immunohistochemistry. Tumors were assigned based on the presence or loss of MMR proteins as proficient or deficient. Correlations were examined with CDX2 and BRCA1 along with clinico-pathological features. Expressional pattern of microRNAs (miRs/miRNAs), such as miR-183-96-182, known to be associated with defective DNA damage repair were evaluated by reverse transcription-quantitative PCR. A total of 22% of the CRC tumors were assigned as deficient in mismatch repair. 71% of the tumors expressed CDX2 while only 21% had nuclear expression of BRCA1. Loss of CDX2 protein was higher in the deficient subtype compared with the proficient subtype. A total of 14% of the tumors had dual loss of MMR and BRCA1 proteins and showed aggressive clinical features in addition to elevated expression of DNA damage repair microRNAs. The present study shows the presence of a small proportion of colorectal tumors with dual loss of key proteins involved in DNA damage repair which may be amenable to specific therapy. The implication of the present observations warrants investigation in a larger patient cohort with prognostic information.
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Affiliation(s)
- Savitha Rajarajan
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore 560034, India
| | - Anupama C E
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore 560034, India
| | - Betsy Jose
- Department of Pathology, St. John's Medical College, Bangalore 560034, India
| | - Marjorie Correa
- Department of Pathology, St. John's Medical College, Bangalore 560034, India
| | - Sagar Sengupta
- National Institute of Immunology, New Delhi 110067, India
| | - Jyothi S Prabhu
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore 560034, India
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Hou JT, Zhao LN, Zhang DJ, Lv DY, He WL, Chen B, Li HB, Li PR, Chen LZ, Chen XL. Prognostic Value of Mismatch Repair Genes for Patients With Colorectal Cancer: Meta-Analysis. Technol Cancer Res Treat 2019; 17:1533033818808507. [PMID: 30411662 PMCID: PMC6259062 DOI: 10.1177/1533033818808507] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
DNA mismatch repair was proposed to play a pivotal role in the development and prognosis of colorectal cancer. However, the prognostic value of mismatch repair on colorectal cancer is still unknown. The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched. The articles about mismatch repair (including hMLH1, hMSH2, hMSH3, hMSH6, hPMSH1, and hPMSH2) deficiency for the prognosis of patients with colorectal cancer were included in the study. The hazard ratio and its 95% confidence interval were used to measure the impact of mismatch repair deficiency on survival time. Twenty-one articles were included. The combined hazard ratio for mismatch repair deficiency on overall survival was 0.59 (95% confidence interval: 0.50-0.69) and that on disease-free survival was 0.57 (95% confidence interval: 0.43-0.75). In subgroup analysis, there were a significant association between overall survival and mismatch repair deficiency in Asian studies (hazard ratio: 0.67; 95% confidence interval: 0.50-0.91) and Western studies (hazard ratio: 0.56; 95% confidence interval: 0.46-0.67). For disease-free survival, the hazard ratios in Asian studies and Western studies were 0.55 (95% confidence interval: 0.38-0.81) and 0.62 (95% confidence interval: 0.50-0.78), respectively. Our meta-analysis indicated that mismatch repair could be used to evaluate the prognosis of patients with colorectal cancer.
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Affiliation(s)
- Jiang-Tao Hou
- 1 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li-Na Zhao
- 1 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ding-Jun Zhang
- 2 The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dong-Yong Lv
- 3 Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei-Ling He
- 4 The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bin Chen
- 1 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui-Biao Li
- 1 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Pei-Ru Li
- 2 The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Li-Zhen Chen
- 5 School of Nursing Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xin-Lin Chen
- 6 School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
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Otto W, Macrae F, Sierdziński J, Smaga J, Król M, Wilińska E, Zieniewicz K. Microsatellite instability and manifestations of angiogenesis in stage IV of sporadic colorectal carcinoma. Medicine (Baltimore) 2019; 98:e13956. [PMID: 30608431 PMCID: PMC6344194 DOI: 10.1097/md.0000000000013956] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 11/05/2018] [Accepted: 12/11/2018] [Indexed: 12/20/2022] Open
Abstract
Angiogenesis represents one of the critical mechanisms that facilitates carcinoma development. The study objective was to evaluate whether the microsatellite instability of colorectal carcinoma has impact on the angiogenesis activity in liver metastases.In a cohort of 80 randomly selected patients with stage IV colorectal carcinoma, 30% were recognized as microsatellite unstable (Microsatellite instability high-frequency (MSI-H)). The endothelial progenitor cell fraction (CD309+) was counted within the subpopulation of CD34+CD45+ cell and CD34+CD45- cells by flow cytometer. vascular endothelial growth factor (VEGF) factor levels were quantified in serum samples by enzyme-linked immunosorbent assay (ELISA). A control group consisted of 36 healthy volunteers. The relationship of genomic instability to angiogenesis activity was evaluated by multivariate analysis in comparison to the controls, adopting a P < .05 value as statistically significant.The expression of endothelial progenitor cells (EPCs) and VEGF was significantly higher in MSI-H compared to both microsatellite stability (MSS) patients and healthy controls (P < .008). Multi-parametric analysis showed microsatellite instability (OR=9.12, P < .01), metastases in both lobes (OR = 32.83, P < .001) and simultaneous metastases outside liver (OR = 8.32, P < .01), as independent factors associated with increased angiogenesis as assessed by measures of EPC and VEGF. A higher percentage of EPCs within the white blood cell fraction (total % EPCs / white blood cells (WBC)) and higher serum concentrations of VEGF were present in patients with MSI-H colorectal cancer, and not with MSS cancers (P < .001).MSI-H patients with colorectal cancer metastases are associated with the overexpression of circulating EPCs and VEGF, potentially driving angiogenesis. This should be considered in therapeutic decision-making.
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Affiliation(s)
| | - Finlay Macrae
- Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, and Department of Medicine, The University of Melbourne, Australia
| | | | | | - Maria Król
- Department of Oncology, Hematology & Internal Medicine
| | - Ewa Wilińska
- Department of Pathology Central Teaching Hospital, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland
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Tyrrell HE, Kerr D. Prognostic markers for colorectal cancer. Oncotarget 2018; 9:33060-33061. [PMID: 30237850 PMCID: PMC6145697 DOI: 10.18632/oncotarget.26012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Accepted: 08/15/2018] [Indexed: 11/25/2022] Open
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Kleppe A, Albregtsen F, Vlatkovic L, Pradhan M, Nielsen B, Hveem TS, Askautrud HA, Kristensen GB, Nesbakken A, Trovik J, Wæhre H, Tomlinson I, Shepherd NA, Novelli M, Kerr DJ, Danielsen HE. Chromatin organisation and cancer prognosis: a pan-cancer study. Lancet Oncol 2018; 19:356-369. [PMID: 29402700 PMCID: PMC5842159 DOI: 10.1016/s1470-2045(17)30899-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 11/21/2017] [Accepted: 11/27/2017] [Indexed: 01/11/2023]
Abstract
BACKGROUND Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation. METHODS Machine learning algorithms analysed the chromatin organisation in 461 000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival. FINDINGS In all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1·7, 95% CI 1·2-2·5, in the discovery cohort; 1·8, 1·0-3·0, in the Gloucester validation cohort; 2·2, 1·1-4·5, in the QUASAR 2 validation cohort; 3·1, 1·9-5·0, in the ovarian carcinoma cohort; 2·5, 1·8-3·4, in the uterine sarcoma cohort; 2·3, 1·2-4·6, in the prostate carcinoma cohort; and 4·3, 2·8-6·8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1·7, 95% CI 1·1-2·5, in the discovery cohort; 1·9, 1·1-3·2, in the Gloucester validation cohort; 2·6, 1·2-5·6, in the QUASAR 2 cohort; 1·8, 1·1-3·0, for ovarian carcinoma; 1·6, 1·0-2·4, for uterine sarcoma; 1·43, 0·68-2·99, for prostate carcinoma; and 1·9, 1·1-3·1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2·9, 95% CI 1·0-8·4) and microsatellite stable (1·8, 1·2-2·7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1·3, 0·7-2·4) or chromatin heterogeneous (0·8, 0·3-2·0) stage II colorectal cancer. INTERPRETATION The consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high-risk patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings. FUNDING The Research Council of Norway, the South-Eastern Norway Regional Health Authority, the National Institute for Health Research, and the Wellcome Trust.
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Affiliation(s)
- Andreas Kleppe
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Department of Informatics, University of Oslo, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - Fritz Albregtsen
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Department of Informatics, University of Oslo, Oslo, Norway
| | | | - Manohar Pradhan
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - Birgitte Nielsen
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - Tarjei S Hveem
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - Hanne A Askautrud
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - Gunnar B Kristensen
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Department of Gynecologic Oncology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Arild Nesbakken
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jone Trovik
- Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Håkon Wæhre
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - Ian Tomlinson
- Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Neil A Shepherd
- Gloucestershire Cellular Pathology Laboratory, Cheltenham General Hospital, Cheltenham, UK
| | - Marco Novelli
- Department of Histopathology, University College London, London, UK
| | - David J Kerr
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK
| | - Håvard E Danielsen
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Department of Informatics, University of Oslo, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.
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Danielsen HE, Hveem TS, Domingo E, Pradhan M, Kleppe A, Syvertsen RA, Kostolomov I, Nesheim JA, Askautrud HA, Nesbakken A, Lothe RA, Svindland A, Shepherd N, Novelli M, Johnstone E, Tomlinson I, Kerr R, Kerr DJ. Prognostic markers for colorectal cancer: estimating ploidy and stroma. Ann Oncol 2018; 29:616-623. [PMID: 29293881 PMCID: PMC5889021 DOI: 10.1093/annonc/mdx794] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background We report here the prognostic value of ploidy and digital tumour-stromal morphometric analyses using material from 2624 patients with early stage colorectal cancer (CRC). Patients and methods DNA content (ploidy) and stroma-tumour fraction were estimated using automated digital imaging systems and DNA was extracted from sections of formalin-fixed paraffin-embedded (FFPE) tissue for analysis of microsatellite instability. Samples were available from 1092 patients recruited to the QUASAR 2 trial and two large observational series (Gloucester, n = 954; Oslo University Hospital, n = 578). Resultant biomarkers were analysed for prognostic impact using 5-year cancer-specific survival (CSS) as the clinical end point. Results Ploidy and stroma-tumour fraction were significantly prognostic in a multivariate model adjusted for age, adjuvant treatment, and pathological T-stage in stage II patients, and the combination of ploidy and stroma-tumour fraction was found to stratify these patients into three clinically useful groups; 5-year CSS 90% versus 83% versus 73% [hazard ratio (HR) = 1.77 (95% confidence interval (95% CI): 1.13-2.77) and HR = 2.95 (95% CI: 1.73-5.03), P < 0.001]. Conclusion A novel biomarker, combining estimates of ploidy and stroma-tumour fraction, sampled from FFPE tissue, identifies stage II CRC patients with low, intermediate or high risk of CRC disease specific death, and can reliably stratify clinically relevant patient sub-populations with differential risks of tumour recurrence and may support choice of adjuvant therapy for these individuals.
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Affiliation(s)
- H E Danielsen
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK; Department of Informatics, University of Oslo, Oslo, Norway
| | - T S Hveem
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Informatics, University of Oslo, Oslo, Norway
| | - E Domingo
- Department of Oncology, University of Oxford, Oxford, UK; Molecular and Population Genetics Laboratory, University of Oxford, Oxford, UK; Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - M Pradhan
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - A Kleppe
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Informatics, University of Oslo, Oslo, Norway
| | - R A Syvertsen
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - I Kostolomov
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - J A Nesheim
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - H A Askautrud
- Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
| | - A Nesbakken
- Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo; Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo
| | - R A Lothe
- Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo; Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo
| | - A Svindland
- Institute of Clinical Medicine, University of Oslo, Oslo; Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - N Shepherd
- Gloucestershire Cellular Pathology Laboratory, Cheltenham General Hospital, Cheltenham
| | - M Novelli
- Research Department of Pathology, University College London Medical School, London, UK
| | - E Johnstone
- Department of Oncology, University of Oxford, Oxford, UK
| | - I Tomlinson
- Molecular and Population Genetics Laboratory, University of Oxford, Oxford, UK
| | - R Kerr
- Department of Oncology, University of Oxford, Oxford, UK
| | - D J Kerr
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.
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Head RJ, Fay MF, Cosgrove L, Y. C. Fung K, Rundle-Thiele D, Martin JH. Persistence of DNA adducts, hypermutation and acquisition of cellular resistance to alkylating agents in glioblastoma. Cancer Biol Ther 2017; 18:917-926. [PMID: 29020502 PMCID: PMC5718815 DOI: 10.1080/15384047.2017.1385680] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 09/01/2017] [Accepted: 09/24/2017] [Indexed: 01/13/2023] Open
Abstract
Glioblastoma is a lethal form of brain tumour usually treated by surgical resection followed by radiotherapy and an alkylating chemotherapeutic agent. Key to the success of this multimodal approach is maintaining apoptotic sensitivity of tumour cells to the alkylating agent. This initial treatment likely establishes conditions contributing to development of drug resistance as alkylating agents form the O6-methylguanine adduct. This activates the mismatch repair (MMR) process inducing apoptosis and mutagenesis. This review describes key juxtaposed drivers in the balance between alkylation induced mutagenesis and apoptosis. Mutations in MMR genes are the probable drivers for alkylation based drug resistance. Critical to this interaction are the dose-response and temporal interactions between adduct formation and MMR mutations. The precision in dose interval, dose-responses and temporal relationships dictate a role for alkylating agents in either promoting experimental tumour formation or inducing tumour cell death with chemotherapy. Importantly, this resultant loss of chemotherapeutic selective pressure provides opportunity to explore novel therapeutics and appropriate combinations to minimise alkylation based drug resistance and tumour relapse.
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Affiliation(s)
- R. J. Head
- University of South Australia, Adelaide, SA, Australia
| | - M. F. Fay
- University of Newcastle, Newcastle, NSW, Australia
- Genesis Cancer Care, NSW, Australia
- University of Queensland, Brisbane, QLD, Australia
| | - L. Cosgrove
- CSIRO Health & Biosecurity, Adelaide, SA, Australia
| | | | - D. Rundle-Thiele
- School of Medicine, Flinders University, Bedford Park, SA, Australia
| | - J. H. Martin
- University of Newcastle, Newcastle, NSW, Australia
- University of Queensland, Brisbane, QLD, Australia
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The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing. Crit Rev Oncol Hematol 2017; 116:38-57. [PMID: 28693799 DOI: 10.1016/j.critrevonc.2017.05.006] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 03/02/2017] [Accepted: 05/15/2017] [Indexed: 02/08/2023] Open
Abstract
Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR). Many institutions now advocate universal tumor screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing. The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing. Aside from screening for Lynch syndrome, MMR testing is important because of its prognostic and therapeutic implications. Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable (MSS) CRCs. For example, response to conventional chemotherapy has been reported to be less in MSI tumours. More recently, MSI tumours have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy. This provides a rationale for routine testing for MSI or dMMR in CRC.
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Rovcanin B, Ivanovski I, Djuric O, Nikolic D, Petrovic J, Ivanovski P. Mitotic crossover - an evolutionary rudiment which promotes carcinogenesis of colorectal carcinoma. World J Gastroenterol 2014; 20:12522-12525. [PMID: 25253953 PMCID: PMC4168086 DOI: 10.3748/wjg.v20.i35.12522] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 04/22/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Mitotic crossover is a natural mechanism that is a main source of the genetic variability of primitive organisms. In complex organisms such as mammals, it represents an evolutionary rudiment which persisted as one of the numerous DNA repair mechanisms, and results in the production of homozygous allele combinations in all heterozygous genes located on the chromosome arm distal to the crossover. This event is familiar as loss of heterozygosity, which is one of the key mechanisms responsible for the development and progression of almost all cancers. We propose the hypothesis in which mitotic crossover is a principal source of the increased loss of heterozygosity that leads to the initiation and progression of colorectal carcinoma. The hypothesis could be tested by in vitro inhibition of Rad51 protein, orthotopic grafting of human colon cancer tissue into the gut of mice, and treatment with potential inhibitors. After these procedures, the frequency of mitotic crossover would be estimated. The development of selective inhibitors of mitotic crossover could stop further carcinogenesis of colorectal carcinoma, as well as many other neoplastic events. Loss of heterozygosity is an event responsible for carcinogenesis, its reduction by selective inhibitors of mitotic crossover could have a positive effect on cancer chemoprevention, as well as on growth reduction and a cessation in the progression of earlier developed tumors.
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Saridaki Z, Souglakos J, Georgoulias V. Prognostic and predictive significance of MSI in stages II/III colon cancer. World J Gastroenterol 2014; 20:6809-6814. [PMID: 24944470 PMCID: PMC4051919 DOI: 10.3748/wjg.v20.i22.6809] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Revised: 12/29/2013] [Accepted: 03/05/2014] [Indexed: 02/07/2023] Open
Abstract
In colon cancer, classic disease staging remains the key prognosis and treatment determinant. Although adjuvant chemotherapy has an established role in stage III colon cancer patients, in stage II it is still a subject of controversy due to its restriction to a small subgroup of patients with high-risk histopathologic features. Patients with stage II tumors form a highly heterogeneous group, with five-year relative overall survival rates ranging from 87.5% (IIA) to 58.4% (IIC). Identifying those for whom adjuvant chemotherapy would be appropriate and necessary has been challenging, and prognostic markers which could serve in the selection of patients more likely to recur or benefit from adjuvant chemotherapy are eagerly needed. The stronger candidate in this category seems to be microsatellite instability (MSI). The recently reported European Society for Medical Oncology guidelines suggest that MSI should be evaluated in stage II colorectal cancer patients in order to contribute in treatment decision-making regarding chemotherapy administration. The hypothetical predictive role of MSI regarding its response to 5-fluorouracil-based adjuvant chemotherapy has proven a much more difficult issue to address. Almost every possible relation between MSI and chemotherapy outcome has been described in the adjuvant colon cancer setting in the international literature, and the matter is far from being settled. In this current report we critically evaluate the prognostic and predictive impact of MSI status in patients with stage II and stage III colon cancer patients.
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Ribonucleotide reductase small subunit M2 serves as a prognostic biomarker and predicts poor survival of colorectal cancers. Clin Sci (Lond) 2013; 124:567-78. [PMID: 23113760 PMCID: PMC3562074 DOI: 10.1042/cs20120240] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The overexpression of RRM2 [RR (ribonucleotide reductase) small subunit M2] dramatically enhances the ability of the cancer cell to proliferate and to invade. To investigate further the relevance of RRM2 and CRCs (colorectal cancers), we correlated the expression of RRM2 with the clinical outcome of CRCs. A retrospective outcome study was conducted on CRCs collected from the COH [(City of Hope) National Medical Center, 217 cases] and ZJU (Zhejiang University, 220 cases). IHC (immunohistochemistry) was employed to determine the protein expression level of RRM2, and quantitative real-time PCR was employed to validate. Multivariate logistic analysis indicated that the adjusted ORs (odds ratios) of RRM2-high for distant metastases were 2.06 [95% CI (confidence interval), 1.01-4.30] and 5.89 (95% CI, 1.51-39.13) in the COH and ZJU sets respectively. The Kaplan-Meier analysis displayed that high expression of RRM2 had a negative impact on the OS (overall survival) and PFS (progress-free survival) of CRC in both sets significantly. The multivariate Cox analysis further demonstrated that HRs (hazard ratios) of RRM2-high for OS were 1.88 (95% CI, 1.03-3.36) and 2.06 (95% CI, 1.10-4.00) in the COH and ZJU sets respectively. Stratification analysis demonstrated that the HR of RRM2 dramatically increased to 12.22 (95% CI, 1.62-258.31) in the MMR (mismatch repair) gene-deficient subgroup in the COH set. Meanwhile, a real-time study demonstrated that down-regulation of RRM2 by siRNA (small interfering RNA) could significantly and specifically reduce the cell growth and adhesion ability in HT-29 and HCT-8 cells. Therefore RRM2 is an independent prognostic factor and predicts poor survival of CRCs. It is also a potential predictor for identifying good responders to chemotherapy for CRCs.
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Shin JS, Tut TG, Yang T, Lee CS. Radiotherapy response in microsatellite instability related rectal cancer. KOREAN JOURNAL OF PATHOLOGY 2013; 47:1-8. [PMID: 23482947 PMCID: PMC3589603 DOI: 10.4132/koreanjpathol.2013.47.1.1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 01/21/2013] [Indexed: 01/05/2023]
Abstract
Preoperative radiotherapy may improve the resectability and subsequent local control of rectal cancers. However, the extent of radiation induced regression in these tumours varies widely between individuals. To date no reliable predictive marker of radiation sensitivity in rectal cancer has been identified. At the cellular level, radiation injury initiates a complex molecular network of DNA damage response (DDR) pathways that leads to cell cycle arrest, attempts at re-constituting the damaged DNA and should this fail, then apoptosis. This review presents the details which suggest the roles of DNA mismatch repair proteins, the lack of which define a distinct subset of colorectal cancers with microsatellite instability (MSI), in the DDR pathways. Hence routine assessment of the MSI status in rectal cancers may potentially serve as a predictor of radiotherapy response, thereby improving patient stratification in the administration of this otherwise toxic treatment.
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Affiliation(s)
- Joo-Shik Shin
- Discipline of Pathology, University of Western Sydney School of Medicine, Liverpool, NSW, Australia. ; Cancer Pathology and Cell Biology Laboratory, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia. ; Department of Anatomical Pathology, Liverpool Hospital, Sydney South West Area Pathology Service, Liverpool, NSW, Australia
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Stojadinovic A, Nissan A, Wainberg Z, Shen P, McCarter M, Protic M, Howard RS, Steele SR, Peoples GE, Bilchik A. Time-dependent trends in lymph node yield and impact on adjuvant therapy decisions in colon cancer surgery: an international multi-institutional study. Ann Surg Oncol 2012; 19:4178-85. [PMID: 22805869 DOI: 10.1245/s10434-012-2501-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Lymph node yield (LNY) and accuracy of nodal assessment are critical to staging and treatment planning in colon cancer (CC). A nationally agreed upon 12-node minimum is a quality standard in CC. The impact of this quality measure on LNY and impact on therapeutic decisions are evaluated in two international, multi-center, prospective trials comprising a well-characterized cohort assembled over 8 years (2001-2009) with long-term follow-up. HYPOTHESIS Quality adherence through increased LNY improves staging accuracy and impacts adjuvant therapy decisions. METHODS Retrospective analysis of prospective data to assess time-dependent LNY, the dependent variable in multivariate linear regression analysis adjusted for age, gender, body-mass-index (BMI), tumor size/stage/grade, anatomic location and surgery date. RESULTS Two-hundred-forty-five patients with non-metastatic CC, median age 70 years, BMI 26 kg/m(2), tumor size 4.0 cm, and LNY 17 nodes were studied. Seventy-two percent had T3 (70 %)/T4 (2 %) tumors. Adherence to the 12-node minimum was 70 %(2001-2002), 81 % (2003-2004), 90 % (2005-2006), 94 % (2007-2008). LNY significantly increased over time (Median LNY: 2001-2004 = 15 vs. 2005-2008 = 17; P < 0.001) on multivariate analysis controlling for tumor size (P < 0.001), and right-sided tumor location (P < 0.001). Adjuvant therapy administration and indication for chemotherapy according to LNY (<12 vs. 12 + LNs = 33 % vs. 39 %; P = 0.48) and time period (2001-2004 vs. 2005-2008 = 39 % vs. 37 %; P = 0.89) remained unchanged. CONCLUSIONS Despite the independent predictors of nodal yield (tumor location and size), year of study still had a significant impact on nodal yield. Despite increased quality adherence and LNY over time, there appears to be a delayed impact on adjuvant therapy decisions once quality standard adherence takes effect.
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Kelly P, Paulin F, Lamont D, Baker L, Clearly S, Exon D, Thompson A. Pre-treatment plasma proteomic markers associated with survival in oesophageal cancer. Br J Cancer 2012; 106:955-61. [PMID: 22294182 PMCID: PMC3305965 DOI: 10.1038/bjc.2012.15] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Background: The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy can improve survival, but prognostic and predictive biomarkers are required. This study built upon preclinical approaches to identify prognostic plasma proteomic markers in oesophageal cancer. Methods: Plasma samples collected before and during the treatment of oesophageal cancer and non-cancer controls were analysed by surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) mass spectroscopy (MS). Protein peaks were identified by MS in tryptic digests of purified fractions. Associations between peak intensities obtained in the spectra and clinical endpoints (survival, disease-free survival) were tested by univariate (Fisher's exact test) and multivariate analysis (binary logistic regression). Results: Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the oesophageal cancer and control groups at baseline. Three peaks, confirmed as apolipoprotein A-I, serum amyloid A and transthyretin, in baseline (pre-treatment) samples were associated by univariate and multivariate analysis with disease-free survival and overall survival. Conclusion: Plasma proteins can be detected prior to treatment for oesophageal cancer that are associated with outcome and merit testing as prognostic and predictive markers of response to guide chemotherapy in oesophageal cancer.
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Affiliation(s)
- P Kelly
- Dundee Cancer Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
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Review of histopathological and molecular prognostic features in colorectal cancer. Cancers (Basel) 2011; 3:2767-810. [PMID: 24212832 PMCID: PMC3757442 DOI: 10.3390/cancers3022767] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2011] [Revised: 06/14/2011] [Accepted: 06/15/2011] [Indexed: 02/06/2023] Open
Abstract
Prediction of prognosis in colorectal cancer is vital for the choice of therapeutic options. Histopathological factors remain paramount in this respect. Factors such as tumor size, histological type and subtype, presence of signet ring morphology and the degree of differentiation as well as the presence of lymphovascular invasion and lymph node involvement are well known factors that influence outcome. Our understanding of these factors has improved in the past few years with factors such as tumor budding, lymphocytic infiltration being recognized as important. Likewise the prognostic significance of resection margins, particularly circumferential margins has been appreciated in the last two decades. A number of molecular and genetic markers such as KRAS, BRAF and microsatellite instability are also important and correlate with histological features in some patients. This review summarizes our current understanding of the main histopathological factors that affect prognosis of colorectal cancer.
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Tejpar S, Saridaki Z, Delorenzi M, Bosman F, Roth AD. Microsatellite instability, prognosis and drug sensitivity of stage II and III colorectal cancer: more complexity to the puzzle. J Natl Cancer Inst 2011; 103:841-4. [PMID: 21597023 DOI: 10.1093/jnci/djr170] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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Sargent DJ, Sinicrope F, Gallinger S. Reply to C.D. Atkins. J Clin Oncol 2010. [DOI: 10.1200/jco.2010.32.0093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Atkins CD. Predictive Value of Defective Mismatch Repair in Adjuvant Colon Cancer. J Clin Oncol 2010; 28:e746; author reply e747. [DOI: 10.1200/jco.2010.31.8824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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