Skip to main content
Premium Trial:

Request an Annual Quote

Hereditary Colorectal Cancer Syndrome Caused by Recessive Mutations in Mismatch Repair Gene

NEW YORK (GenomeWeb) – A new study suggests mutations affecting both copies of the mismatch repair gene MSH3 can produce a recessive form of colorectal adenomatous polyposis — a condition marked by rampant, benign polyps that, if left untreated, may morph into colorectal cancer.

A team led by researchers at the University of Bonn in Germany carried out exome sequencing on more than 100 unrelated individuals with unexplained colorectal adenomatous polyposis. As the group reported online this week in the American Journal of Human Genetics, the search led to distinct compound heterozygous loss-of-function MSH3 germline changes in two colorectal adenomatous polyposis patients.

From these findings and analyses of MSH3 expression, the team concluded that recessively inherited mutations in this DNA repair gene can be added to the growing list of colorectal polyp-producing mutations that increase colorectal cancer risk — information that may help identify individuals in colorectal adenomatous polyposis-prone families for enhanced screening and disease surveillance.

"[S]iblings have a 25 percent chance of developing the disease; however, the parents and children of affected persons only have a very low risk of developing the disease," co-first author Isabel Spier, a human genetics researcher at the University of Bonn, said in a statement, explaining that "[o]nly proven carriers would need to take part in the intensive surveillance program."

Although past studies have unearthed colorectal adenomatous polyposis-causing changes to genes such as APC, MUTYH, POLE, POLD1, and NTHL1, the team explained, nearly one third of families affected by the condition carry no germline changes in those genes.

In particular, the study's authors noted that the "identification of further genetic causes will extend the knowledge of disease mechanisms, biological pathways, and potential therapeutic targets."

With Roche NimbleGen human exome arrays, the researchers captured protein-coding portions of the genome in samples from 102 unrelated colorectal adenomatous polyposis patients who did not have germline mutations in known risk genes. They then sequenced the exomes to a mean depth of 56-fold using the Illumina HiSeq 2000 and aligned the resulting reads to version 19 of the human reference genome.

Mutations in MSH3 came into focus when the team analyzed the data with an eye toward rare, recessive variants expected to forestall formation of functional gene products. Two of the sequenced individuals had distinct loss-of-function and compound heterozygous mutations in the gene — mutations that were identical in samples from the individuals' affected siblings. Along with polyposis, the four individuals had been affected by colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and early-onset astrocytoma.

When the researchers took a closer look at tumors that formed in individuals with colorectal adenomatous polyposis and biallelic MSH3 germline mutations, they found that the MSH3 protein was missing from the nuclei of cells, where it normally participates in the mismatch repair pathway. Its absence is believed to at least partly explain the microsatellite instability detected in the tumors.

A potential role for the mismatch repair pathway in colorectal adenomatous polyposis and colorectal cancer risk was bolstered by the discovery of biallelic mutations affecting another mismatch repair gene, PMS2, in the germline of a third sequenced patient. That individual had experienced colorectal polyposis at a young age, along with adenoma, a neuroectodermal tumor, and other symptoms.

In addition, the researchers found potentially causative variants in 14 more candidate genes, identified from 26 individuals, which they noted require "exploration in larger cohorts and via functional analysis."