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Genomic Analysis of Germline Variation Associated with Survival of Patients with Colorectal Cancer Treated with Chemotherapy Plus Biologics in CALGB/SWOG 80405 (Alliance).

Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. innocent@unc.edu. Duke Cancer Institute, Duke University, Durham, North Carolina. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Alliance Statistics and Data Management Center, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia. Division of Surgical Oncology, Department of Surgery, Brigham & Women's Hospital, Boston, Massachusetts. Taneja College of Pharmacy, University of South Florida, Tampa, Florida. UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Clinical Genome Research, Institute of Medical Science, the University of Tokyo, Tokyo, Japan. Department of Medicine, University of California at San Francisco, San Francisco, California. Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Department of Medicine, University of Chicago, Chicago, Illinois. Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(1):267-275
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Abstract

PURPOSE Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405. EXPERIMENTAL DESIGN Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for approximately 700,000 SNPs. The association between SNPs and overall survival (OS) was tested in 613 patients of genetically estimated European ancestry using Cox proportional hazards models. RESULTS The four most significant SNPs associated with OS were three haplotypic SNPs between microsomal glutathione S-transferase 1 (MGST1) and LIM domain only 3 (LMO3, representative HR, 1.56; P = 1.30 × 10-6), and rs11644916 in AXIN1 (HR, 1.39, P = 4.26 × 10-6). AXIN1 is a well-established tumor suppressor gene in colorectal cancer, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG, or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 patients with stage IV colorectal cancer from The Cancer Genome Atlas (TCGA), rs11649255 in AXIN1 [in almost complete linkage disequilibrium (LD) with rs11644916], was associated with shorter OS (HR, 2.24, P = 0.0096). Using rs11648673 in AXIN1 (in very high LD with rs11644916 and with functional evidence), luciferase activity in three colorectal cancer cell lines was reduced. CONCLUSIONS This is the first large genome-wide association study ever conducted in patients with mCRC treated with first-line standard treatment in a randomized phase III trial. A common SNP in AXIN1 conferred worse OS and the effect was replicated in TCGA. Further studies in colorectal cancer experimental models are required.

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