Arti S. Pandey

Anticipation in families with MLH1‐associated Lynch syndrome

AbstractBackgroundLynch 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.MethodsData 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.ResultsA 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.ConclusionsThe 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.