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TP53 Variants May Influence Cancer Risk in Taiwanese Lynch Syndrome Cohort

NEW YORK (GenomeWeb) – A retrospective study of Lynch syndrome patients in Taiwan suggests certain variants in the tumor suppressor gene TP53 may dial down the risk of colorectal cancer (CRC) development.

Researchers from Taipei Medical University, China Medical University, the Taiwan National Health Research Institutes, and elsewhere profiled TP53 polymorphisms in hundreds of individuals with germline mutations in the MLH1 or MSH2 mismatch repair (MMR) genes — alterations associated with the inherited, CRC predisposing syndrome. Their results, published online today in PLOS One, point to alleles at the rs1042522 and rs12947788 sites in TP53 that appeared to correspond to slightly lower-than-usual CRC risk in the Lynch syndrome cohort from Taiwan.

"[T]he study results revealed that the variant C allele of rs1042522and the variant T allele of rs12947788 were associated with decreased CRC risk in patients with MMR gene germline mutations in Taiwan," corresponding authors Chih-Ching Yeh and Chao Hsiung and their co-authors wrote.

Starting from the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium, the researchers narrowed in on 184 individuals with germline mutations in MLH1 and 76 individuals with germline mutations in MSH2 from more than five dozen Lynch syndrome-affected families. From the original group of 260 individuals with Lynch syndrome, more than 46 percent developed CRC, they reported, and 80 percent of those cases involved individuals with MLH1 mutations.

Using the Sequenom iPLEX MassArray platform, the team genotyped variants in TP53 across the Lynch syndrome group, looking for potential ties between CRC risk and TP53 variants.

In particular, the researchers found that individuals with cytosine at one or both rs1042522 alleles seemed somewhat less CRC prone, as were Lynch syndrome patients with the minor haplotype version of variants at rs12947788. On the other hand, alternative alleles at the same sites appeared to coincide with earlier CRC onset.

The team did not see any significant ties between individuals' self-reported lifestyle factors — from coffee or tea consumption to cigarette smoking and alcohol use — and variants in TP53 that appeared to influence CRC risk. Almost 72 percent of the cohort was comprised of never smokers and almost 70 percent did not consume alcohol.

The study's authors pointed out that prior studies have uncovered inconsistent associations between TP53 gene variation and CRC risk. They speculated that such inconsistencies "may be due to differences among study populations with different allele frequencies of TP53 polymorphisms." 

Future studies that include individuals with germline mutations in other MMR genes, such as MSH6 or PMS2, are expected to provide a more complete view of variants in TP53 and other genes that might moderate CRC risk in individuals with Lynch syndrome, the team noted.