A collaborative research team from the Hefei Institutes of Physical Science of the Chinese Academy of Sciences and the Second Hospital of Anhui Medical University has, for the first time, dissected the somatic mutation profile of familial colorectal cancer with coinheritance of mutations in both APC and MLH1 genes.

The results were published in Genes & Diseases.

Inherited mutations in cancer susceptibility genes account for about 10% of all cases of colorectal cancer. Germline mutations in the APC gene and the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) cause the most frequent forms of hereditary colorectal cancer, familial adenomatous polyposis and Lynch syndrome, respectively. It is highly unusual for simultaneous mutations in both the APC and mismatch repair genes to cause hereditary colorectal cancer.

In this study, the researchers used whole exome sequencing to identify germline mutations in both the APC and MLH1 genes in a 20-year-old patient with colorectal cancer and multiple polyposis. They investigated the nature of the somatic mutations present in the patient's colorectal cancer. The significant mutation rates of C-T transitions and 5+ base InDels predominated in the patient's colorectal tumor, indicating a high somatic mutation burden.

In addition, the single-nucleotide substitution mutational signature in the patient's colorectal tumor showed correlation with increasing age at cancer diagnosis.

This study is the first to report the somatic mutational profile of a colorectal tumor with concurrent APC and MLH1 germline mutations. The simultaneous germline mutations in APC and MLH1 genes may accelerate the genome instability, thereby promoting early tumor onset and rapid tumor progression.

The pedigree of the studied family, and hematoxylin-eosin staining of colorectal adenocarcinoma or adenomas in all patients. (Image by CHENG Yunsheng)