@article{ajmbr20241224,
author={{Alotaibi, Reem and Alotaibi, Aeshah and Alhamwan, Turki and Alruwaili, Ebtesam and Alsufyani, Saeed and Walby, Munira},
title={Anticipation in Families with MLH1-associated Lynch Syndrome},
journal={American Journal of Medical and Biological Research},
volume={12},
number={2},
pages={61--67},
year={2024},
url={https://pubs.sciepub.com/ajmbr/12/2/4},
issn={2328-4099},
abstract={<b>Background</b> Lynch syndrome (LS) is an autosomal-dominant, hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in one of the mismatch-repair genes <i>MLH1</i>, <i>MSH2/EPCAM</i>, <i>MSH6</i>, or <i>PMS2</i>. Individuals who have <i>MLH1</i> 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 <i>MLH1</i>-associated LS. The objective of this study was to assess anticipation in families with <i>MLH1-</i>associated LS by using statistical models while controlling for potential confounders. <b>Methods</b><b> </b>Data from 31 families with <i>MLH1</i> PVs were obtained from an academic registry. Wilcoxon signed-rank tests on parent¨Cchild-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. <b>Results</b><b> </b>A trend toward younger ages at diagnosis of CRC/EC in successive generations, ranging from 3.2 to 15.7 years, was observed in <i>MLH1</i> 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 <i>MLH1</i> variants with no Mlh1 activity were at a 78% greater hazard for CRC/EC than those who retained Mlh1 activity. <b>Conclusions</b><b> </b>The current results demonstrated evidence in support of anticipation in families with <i>MLH1-</i>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.},
doi={10.12691/ajmbr-12-2-4}
publisher={Science and Education Publishing}
}