Investigating Genetic Risk to Oxaliplatin-Induced Sinusoidal Obstruction Syndrome in Colorectal Cancer Through Routinely Available Next-Generation Sequencing Data.

Sinusoidal obstruction syndrome (SOS) is a known adverse effect of oxaliplatin, causing significant morbidity and cessation of chemotherapy. Recent studies suggest single-nucleotide polymorphisms of certain genes may predispose carriers to oxaliplatin-induced liver toxicity. This study aims to evaluate candidate SOS-predisposing single-nucleotide polymorphisms by correlating routinely available next-generation sequencing (NGS) data with clinical and histologic evidence of SOS. Seventy-nine colorectal cancer cases with liver metastases and clinical NGS data were identified. A combination of clinical, biochemical, and histologic criteria was used to identify 12 cases with confirmed SOS. In addition, 10 control cases were selected with no clinical or histologic evidence of SOS. Clinical data and SOS-related findings were collected. For each patient, the expanded panel NGS data obtained for clinical management were reanalyzed to assess 12 polymorphisms in ERCC1, ERCC2, ABCB1, GSTP1, DPYD, MTHFR, ABCC2, UGT1A1, GSTT1, and GSTM1 known to be associated with oxaliplatin toxicity, as identified in the PharmGKB database. Statistical analyses, including the Fisher exact test and odds ratios, were performed. The strongest nominal signal was observed in the prevalence of ERCC1 rs11615 (A>G) in SOS and control groups (allelic P = .006; false discovery rate q = 0.072). The odds ratio for developing SOS associated with rs11615 (A>G) was 0.15 (95% CI: 0.04-0.59), indicating a protective effect of ERCC1 rs11615 (A>G). There was a noticeable numerical increase in ascites frequency, levels of aspartate aminotransferase and alanine aminotransferase, and the frequency of neuropathy in the SOS group, although not statistically significant. These findings highlight the use of expanded analysis of routinely obtained NGS panel results at the time of colorectal cancer diagnosis at many medical centers to personalize the chemotherapy regimen. Our data suggest that patients who carry the ERCC1 rs11615 (A>G) variant may be protected from developing oxaliplatin-induced SOS, and those lacking the G allele should be monitored more carefully after oxaliplatin use.