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

Abstract

A germ-line mutation in one of the mismatch repair (MMR) genes causes Lynch syndrome (LS), an autosomal dominant disorder characterized by the clustering of colorectal cancer (CRC) and endometrial cancer (EC) within affected families. Higher risks have been reported for other cancers such as ovarian and urothelial cell cancer. However, thus far only one study has confirmed these risks in PMS2 mutation carriers. 1The MMR proteins normally act together to repair mismatches that occur during cell replication. MSH2 and MSH6 form a heterodimer that recognizes base-base mismatches and insertion/deletion mispairs, whereas MLH1 and PMS2 form a heterodimer that supports initiated repair.2 A mutation can result in complete loss of protein or a protein with impaired function. Cancer risks associated with PMS2 are lower than those reported for MLH1 and MSH2. 1,3 Phenotypes resulting from germ-line MMR gene mutations vary both among and within families. 4 Interfamilial variance might be partly attributable to known genotype-phenotype Purpose: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype.Methods: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally.Results: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC.Conclusions: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-oforigin effect.

Comprehensive Mutation Analysis ofPMS2in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome

“…The established effect of genomic variants on RNA expression can also be used in genotype–phenotype correlation studies. RNA analysis results reported in this study contributed to a genotype–phenotype study of heterozygous pathogenic PMS2 variants found in European Lynch syndrome patients [Suerink et al., ].…”

SNP association study in PMS2-associated Lynch syndrome

“…A second limitation might be that we did not correct for the specific mutation present in each family, mainly because in the majority of families the segregating PMS2 mutation is rare or even unique. A previous study by our group did not identify such a correlation with CRC risk in PMS2 carriers (Supplemental Tables 2a + 2b Table: for more details) [ 34 ].…”

An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome

“…Firstly, genotype-phenotype correlations in Lynch syndrome and CMMRD have been proposed (although thus far no conclusive evidence has been yielded and some studies even show contradictory results). [30][31][32][33][34][35] If correlations exist, variants with a milder phenotype might be overrepresented in a CMMRD cohort. For PMS2, age at cancer diagnosis and risk estimates were within the range of previous retrospective studies that corrected for ascertainment bias, indicating that we have not selected a cohort of (solely) low-risk PMS2 alleles.…”