@article{TEXTUAL,
      recid = {13784},
      author = {Pandey, Arti S. and Drogan, Christine and Huo, Dezheng and  Postula, Kristen and Garg, Shreshtha M. and Kupfer, Sonia  S.},
      title = {Anticipation in families with  &amp;lt;i&amp;gt;MLH1&amp;lt;/i&amp;gt;-associated Lynch syndrome},
      journal = {Cancer},
      address = {2024-10-22},
      number = {TEXTUAL},
      abstract = {&lt;p&gt;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.&lt;/p&gt;  &lt;p&gt;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.&lt;/p&gt; &lt;p&gt;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.&lt;/p&gt;  &lt;p&gt;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.&lt;/p&gt;},
      url = {http://knowledge.uchicago.edu/record/13784},
}