Dataset Information

DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility.

ABSTRACT: Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5?×?10^-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7?×?10^-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8?×?10^-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

SUBMITTER: Pardini B

PROVIDER: S-EPMC7301215 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility.

Pardini Barbara B Corrado Alda A Paolicchi Elisa E Cugliari Giovanni G Berndt Sonja I SI Bezieau Stephane S Bien Stephanie A SA Brenner Hermann H Caan Bette J BJ Campbell Peter T PT Casey Graham G Chan Andrew T AT Chang-Claude Jenny J Cotterchio Michelle M Gala Manish M Gallinger Steven J SJ Haile Robert W RW Harrison Tabitha A TA Hayes Richard B RB Hoffmeister Michael M Hopper John L JL Hsu Li L Huyghe Jeroen J Jenkins Mark A MA Le Marchand Loic L Lin Yi Y Lindor Noralane M NM Nan Hongmei H Newcomb Polly A PA Ogino Shuji S Potter John D JD Schoen Robert E RE Slattery Martha L ML White Emily E Vodickova Ludmila L Vymetalkova Veronika V Vodicka Pavel P Gemignani Federica F Peters Ulrike U Naccarati Alessio A Landi Stefano S

International journal of cancer 20190704 2

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2 ...[more]

PMID: 31209889

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Project description:Backgrounds: Colorectal cancer (CRC) with high incidence, has the third highest mortality of tumors. DNA damage and repair influence a variety of tumors. However, the role of these genes in colon cancer prognosis has been less systematically investigated. Here, we aim to establish a corresponding prognostic signature providing new therapeutic opportunities for CRC. Method: After related genes were collected from GSEA, univariate Cox regression was performed to evaluate each gene's prognostic relevance through the TCGA-COAD dataset. Stepwise COX regression was used to establish a risk prediction model through the training sets randomly separated from the TCGA cohort and validated in the remaining testing sets and two GEO datasets (GSE17538 and GSE38832). A 12-DNA-damage-and-repair-related gene-based signature able to classify COAD patients into high and low-risk groups was developed. The predictive ability of the risk model or nomogram were evaluated by different bioinformatics- methods. Gene functional enrichment analysis was performed to analyze the co-expressed genes of the risk-based genes. Result: A 12-gene based prognostic signature established within 160 significant survival-related genes from DNA damage and repair related gene sets performed well with an AUC of ROC 0.80 for 5 years in the TCGA-CODA dataset. The signature includes CCNB3, ISY1, CDC25C, SMC1B, MC1R, LSP1P4, RIN2, TPM1, ELL3, POLG, CD36, and NEK4. Kaplan-Meier survival curves showed that the prognosis of the risk status owns more significant differences than T, M, N, and stage prognostic parameters. A nomogram was constructed by LASSO regression analysis with T, M, N, age, and risk as prognostic parameters. ROC curve, C-index, Calibration analysis, and Decision Curve Analysis showed the risk module and nomogram performed best in years 1, 3, and 5. KEGG, GO, and GSEA enrichment analyses suggest the risk involved in a variety of important biological processes and well-known cancer-related pathways. These differences may be the key factors affecting the final prognosis. Conclusion: The established gene signature for CRC prognosis provides a new molecular tool for clinical evaluation of prognosis, individualized diagnosis, and treatment. Therapies based on targeted DNA damage and repair mechanisms may formulate more sensitive and potential chemotherapy regimens, thereby expanding treatment options and potentially improving the clinical outcome of CRC patients.

Dataset Information

DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility.

Publications

DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility.

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