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Studies Expand List of High- and Low-Penetrance Variants Implicated in Colorectal Cancer

NEW YORK (GenomeWeb News) – A pair of studies online this week in Nature Genetics are providing information on new genetic factors that bump up colorectal cancer risk to varying degrees.

In the first of these, members of the Colorectal Tumor Gene Identification, or CORGI, consortium, the Oxford-Illumina 500 Whole-Genome Sequences, or WGS500, consortium, and others searched for high-penetrance risk factors among individuals with early onset colorectal cancer or related polyp conditions predisposing them to the disease.

Through whole-genome sequencing on 20 individuals deemed to be at high risk of colorectal cancer based on their clinical and/or family history — coupled with additional linkage and functional analyses — the team detected colorectal cancer-related mutations affecting the DNA polymerase epsilon- and delta-coding genes POLE and POLD1.

"The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases [epsilon] and [delta] and are predicted to cause a defect in the correction of mis-paired bases inserted during DNA replication," Wellcome Trust Centre for Human Genetics researcher Ian Tomlinson, the study's corresponding author, and colleagues wrote.

Their follow-up analyses suggested that individuals carrying such mutations tend to develop tumors with rampant mutations, but with microsatellite stability, perhaps owing to defective mismatch repair by the altered polymerase enzymes during DNA replication.

Meanwhile, a large group of investigators from China, the US, Japan, Korea, and elsewhere performed a multistage genome-wide association study involving thousands of individuals from China, Japan, and Korea to track down four new SNPs contributing to more moderate increases in colorectal cancer risk in East Asian populations.

Three of the four variants — located on chromosomes 5, 12, and 20 — seem to influence colorectal cancer risk in Europeans, too, based on researchers' analyses of existing case and control data for tens of thousands of Europeans.

"Looking at different ethnic groups is important because the genetic structures can be different enough that variants identified in one population do not explain risk in other populations," that study's co-senior author Wei Zheng, from Vanderbilt University, said in a statement.

"Because of the difference in genetic structures and underlying environment exposures," he added, "it might be easier to discover some risk variants in studies conducted in non-European populations."

Previous studies have uncovered several common SNPs that each seem to dial up colorectal cancer risk slightly in Europeans. And a handful of genes have been implicated as players in highly penetrant Mendelian syndromes such as Lynch syndrome that carry a propensity for colorectal cancer and/or the development of colorectal adenomas — benign polyps that sometimes morph into colon cancer.

In an effort to find new genes at the more highly penetrant end of the colon cancer risk spectrum, authors of the first study started by sequencing the genomes of 20 individuals: 15 individuals enrolled through the Oxford-Illumina WGS500 effort who had had 10 or more colorectal adenomas by their 60th birthdays and five of their adenoma-prone relatives.

Eight of the 20 individuals sequenced had been diagnosed with colorectal cancer at the time of the study, researchers noted, but none were known to carry mutations affecting Mendelian colon cancer syndrome genes.

Using the genome sequence data as well as family linkage data for some of the participants, the team uncovered a mutation in the polymerase epsilon catalytic coding subunit gene POLE in one family and a POLD1 mutation in a second family.

The POLD1 mutation, which affects the polymerase delta coding gene, turned up in another sequenced individual, too, and was subsequently linked to increased risk of both colorectal and endometrial cancer.

For instance, in follow-up screening on thousands of European individuals, researchers found a dozen more colorectal cancer cases involving the POLE mutation and one case in an individual with the POLD1 mutation.

The mutations in question appear to negatively affect the proofreading capabilities of the resulting enzymes, leading to DNA replication errors, according to the researchers' yeast model organism experiments.

Consistent with that notion, results of their other analyses suggested that tumors involving POLE or POLD1 mutations tend to show frequent base substitutions and hyper-mutations.

That's not altogether surprising, the study's authors noted, since several of the best-known colorectal cancer risk genes — including those behind Lynch syndrome and an adenoma-predisposing syndrome called MUTYH-associated polyposis, or MAP — are involved in DNA repair-related processes.

"When added to the DNA mismatch repair defects that underlie Lynch syndrome and the base excision repair defects that cause MAP," Tomlinson and colleagues noted, "the mutations in POLE and POLD1 emphasize the critical role of replication errors and coupled repair of base pair-level mutations in predisposition to colorectal and endometrial cancers."

Moreover, the penetrance of the newly detected mutations appears to be high, hinting that it might be beneficial to use information on POLE and POLD1 mutation status in patient management or colon cancer prevention programs.

"Although further data are required, it may be prudent in the short term to manage mutation carriers in a fashion intermediate between the care for Lynch syndrome and MAP," that team concluded, "with regular and frequent colonoscopic polypectomy and consideration of prophylactic surgery."

Through the GWAS outlined in the second study, on the other hand, an independent team got a peek at the broader genetic architecture of colorectal cancer risk.

For the initial phase of that study, members of the Asia Colorectal Cancer Consortium assessed genotyping data for 2,098 individuals with colorectal cancer and 5,749 unaffected controls. These participants came from China, Korea, and Japan and were tested using Affymetrix or Illumina arrays for five prior GWASs.

Seven SNPs remained linked to the disease after this second stage of the study, which involved validation testing on 64 of the top variants in more than 10,000 colorectal cancer cases and controls from East Asia.

But following a combined analysis of the discovery and validation group data, the team focused on just four variants: SNPs on chromosomes 12, 5, 20, and 10 that fell in and around the CCND2, PITX1, HAO1, and HSPA12A genes, respectively.

All but one of those variants appeared to be associated with colorectal cancer in European populations too, researchers reported. Indeed, the chromosome 12, 5, and 10 variants from the East Asian GWAS showed significant, albeit weaker, ties to colorectal cancer in existing data for more than 26,000 European cases and controls.

Conversely, almost all of the SNPs implicated in colorectal cancer in past studies of Europeans appeared to be associated with disease when the team tested 14,000 East Asian cases and controls — including some individuals from the GWAS discovery cohort.

"Results from our study, along with data from a large study conducted in a population of European ancestry, provide convincing evidence of associations with [colorectal cancer] risk for three new independent susceptibility loci at 5q31.1, 12p13.32, and 20p12.3," Zheng and his colleagues wrote.

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