Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Abstract

In around 30% of families with colorectal adenomatous polyposis, no germline mutation in the previously-implicated genes APC, MUTYH, POLE, POLD1, or NTHL1 can be identified, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis was performed. We identified two unrelated individuals with differing compound-heterozygous loss-of-function germline mutations in the mismatch repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1g>a, c.2760delC, c.3001-2a>c) was indicated on RNA and protein level. Analysis of the diseased individuals’ tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST) and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the loss-of-function effect and causal relevance of the mutations. The pedigrees, genotypes, and the frequency of MSH3 mutations in the general population are consistent with an autosomal recessive mode of inheritance. Both index persons had an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing Constitutional Mismatch Repair Deficiency Syndrome (CMMRD). Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study we describe biallelic germline mutations of MSH3 in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…Biallelic MSH3 mutations have also been identified as predisposing to MSI CRC, however this occurs in longer repeats than is currently investigated by conventional MSI testing. However, the increasing use of NGS may eventually preclude this issue (Adam et al, 2016).…”

“…For example NGS approaches has helped identify suspected LLS patients that actually have Lynch syndrome, as some tumours may be due to constitutional mutations in DNA MMR genes that are not detectable by standard testing (Rodriguez-Soler et al, 2013). NGS testing has also identified somatic mutations coupled with LOH (Geurts-Giele et al, 2014;Haraldsdottir et al, 2014;Kang et al, 2015;Rodriguez-Soler et al, 2013;Sourrouille et al, 2013) and constitutional mutations in additional genes as causes of dMMR (Adam et al, 2016;Castillejo et al, 2014;Cohen et al, 2016;Haraldsdottir et al, 2014;Palles et al, 2013;Segui et al, 2015;Syngal et al, 2015;Weren et al, 2015).…”

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017

“…36 Recent data have suggested that biallelic MSH3 germline mutations are a recessive subtype of colorectal adenomatous polyposis. 37 During the 2017 NCCN Guidelines update, MSH3 was added to a list of genes commonly included on multigene panels (see GENE-5; page 1468). However, given available data, the panel agreed that the strength of evidence linking MSH3 to increased CRC risk is not currently well established.…”

Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood

“…These include bone and soft-tissue sarcomas, genitourinary cancer, and other cancers occurring more frequently from the latter part of the first decade of life. Second is the encouraging data from the implementation of WBMRI in patients with Li-Fraumeni syndrome (3,25) and the high feasibility of the tool in children who do not require anesthesia, which give strong consideration for its use in CMMRD. The current suggestion is to implement WBMRI once a year at 6 year of age or when anesthesia is not needed.…”