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Study Supports Sequencing Potential for Finding Familial Colorectal Cancer Mutations

NEW YORK (GenomeWeb) – Exome sequencing appears to hold promise for uncovering colorectal cancer culprits in individuals with a family history of the disease, though risk mutations remain to be found in many of those with familial forms of the disease, according to a study appearing online last night in the Journal of Clinical Oncology. 

Researchers from the Institute of Cancer Research did targeted sequencing on several genes with ties to bowel cancer — along with two potential risk genes called POLE and POLD1 that were identified more recently — using samples from 626 individuals with early onset, familial colorectal cancer.

Consistent with past results, the team found that mutations in mismatch repair genes such as MLH1, MSH2, MSH6, and PMS2 were relatively common, turning up in more than one-tenth of those tested. Another 3.3 percent of patients carried mutations in other risk genes, including APC, MUTYH, SMAD4, and BMPR1A, while a few more individuals had germline mutations involving POLE or POLD1.

"Our study has found that using just existing tests for known cancer genes, we could identify the genetic causes of familial bowel cancer in perhaps as many as a quarter of cases," senior author Richard Houston, a genetics and epidemiology researcher at the Institute of Cancer Research, said in a statement, arguing that is it "vital that we improve access to genetic testing for cancer patients and their relatives so as many as possible can have a genetic diagnosis."

"Of course, we are still left with three-quarters of patients where no genetic cause could be identified," Houston added, "and that underlines the need for further research to identify new cancer genes."

Although the complete collection of genetic glitches that can cause colorectal cancer have yet to be fully untangled, mutations in at least 10 different genes have been implicated in inherited forms of the disease, which tend to be diagnosed in individuals when they are relatively young.

Familial forms of colorectal cancer fall into several syndromes, they added, which can be identified with the help of genetic testing to pinpoint individuals apt to benefit from more-frequent-than-usual colonoscopy screens and so on.

Along with diagnostic clues, the nature of the gene mutations contributing to early onset, familial colorectal cancer may also help in predicting patient outcomes and treatment response, the team noted. And that has prompted interest in a more comprehensive understanding of the high-penetrance mutations that can lead to colorectal cancer — and their relative contributions to familial cases.

For their current study, Houston and colleagues used the Illumina HiSeq 2000 to do paired end sequencing on protein-coding genes captured from germline DNA of 626 colorectal cancer patients, focusing on mutations and/or copy number changes affecting mismatch repair genes and other known or suspected colorectal cancer-related genes.

Not surprisingly, given the oft-described role of mismatch repair genes in inherited colorectal cancer risk, the team tracked down colorectal cancer-related MMR gene mutations in 68 of the individuals — almost 11 percent of those tested. Of those, 46 individuals had family histories that fit the criteria used for a syndrome known as hereditary non-polyposis colorectal cancer.

Dozens more individuals carried MMR gene alterations of unknown significance, though at least some showed signs of possible pathogenesis.

The researchers also found 10 individuals with germline mutations in the APC gene, including five APC glitches deemed risky for colorectal cancer by the International Society for Gastrointestinal Hereditary Tumors Incorporated classification panel. Still more individuals carried mutations in APC that may or may not interfere with the function of the resulting protein, they noted.

Likewise, the team uncovered both new and known mutations in other established risk genes such as MUTYH, SMAD4, and BMPR1A, and in the more recently described colorectal cancer candidate genes POLE and POLD1. 

All told, the researchers could account for almost 13 percent of the familial colorectal cancer cases by focusing on mutations that have already been defined as pathogenic in the disease. Even so, they argued that including mutations with more tenuous ties to colorectal cancer risk syndromes could explain as many as one-quarter of the inherited cases.

Just over three-quarters of the individuals tested did not carry high-penetrance mutations in the genes that have been linked to cancer. Those cases tended to include individuals who were older at the time of their diagnoses, the study's authors noted, and additional research is needed to search for germline mutations in yet-undetected risk genes in this group of patients.

Nevertheless, they argued that the findings point to the possibility of applying high-throughput sequencing more widely in testing for colorectal cancer-related gene mutations.

"The advent of [next-generation sequencing] affords an opportunity to rapidly screen patients for a comprehensive panel of [colorectal cancer] genes in a cost-effective fashion," they wrote, "and thus allow those at increased risk of [colorectal cancer] to be readily identified allowing better targeting of surveillance and treatment."