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

Author(s):
Werf-'t Lam, A.S. van der; Rodriguez-Girondo, M.; Villasmil, M.; Tops, C.M. (0000-0002-6769-7290); Hest, L. van; Gille, H.J.P.; Duijkers, F.A.M.; Wagner, A.; Eikenboom, E.; Letteboer, T.G.W.; Jong, M.M. de; Bajwa-ten Broeke, S.W.; Bleeker, F.; Garcia, E.B.G.; Dominguez-Valentin, M.; Moller, P.; Suerink, M.; Nielsen, M. (0000-0002-5351-1870)
Published
2024
Publication type
Article / Letter to editor

Abstract

Background: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) withinfamilies carrying (likely) disease-causing MSH6 germline variants.Patients and Methods: A cohort of 1615 MSH6 variant carriers (310 LS families) wasanalyzed. Participants were categorized based on RNA expression and parental inheritanceof the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, consid-ering external information to address ascertainment bias. The findings were cross-validatedusing the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC).Results: No significant association was observed between genotype and colorectalcancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77–1.46). Patients lack-ing 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).

cancer riskscolorectal carcinomaendometrial carcinomaLynch syndrome
Date issued
2024-05-31
Language
English
Is part of
Genes, Chromosomes & Cancer (2024), No. 5
hdl
1887/4168782
doi
10.1002/gcc.23237