Title: Genomic Analysis of Germline Variation Associated with Survival of Patients with Colorectal Cancer Treated with Chemotherapy Plus Biologics in CALGB/SWOG 80405 (Alliance).
Authors: Innocenti, Federico; Sibley, Alexander B; Patil, Sushant A; Etheridge, Amy S; Jiang, Chen; Ou, Fang-Shu; Howell, Stefanie D; Plummer, Sarah J; Casey, Graham; Bertagnolli, Monica M; McLeod, Howard L; Auman, James T; Blanke, Charles D; Furukawa, Yoichi; Venook, Alan P; Kubo, Michiaki; Lenz, Heinz-Josef; Parker, Joel S; Ratain, Mark J; Owzar, Kouros
Published In Clin Cancer Res, (2021 01 01)
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.
PubMed ID:
32958699
MeSH Terms: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols/pharmacology; Antineoplastic Combined Chemotherapy Protocols/therapeutic use*; Bevacizumab/pharmacology; Bevacizumab/therapeutic use; Biological Products/pharmacology; Biological Products/therapeutic use*; Camptothecin/analogs & derivatives*; Camptothecin/pharmacology; Camptothecin/therapeutic use; Cetuximab/pharmacology; Cetuximab/therapeutic use; Colorectal Neoplasms/drug therapy; Colorectal Neoplasms/genetics; Colorectal Neoplasms/mortality*; Drug Resistance, Neoplasm/genetics*; Female; Fluorouracil/pharmacology; Fluorouracil/therapeutic use; Genome-Wide Association Study; Humans; Leucovorin/pharmacology; Leucovorin/therapeutic use; Male; Middle Aged; Organoplatinum Compounds/pharmacology; Organoplatinum Compounds/therapeutic use; Polymorphism, Single Nucleotide; Risk Assessment/methods; Young Adult