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

Manon Suerink, Heleen M. van der Klift, Sanne W. ten Broeke, Olaf M. Dekkers, Inge Bernstein, Gabriel Capella Munar, Encarna Gomez Garcia, Nicoline Hoogerbrugge, Tom G. W. Letteboer, Fred H. Menko, Annika Lindblom, Arjen Mensenkamp, Pal Moller, Theo A. van Os, Nils Rahner, Bert J. W. Redeker, Maran Olderode, Liesbeth Spruijt, Yvonne J. Vos, Anja WagnerHans Morreau, Frederik J. Hes, Hans F. A. Vasen, Carli M. Tops, Juul T. Wijnen, Maartje Nielsen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)405-409
JournalGenetics in Medicine
Issue number4
Publication statusPublished - Apr 2016


  • genotype-phenotype correlations
  • hereditary colon cancer
  • Lynch syndrome
  • PMS2
  • parent-of-origin effect

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