Delineating genotype and parent-of-origin effect on the phenotype in MSH6-associated Lynch syndrome

Anne Sophie van der Werf-'t Lam, Mar Rodriguez-Girondo, Mandy Villasmil, Carli M. Tops, Liselotte van Hest, Hans J.P. Gille, Floor A.M. Duijkers, Anja Wagner, Ellis Eikenboom, Tom G.W. Letteboer, Mirjam M. de Jong, Sanne W. Bajwa-ten Broeke, Fonnet Bleeker, Encarna B. Gomez Garcia, Mev Dominguez-Valentin, Pal Møller, Manon Suerink, Maartje Nielsen*

*Corresponding author for this work

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This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants. 

Patients and Methods: 

A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC). 


No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77–1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43–1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46–0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52–1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65–1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64–1.19). 

Discussion and Conclusion: 

No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

Original languageEnglish
Article numbere23237
JournalGenes Chromosomes and Cancer
Issue number5
Publication statusPublished - May 2024

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Publisher Copyright:
© 2024 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.


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