Prevalence and Spectrum of Predisposition Genes With Germline Mutations Among Chinese Patients With Bowel Cancer

Abstract

Background: Bowel cancer is the third-most common cancer and the second leading cause of cancer-related death worldwide. Bowel cancer has a substantial hereditary component; however, additional hereditary risk factors involved in bowel cancer pathogenesis have not been systematically defined.Materials and Methods: A total of 573 patients with bowel cancer were enrolled in the present study, of whom 93.72% had colorectal cancer (CRC). Germline mutations were integrated with somatic mutation information via utilizing target next-generation sequencing.Results: Pathogenic/Likely Pathogenic (P/LP) germline alterations were identified in 47 (8.2%) patients with bowel cancer and the ratio of the number of these patients with family history was significantly higher in the P/LP group than that noted in the non-pathogenic (Non-P) group. Certain rare germline alterations were noted, such as those noted in the following genes: FANCD2, CDH1, and FLCN. A total of 32 patients (68.1%) had germline alterations in the DNA-damage repair (DDR) genes and homologous recombination (HR) accounted for the highest proportion of this subgroup. By comparing 573 patients with bowel cancer with reference controls (China_MAPs database), significant associations (p < 0.01) were observed between the incidence of bowel cancer and the presence of mutations in APC, ATM, MLH1, FANCD2, MSH3, MSH6, PMS1, and RAD51D. Somatic gene differential analysis revealed a marked difference in 18 genes and a significant difference was also noted in tumor mutation burden (TMB) between germline mutation carriers and non-germline mutation subjects (p < 0.001). In addition, TMB in DDR mutation groups indicated a dramatic difference compared with the non-DDR mutation group (p < 0.01). However, no statistically significant differences in TMB were noted among detailed DDR pathways for patients with bowel cancer, irrespective of the presence of germline mutations. Moreover, a significantly higher level (p < 0.0001) of mutation count was observed in the DDR group from The Cancer Genome Atlas (TCGA) database and the DDR and non-DDR alteration groups displayed various immune profiles.Conclusion: Chinese patients with bowel cancer exhibited a distinct spectrum of germline variants, with distinct molecular characteristics such as TMB and DDR. Furthermore, the information on somatic mutations obtained from TCGA database indicated that a deeper understanding of the interactions among DDR and immune cells would be useful to further investigate the role of DDR in bowel cancer.

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“…They serve as negative prognostic factors for carcinogenesis and anti-EGFR therapy [53] because intracellular signal interruption leads to uncontrolled cellular proliferation and cancer. MSH3 mutations have been mainly linked to endometrial cancer, but there are reports of its relationship with inflammatory processes, such as ulcerative colitis and Crohn's disease, which considerably increase the likelihood of CRC development [54,55]. MSH3-associated CRC seems to follow the classic APC pathway, as patients with adenomas and CRC carrying APC mutations showed MSH3 deficiency [56], as confirmed in this study.…”