Abstract
The spectrum of somatic genetic variation in colorectal adenomas caused by biallelic pathogenic germline variants in the MSH3 gene, was comprehensively analysed to characterise mutational signatures and identify potential driver genes and pathways of MSH3-related tumourigenesis. Three patients from two families with MSH3-associated polyposis were included. Whole exome sequencing of nine adenomas and matched normal tissue was performed. The amount of somatic variants in the MSH3-deficient adenomas and the pattern of single nucleotide variants (SNVs) was similar to sporadic adenomas, whereas the fraction of small insertions/deletions (indels) (21–42% of all small variants) was significantly higher. Interestingly, pathogenic somatic APC variants were found in all but one adenoma. The vast majority (12/13) of these were di-, tetra-, or penta-base pair (bp) deletions. The fraction of APC indels was significantly higher than that reported in patients with familial adenomatous polyposis (FAP) (p < 0.01) or in sporadic adenomas (p < 0.0001). In MSH3-deficient adenomas, the occurrence of APC indels in a repetitive sequence context was significantly higher than in FAP patients (p < 0.01). In addition, the MSH3-deficient adenomas harboured one to five (recurrent) somatic variants in 13 established or candidate driver genes for early colorectal carcinogenesis, including ACVR2A and ARID genes. Our data suggest that MSH3-related colorectal carcinogenesis seems to follow the classical APC-driven pathway. In line with the specific function of MSH3 in the mismatch repair (MMR) system, we identified a characteristic APC mutational pattern in MSH3-deficient adenomas, and confirmed further driver genes for colorectal tumourigenesis.
Highlights
3–5% of all colorectal cancer (CRC) cases arise secondary to monogenic inherited tumour predisposition syndromes
The first is autosomal dominant familial adenomatous polyposis (FAP, OMIM #175100), which is caused by heterozygous germline variants in the tumour-suppressor gene and Wnt signalling pathway regulator APC [3, 4].The second is autosomal recessive MUTYHassociated polyposis (MAP, OMIM #608456), which is caused by biallelic germline variants in the base-excision-repair gene MUTYH [5]
These include autosomal dominant Polymerase Proofreading associated polyposis (PPAP), which is caused by specific germline missense variants in the proofreading domain of the polymerase genes POLE or POLD1 [6, 7] and autosomal recessive NTHL1-associated polyposis (NAP), which is caused by biallelic germline variants in the base-excision-repair gene NTHL1 [8, 9]
Summary
3–5% of all colorectal cancer (CRC) cases arise secondary to monogenic inherited tumour predisposition syndromes These comprise Lynch syndrome (hereditary colon cancer without polyposis; HNPCC; OMIM # 120435), which is caused by heterozygous germline variants in the EPCAM gene or in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) and represents the most common type, and several gastrointestinal polyposis syndromes [1, 2]. The introduction of whole exome sequencing (WES) approaches has enabled the identification of further disease subtypes These include autosomal dominant Polymerase Proofreading associated polyposis (PPAP), which is caused by specific germline missense variants in the proofreading domain of the polymerase genes POLE or POLD1 [6, 7] and autosomal recessive NTHL1-associated polyposis (NAP), which is caused by biallelic germline variants in the base-excision-repair gene NTHL1 [8, 9]
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