Investigating parent of origin effects (POE) and anticipation in Irish Lynch Syndrome kindreds.

Abstract

e12031 Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progressively earlier onset and increased severity of disease in successive generations of a family. We sought evidence for a specific POE effect in Lynch syndrome families by studying the ages at diagnosis in the offspring of affected parent-child pairs. In addition, a paired t-test and a specifically developed bivariate statistical approach were used to assess a possible role of anticipation. Methods: Affected parent-child pairs (APCPs) (N = 53) were evaluated from kindreds (N = 20) with known germline MMR mutations. Differences in the mean age of LS associated cancer diagnosis were compared between various groups via t-tests: all p-values were 2-sided. Different group comparisons include: (1) unique parental ages (mothers vs. fathers) (2) affected offspring ages (mothers vs. fathers (3) age of affected female offspring (mothers vs. fathers (4) age of affected male offspring (mothers vs. fathers. Results: There were no statistically significant differences in diagnosis of offspring or parents. Sons of affected mothers were more likely to be affected than daughters of affected mothers. However, the affected cohort/study number is small and while affected sons of affected mothers were diagnosed with cancer almost 3 years younger than female offspring (39.7 vs 42.5), this finding failed to reach clinical significance. Comparison in age at diagnosis in 53 affected parent-child pairs with Lynch syndrome associated malignancies Conclusions: These data demonstrate a similar age at diagnosis among all offspring of affected mothers that was indistinguishable from affected fathers. This study will be expanded to recruit more eligible affected parent child pairs to increase the power of this evaluation. The Veiland & Huang algorithm will be used to compare mean ages of affected parents and children.