Does Maternal Or Paternal Inheritance Of Brca Mutation Affect The Age Of Cancer Diagnosis?

1510 Background: Genetic diseases may display parent-of-origin effects in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Female carriers of their fathers’ Lynch syndrome gene mutations develop cancer at an earlier age than those inheriting mutations from their mothers suggesting that Lynch syndrome genes may be subject to imprinting effects. Imprinting effect is evident in autosomal dominant hereditary paraganglioma, leading to tumors only if inherited from paternal germline. Methods: From 2004-2010 we analyzed 1,351 consecutive patients presenting for genetic counseling. In 148 patients with BRCA 1 or 2 the parent of origin for the mutation was known. Of these 148 patients, 2 had both BRCA1 and BRCA2 mutated paternally inherited. 63 inherited the deleterious BRCA mutation from fathers (45 affected with cancer) and 83 individuals inherited the deleterious mutation from mothers (54 affected). No ovarian cancers were identified in our cohort of BRCA 2 mutations of maternal inheritance. Two-sample t-test was used to compare the mean age at diagnosis in patients with BRCA 1 or 2 mutations of paternal or maternal inheritance. Results: Paternal inheritance of BRCA resulted in an earlier age of diagnosis of breast and ovarian cancer. These differences were significant with paternal inheritance of BRCA2 mutations; a non-significant trend was found in paternally inherited BRCA1 mutations. Conclusions: Women with paternally inherited mutations in BRCA gene mutations have cancers diagnosed at earlier ages compared with women who inherit gene mutations from their mothers. Maternal and paternal inherited BRCA alleles may not be exchangeable. In this small sample clear differences at age of cancer diagnosis are apparent in paternal inheritance of BRCA 2 gene mutation. These findings have important implications for surgical risk reduction strategies if they are duplicated in larger cohorts. Maternal allele (mean ± SD yrs) Paternal allele (mean ± SD yrs) Two-sample t-test p value Breast cancer BRCA1 47.0 ± 11.6 41.1 ± 7.4 p<0.0778 BRCA2 49.4 ± 10.2 40.8 ± 5.7 p<0.0030 Ovarian cancer BRCA1 56.3 ± 7.0 44.4 ± 3.8 p<0.0080