Molecular mutation characteristics of mismatch and homologous recombination repair genes in gastrointestinal cancer

Gastrointestinal cancer is one of the most common types of cancer with high mortality rates. Mutations in several genes are reportedly involved in the progression of gastrointestinal cancer, including tumor protein 53 (TP53), APC regulator of WNT signaling pathway (APC), KRAS proto-oncogene GTPase (KRAS) and erb-b2 receptor tyrosine kinase 2 (ERBB2). Most notably, there are numerous mutations in DNA repair genes, including mismatch repair (MMR) and homologous recombination (HR) genes. The focus of the present study was to investigate the effects of MMR and HR gene mutations on genomic instability in gastrointestinal cancer. Using targeted capture and massively parallel genomic sequencing, 137 gastrointestinal cancer patients were analyzed for somatic single-nucleotide variants (SNVs) and insertion-deletion (indel) mutations in the exon regions of 183 cancer driver genes, including 4 MMR genes [MutL homolog MLH1, MLH2, MLH6 and PMS1 homolog 2, mismatch repair system component (PMS2)] and 15 HR genes [BRCA1 DNA repair associated (BRCA1), BRCA2 DNA repair associated (BRCA2), ATM serine/threonine kinase (ATM), phosphatase and tensin homolog, BLM RecQ like helicase, FA complementation group A, FA complementation group C, FA complementation group D2, FA complementation group E, FA complementation group F, FA complementation group G, nibrin, partner and localizer of BRCA2 and Werner syndrome RecQ like helicase]. A number of frequently mutated genes, including but not limited to, mechanistic target of rapamycin kinase, neurofibromin 1, APC and, in particular, DNA repair genes, including PMS2, ATM and BRCA2, were identified. Frequency analysis was performed based on the SNVs and indels in the 183 genes to indirectly indicate the relative status of genomic instability in each patient. Correlation analysis suggested that MMR and HR gene mutations directly affected the count of SNVs and indels. Overall, 56 of the gastrointestinal cancer patients (40%) were found to have an inactivation mutation (stopgain/frameshift/splicing) in one or more of the four MMR genes, whereas 112 patients (82%) harbored at least one HR gene inactivation mutation. In addition, patients with MMR or HR inactivation variants had more SNVs and indels compared with patients with no such mutations. No other clinical characteristics (including sex and age) appeared to have a statistically significant impact. Further analysis indicated that different MMR or HR genes exerted distinct effects on genomic instability. The results obtained in the current study may lay a foundation for investigations into the tumorigenic process and for the development of novel therapeutic strategies for the treatment of gastrointestinal cancer.