Dependence of colorectal cancer risk on the parent-of-origin of mutations in DNA mismatch repair genes

Abstract

Genetic diseases associated with dynamic mutations in microsatellite DNA often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Carriers of germline mutations in mismatch repair (MMR) genes have high risks of colorectal carcinoma (CRC). We investigated whether these risks depend on the parent-of-origin of the mutation. We studied 422 subjects, including 89 MMR gene mutation carriers, from 17 population-based families who were each recruited via a CRC case diagnosed before age 45 years and found to carry a MMR gene mutation. The POE hazard ratio (HRPOE), defined to be the CRC incidence for carriers with maternally derived mutations divided by the corresponding paternal incidence, was estimated using a novel application of modified segregation analysis. HRPOE (95% confidence interval) was estimated to be 3.2 (1.1–9.8) for males (P=0.03) and 0.8 (0.2–2.8) for females (P=0.5) and the corresponding cumulative risks to age 80 years were 88% (54%–100%) for male carriers with maternally derived mutations and 38–48% for all other carriers. If confirmed by larger studies, these results will have important implications for the etiology of CRC and for the clinical management of MMR gene mutation carriers.

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers

“…8,9 However, a trend was observed toward a lower HR for CRC in females with a paternally inherited mutation. This is broadly in line with the results of van Vliet et al 8 for the males in their research population, although their results showed a much higher, and significant, HR of 3.2 (P = 0.03) for males when comparing maternally inherited mutations with paternally inherited mutations.…”

“…A possible explanation for the differences in POE findings could be the fact that van Vliet et al 8 used another statistical approach-a modified segregation analyses. We did not use this broad approach because, to the best of our knowledge, no bias or confounders were present in our cohort that would make a modified segregation analysis necessary.…”

“…This was not the case (P = 0.12). 8,9 With the ever-wider adoption of whole genome DNA analysis, more families with PMS2 mutations will be identified in the near future, including some with no apparent history suggestive of LS. Because many of these families may have milder phenotypes, studies such as ours provide useful advice on surveillance programs for these mutation carriers.…”

“…Although a POE has previously been reported in LS, studies have shown conflicting results. 8,9 The aims of our study were to investigate genotype-phenotype relationships in PMS2 mutation carriers and to explore a possible parent-of-origin effect in PMS2. Significant results would have implications for the surveillance and management of patients and their families.…”

Parental Age Affects Somatic Mutation Rates in the Progeny of Flowering Plants

“…Indeed, it was shown that the paternal germline is more mutagenic than the maternal one with respect to base substitutions and replication slippage errors at microsatellites (Sun et al, 2012). It is also known that carriers of germline mutations in mismatch repair (MMR) genes in humans are prone to get colorectal cancer and that the risk depends on the parent-of-origin of the mutation (van Vliet et al, 2011). The molecular basis of these parental effects is not entirely clear but is likely to involve higher rates of nondisjunction during female meiosis, higher mutation rates during spermatogenesis, and probably additional effects of aging.…”