Genome‐wide study of genetic polymorphisms predictive for outcome from first‐line oxaliplatin‐based chemotherapy in colorectal cancer patients

Abstract

We conducted the first large genome‐wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first‐line oxaliplatin‐based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population‐based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression‐free survival. The analysis was performed for studies individually, and the results were combined using fixed‐effect meta‐analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene‐based analysis as well as in silico bioinformatics analysis for CRC‐relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin‐based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10−8). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10−7). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene‐based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10−6). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first‐line treatment and improve clinical outcomes.

An SNP Marker Predicts Colorectal Cancer Outcomes with 5-Fluorouracil-Based Adjuvant Chemotherapy Post-Resection

“…Numerous studies have illuminated various genetic variations associated with the therapeutic effectiveness in CRC, offering insights into potential genetic biomarkers relevant to CRC treatment. These include therapies targeting epithelial growth factor receptor (EGFR) [ 9 , 10 ], immunotherapies [ 11 ], and chemotherapy regimens involving agents such as 5-FU [ 12 , 13 , 14 , 15 ] and oxaliplatin [ 16 , 17 , 18 , 19 ]. Notably, a comprehensive genome-wide association study (GWAS) has revealed single nucleotide polymorphism (SNP) biomarkers that may predict the clinical outcomes of both intermediate and advanced CRC patients undergoing oxaliplatin-based adjuvant chemotherapy [ 19 ].…”

“…These include therapies targeting epithelial growth factor receptor (EGFR) [ 9 , 10 ], immunotherapies [ 11 ], and chemotherapy regimens involving agents such as 5-FU [ 12 , 13 , 14 , 15 ] and oxaliplatin [ 16 , 17 , 18 , 19 ]. Notably, a comprehensive genome-wide association study (GWAS) has revealed single nucleotide polymorphism (SNP) biomarkers that may predict the clinical outcomes of both intermediate and advanced CRC patients undergoing oxaliplatin-based adjuvant chemotherapy [ 19 ]. However, a comprehensive study, especially in the context of a GWAS, investigating 5-FU-based adjuvant therapy, is currently lacking.…”