Association of MLH1 single nucleotide polymorphisms with clinical outcomes of first-line irinotecan-based chemotherapy in colorectal cancer

Abstract

Purpose: Several studies have proved that single nucleotide polymorphisms (SNPs) of mismatch repair system genes are closely related to the development of colorectal cancer (CRC) by causing microsatellite instability, while effects of the SNPs of MMR system-related genes on the clinical outcomes of cytotoxic chemotherapy are less understood. The aim of this study explored the influence of MLH1 SNPs on clinical outcomes of first-line irinotecan-based chemotherapy in CRC. Patients and methods: A total of 125 metastatic colorectal cancer (mCRC) patients who received first-line irinotecan-based chemotherapy (none of them combined with bevacizumab or cetuximab) were enrolled in this study. Blood samples or formalin-fixed paraffin-embedded tissues of study population were taken. DNA isolation and genotyping analyzed were obtained for potential functional polymorphisms of MLH1 rs1800734 by real-time PCR. Progression-free survival (PFS) was the primary endpoint and tumor response rate (RR) was the secondary endpoint of this study. Results: Of all the assessable population, the result showed no statistical difference among the three types SNPs of MLH1 rs1800734 (AA, AG, GG) for RR (P=0.859), and also without significant difference for AA + AG combined variants vs GG variant (P=0.849). The median PFS for AA, AG, and GG variants of MLH1 rs1800734 SNPs were 9.4 months, 7.0 months, and 6.9 months, respectively (log-rank P=0.031). Interestingly, compared with AA variant of MLH1 rs1800734 SNPs, GG variant showed a shorter PFS (HR: 3.49; 95 CI: 1.02–11.94; P=0.046). Furthermore, the median PFS of AA + AG combined variants and GG variant were 8.3 months and 6.9 months (log-rank P=0.037), and GG variant have a decreased trend with no significant difference (HR: 1.57; 95 CI: 0.98–2.53; P=0.061). Conclusion: The AA variant of MLH1 rs1800734 SNPs has a longer PFS in first-line irinotecan-based chemotherapy for mCRC patients, and the result needs to be further confirmed by prospective studies in the future.