Anticipation in Families with MLH1-associated Lynch Syndrome

Reem Alotaibi^1, , Aeshah Alotaibi², Turki Alhamwan², Ebtesam Alruwaili³, Saeed Alsufyani⁴ and Munira Walby²

¹Laboratory, Ministry of Health, Riyadh, Saudi Arabia

²Nursing, Ministry of Health, Riyadh, Saudi Arabia

³Health Informatics, Ministry of Health, Riyadh, Saudi Arabia

⁴Health Services, Ministry of Health, Taif, Saudi Arabia

Cite this paper:
Reem Alotaibi, Aeshah Alotaibi, Turki Alhamwan, Ebtesam Alruwaili, Saeed Alsufyani and Munira Walby. Anticipation in Families with MLH1-associated Lynch Syndrome. American Journal of Medical and Biological Research. 2024; 12(2):61-67. doi: 10.12691/ajmbr-12-2-4

Abstract

Background Lynch syndrome (LS) is an autosomal-dominant, hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in one of the mismatch-repair genes MLH1, MSH2/EPCAM, MSH6, or PMS2. Individuals who have MLH1 PVs have high lifetime risks of colorectal cancer (CRC) and endometrial cancer (EC). There is controversy regarding whether a younger age at diagnosis (or anticipation) occurs in MLH1-associated LS. The objective of this study was to assess anticipation in families with MLH1-associated LS by using statistical models while controlling for potential confounders. Methods Data from 31 families with MLH1 PVs were obtained from an academic registry. Wilcoxon signed-rank tests on parent–child-pairs as well as parametric Weibull and semiparametric Cox proportional hazards and Cox mixed-effects models were used to calculate hazard ratios or to compare mean ages at CRC/EC diagnosis by generation. Models were also corrected for ascertainment bias and birth-cohort effects. Results A trend toward younger ages at diagnosis of CRC/EC in successive generations, ranging from 3.2 to 15.7 years, was observed in MLH1 PV carrier families. A greater hazard for cancer in younger generations was not precluded by the inclusion of birth cohorts in the model. Individuals who had MLH1 variants with no Mlh1 activity were at a 78% greater hazard for CRC/EC than those who retained Mlh1 activity. Conclusions The current results demonstrated evidence in support of anticipation in families with MLH1-associated LS across all statistical models. Mutational effects on Mlh1 activity influenced the hazard for CRC/EC. Screening based on the youngest age of cancer diagnosis in MLH1-LS families is recommended.

Keywords:
LS syndrome CRC

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