• GI malignancies
• Molecular medicine
• Multiomics
• Precision oncology
• Targeted therapies

• Humans
• Precision Medicine
• Gastrointestinal Neoplasms/surgery
• Gastrointestinal Neoplasms/pathology
• Medical Oncology
• Pancreatic Neoplasms
• Colorectal Neoplasms/surgery

• Clinical characteristics
• Colorectal cancer
• KRAS
• Molecular mutation
• Post-translational modifications

• Humans
• Proto-Oncogene Proteins B-raf/genetics
• Retrospective Studies
• Proto-Oncogene Proteins p21(ras)/genetics
• Mutation
• Microsatellite Instability
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Protein Processing, Post-Translational
• Class I Phosphatidylinositol 3-Kinases/genetics
• Lung Neoplasms

• colorectal cancer
• immune checkpoint inhibitors
• immune escape
• immune evasion
• microsatellite instability
• mismatch-repair deficiency
• resistance to immune checkpoint inhibitors

Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/β-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients.

The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients.

The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that β-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. β-Catenin overexpression (HR: 0.137 (95% CI: 0.131–0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146–0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126–0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772–0.198)) also presented risk for shorter DFS.

The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/β-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.

• CCA subtype
• biomarker
• next-generation sequencing (NGS)
• prognosis
• tumor mutational burden (TMB)

• Colorectal cancer
• Gene mutation
• Meta-analysis
• Prognosis
• SMAD4

• drosophila mothers against decapentaplegic protein 7
• drosophila mothers against decapentaplegic protein 9
• lung adenocarcinoma
• prognostic value

• Adenocarcinoma of Lung/genetics
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/blood
• Gene Expression/genetics
• Humans
• Prognosis
• Smad7 Protein/analysis
• Smad7 Protein/blood

• actionable mutations
• chemoresistance
• colorectal cancer
• less frequently mutated genes
• precision medicine
• treatment response

• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/therapy
• Genes, Neoplasm
• Humans
• Mutation
• Precision Medicine

• LRGS/2014/UKM-UKM/K/01 Ministry of Higher Education, Malaysia

• Microbiome
• Signal Transduction
• TCGA
• Tumor Suppressor

• Animals
• Bacteria/genetics
• Bacteria/isolation & purification
• Carcinoembryonic Antigen/genetics
• Carcinoembryonic Antigen/metabolism
• Carcinogenesis/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/microbiology
• Colorectal Neoplasms/mortality
• Disease Models, Animal
• Feces/microbiology
• GPI-Linked Proteins/genetics
• GPI-Linked Proteins/metabolism
• Gain of Function Mutation
• Gastrointestinal Microbiome/physiology
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• Humans
• Metagenomics
• Mice
• Mice, Transgenic
• Protein Domains/genetics
• Receptor, Transforming Growth Factor-beta Type I/metabolism
• Signal Transduction/genetics
• Smad4 Protein/genetics
• Smad4 Protein/metabolism
• Spheroids, Cellular
• Survival Analysis
• Transforming Growth Factor beta/metabolism

• I01 BX003732 BLRD VA
• R01 AA023146 NIAAA NIH HHS
• R01 CA236591 NCI NIH HHS
• U01 CA230690 NCI NIH HHS

CpG Island Methylator Phenotype (CIMP) is an epigenetic phenotype in CRC characterized by hypermethylation of CpG islands in promoter regions of tumor suppressor genes, leading to their transcriptional silencing and loss of function. While the prevalence of CRC differs across geographical regions, no studies have compared prevalence of CIMP-High phenotype across regions. The purpose of this project was to compare the prevalence of CIMP across geographical regions after adjusting for variations in methodologies to measure CIMP in a meta-analysis.

We searched PubMed, Medline, and Embase for articles focusing on CIMP published from 2000 to 2018. Two reviewers independently identified 111 articles to be included in final meta-analysis. We classified methods used to quantify CIMP into 4 categories: a) Classical (MINT marker) Panel group b) Weisenberg-Ogino (W-O) group c) Human Methylation Arrays group and d) Miscellaneous group. We compared the prevalence of CIMP across geographical regions after correcting for methodological variations using meta-regression techniques.

The pooled prevalence of CIMP-High across all studies was 22% (95% confidence interval:21–24%; I² = 94.75%). Pooled prevalence of CIMP-H across Asia, Australia, Europe, North America and South America was 22, 21, 21, 27 and 25%, respectively. Meta-regression analysis identified no significant differences in the prevalence of CIMP-H across geographical regions after correction for methodological variations. In exploratory analysis, we observed variations in CIMP-H prevalence across countries.

Although no differences were found for CIMP-H prevalence across countries, further studies are needed to compare the influence of demographic, lifestyle and environmental factors in relation to the prevalence of CIMP across geographical regions.

• CIMP
• Colorectal
• Epigenetics
• Geographic
• Methylation

• Colorectal carcinoma
• Genomic profiling
• Mucinous carcinoma
• Signet ring cell carcinoma

SMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC.

We retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs.

A loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p=.042) and 7-year cancer-specific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p=.022).

We confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

• Biomarker
• Colorectal neoplasms
• Prognosis
• SMAD4

Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-β signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In other cases, such as skin cancer, loss of SMAD4 plays an important initiating role by disrupting DNA damage response and repair mechanisms and enhance genomic instability, suggesting its distinct roles in different types of tumors. This review lists SMAD4 mutations in various types of cancer and summarizes recent advances on SMAD4 with focuses on the function, signaling pathway, and the possibility of SMAD4 as a prognostic indicator.

• SMAD4
• TGF-β
• mouse model
• prognosis
• tumorigenesis

Although loss of heterozygosity (LOH) at chromosome location 18q21 and decreased expression of SMAD4 in invasive colorectal cancers (CRCs) correlate with poor patient survival, the prognostic value of LOH at 18q21 and sub-cellular localization of SMAD4 have not been evaluated in relation to tumor stage.

Genomic DNA samples from 209 formalin-fixed, paraffin-embedded sporadic CRC tissues and their matching controls were analyzed for 18q21 LOH, and corresponding tissue sections were evaluated by immunohistochemistry for expression of SMAD4 and assessed for its sub-cellular localization (nuclear vs. cytoplasmic). In addition, 53 frozen CRCs and their matching control tissues were analyzed for their mutational status and mRNA expression of SMAD4. The phenotypic expression pattern and LOH status were evaluated for correlation with patient survival by the use of Kaplan-Meier and Cox regression models.

LOH of 18q21 was detected in 61% of the informative cases. In 8% of the cases, missense point mutations were detected in Smad4. In CRCs, relative to controls, there was increased SMAD4 staining in the cytoplasm (74%) and decreased staining in the nuclei (37%). LOH of 18q21 and high cytoplasmic localization of SMAD4 were associated with shortened overall survival of Stage II patients, whereas low nuclear expression of SMAD4 was associated with worse survival, but only for patients with Stage III CRCs.

LOH of 18q21 and high cytoplasmic localization of SMAD4 in Stage II CRCs and low nuclear SMAD4 in Stage III CRCs are predictors of shortened patient survival.

• 18q21 LOH
• colorectal cancer
• nuclear/cytoplasmic SMAD4
• survival
• tumor stage

• Colorectal cancer
• Metastasis
• Prognosis
• Serum markers
• Tissue markers

Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose and provide prognostic information for pancreatic cancer. These markers can be used clinically to optimize and personalize therapy for individual patients. In this review, we focused on 3 biomarkers involved in the DNA damage response pathway and the necroptosis pathway: Chromodomain-helicase-DNA binding protein 5, chromodomain-helicase-DNA binding protein 7, and mixed lineage kinase domain-like protein. The aim of this article is to review present literature provided for these biomarkers and current studies in which their effectiveness as prognostic biomarkers are analyzed in order to determine their future use as biomarkers in clinical medicine. Based on the data presented, these biomarkers warrant further investigation, and should be validated in future studies.

• Chromodomain-helicase-DNA binding protein 5
• Chromodomain-helicase-DNA binding protein 7
• Mixed lineage kinase domain-like protein
• Pancreatic adenocarcinoma
• Biomarker

• R43 CA110535 NCI NIH HHS
• R44 CA110535 NCI NIH HHS
• UL1 TR000454 NCATS NIH HHS

AIM: SMAD4 immunohistochemistry is considered a valuable prognostic marker in colorectal cancer, but individual studies have often been small and the results variable. A meta-analysis could potentially clarify these findings. METHODS: In September 2014, a Pubmed and Google Scholar search was conducted to find publications that reported the prognostic value of SMAD4 expression. A meta-analysis was performed to clarify the association between SMAD4 expression and survival outcomes. RESULTS: 137 studies were found, of which 13 were considered eligible. The studies consisted of a total of 3800 patients. Three different endpoints were taken into account, namely, overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS). In addition, the studies were divided into univariate and multivariate analyses. The pooled hazard ratios were given as follows: univariate CSS = 1.75 [95% confidence interval (CI): 0.93-3.32; z= 1.69; P= .09]; multivariate CSS = 2.17 (95% CI: 1.56-3.01; z= 4.65; P= .000); univariate DFS = 2.11 (95% CI: 1.36-3.28; z= 3.32; P= .001); multivariate DFS = 2.15 (95% CI: 1.56-3.01; z= 4.65; P= .000); univariate OS and DFS = 2.30 (95% CI: 1.41-3.73; z= 3.36; P= .001); univariate OS = 2.28 (95% CI: 1.30-4.00; z= 2.89; P= .004). CONCLUSION: The results of the presented meta-analyses indicate that SMAD4 expression status using immunohistochemistry is a prognostic marker for patient survival.

Accumulating evidence indicates that Smad4 (DPC4) plays a fundamental role in the development and prognosis of several types of cancer. The objective of this study was to conduct a meta-analysis to evaluate whether the loss of Smad4 staining could serve as a prognostic marker.

A comprehensive meta-analysis was conducted using major useful databases to determine the relationship between the immunohistochemical detection of Smad4 and the survival of patients with various cancers. We used hazard ratios (HRs) with 95% confidence interval (CIs) as the effect estimation to evaluate the association of Smad4 with overall survival (OS), cancer-specific survival (CSS) or recurrence-free survival (RFS). The relationship between the clinical characteristics of patients and Smad4 was also evaluated using the odds ratio (OR).

A total of 7570 patients from 26 studies were included in the analysis. The pooled results showed that loss of Smad4 staining was a negative predictor of OS with an HR of 1.97 (95% CI: 1.55–2.51; P_{heterogeneity}<0.001) and CSS/RFS (HR = 1.81; 95% CI: 1.30–2.54; P_{heterogeneity}<0.001). In addition, loss of Smad4 staining was more likely to be found in older (OR = 1.69, 95% CI: 1.09–2.61; P_{heterogeneity} = 0.648) colorectal cancer patients with a late tumor stage (OR = 2.31, 95% CI: 1.71–3.10; P_{heterogeneity} = 0.218) and in gastric cancer patients with lymph node metastasis (OR = 2.11, 95% CI: 1.03–4.34; P_{heterogeneity} = 0.038).

Based on these results, our meta-analysis provided evidence that loss of Smad4 staining could act as an unfavorable biomarker in the prognosis of various cancers and should be used as a powerful tool in future clinical trials.

• Humans
• Immunohistochemistry
• Neoplasm Grading
• Neoplasm Metastasis
• Neoplasm Staging
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/mortality
• Neoplasms/pathology
• Odds Ratio
• Prognosis
• Publication Bias
• Smad4 Protein/genetics
• Smad4 Protein/metabolism

Multiplexed quantitation via isobaric chemical tags (e.g., tandem mass tags (TMT) and isobaric tags for relative and absolute quantitation (iTRAQ)) has the potential to revolutionize quantitative proteomics. However, until recently the utility of these tags was questionable due to reporter ion ratio distortion resulting from fragmentation of coisolated interfering species. These interfering signals can be negated through additional gas-phase manipulations (e.g., MS/MS/MS (MS3) and proton-transfer reactions (PTR)). These methods, however, have a significant sensitivity penalty. Using isolation waveforms with multiple frequency notches (i.e., synchronous precursor selection, SPS), we coisolated and cofragmented multiple MS2 fragment ions, thereby increasing the number of reporter ions in the MS3 spectrum 10-fold over the standard MS3 method (i.e., MultiNotch MS3). By increasing the reporter ion signals, this method improves the dynamic range of reporter ion quantitation, reduces reporter ion signal variance, and ultimately produces more high-quality quantitative measurements. To demonstrate utility, we analyzed biological triplicates of eight colon cancer cell lines using the MultiNotch MS3 method. Across all the replicates we quantified 8 378 proteins in union and 6 168 proteins in common. Taking into account that each of these quantified proteins contains eight distinct cell-line measurements, this data set encompasses 174 704 quantitative ratios each measured in triplicate across the biological replicates. Herein, we demonstrate that the MultiNotch MS3 method uniquely combines multiplexing capacity with quantitative sensitivity and accuracy, drastically increasing the informational value obtainable from proteomic experiments.

Colorectal cancers (CRCs) with a high level of microsatellite instability (MSI-H) are clinicopathologically distinct tumors characterized by predominance in females, proximal colonic localization, poor differentiation, mucinous histology, tumor-infiltrating lymphocytes, a Crohn’s-like lymphoid reaction and a favorable prognosis. In terms of their molecular features, MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations, including DNA mismatch repair deficiency, target microsatellite mutations, BRAF mutations, a CpG island methylator phenotype-high (CIMP-H) status, and a low level of genomic hypomethylation. The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences; for example, in Eastern Asian countries, relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries. Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy, there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs. Here, we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs, as well as several putative prognostic or predictive molecular markers, including HSP110 expression, beta2-microglobulin mutations, myosin 1a expression, CDX2/CK20 expression, SMAD4 expression, CIMP status and LINE-1 methylation levels.

• Colorectal cancer
• Microsatellite instability
• DNA mismatch repair
• DNA methylation
• CpG islands
• Prognosis
• Adjuvant chemotherapy

• CDX2 Transcription Factor
• Cell Differentiation
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• CpG Islands
• DNA Methylation
• DNA Repair
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Germ-Line Mutation
• Homeodomain Proteins/metabolism
• Humans
• Long Interspersed Nucleotide Elements/genetics
• Microsatellite Instability
• Microsatellite Repeats/genetics
• Mutation
• Phenotype
• Prognosis
• Proto-Oncogene Proteins/metabolism
• Proto-Oncogene Proteins B-raf/metabolism
• Proto-Oncogene Proteins p21(ras)
• Smad4 Protein/metabolism
• Treatment Outcome
• ras Proteins/metabolism

• ERK pathway
• Smad4
• TGF-β
• colorectal cancer
• metastasis

Cancer is a disease that results from both genetic and epigenetic changes. In recent decades, a number of people have investigated the disparities in gene expression resulting from variable DNA methylation alteration and chromatin structure modification in response to the environment. Especially, colon cancer is a great model system for investigating the epigenetic mechanism for aberrant gene expression alteration. Ionizing radiation (IR) could affect a variety of processes within exposed cells and, in particular, cause changes in gene expression, disruption of cell cycle arrest, and apoptotic cell death. Even though there is growing evidence on the importance of epigenetics and biological processes induced by radiation exposure in various cancer types including colon cancer, specific epigenetic alterations induced by radiation at the molecular level are incompletely defined. This review focuses on discussing possible IR-mediated changes of DNA methylation and histone modification in cancer.

• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Female
• Humans
• Kaplan-Meier Estimate
• Leukoplakia, Oral/metabolism
• Leukoplakia, Oral/pathology
• Male
• Middle Aged
• Proportional Hazards Models
• Risk Factors
• Smad4 Protein/metabolism