Genetic defects in breast cancer susceptibility genes, which are important for maintaining genome integrity and cell cycle checkpoint control, explain only approximately 40% of hereditary breast and ovarian cancers. Compared to the enormous efforts to identify additional susceptibility genes through linkage and genome-wide association studies, little is known about the role of constitutive epimutations to the missing “heritability”. Promoter hypermethylation can inactivate genes that prevent neoplastic transformation in a normal cell. Although constitutive hypermethylation as the first hit in neoplastic transformation has been described for several tumor suppressor genes, in particular in rare cases of hereditary non-polyposis colon cancer, this is an understudied phenomenon. We perform comprehensive epimutation screens of several cancer susceptibility genes in normal body cells (whole blood, fibroblasts, saliva) of patients with a high personal or familial risk for cancer. Our results show that constitutive epimutations, i.e. in BRCA1 and RAD51C contribute to both sporadic and familial cases, which often may appear as phenocopies of tumors with germline mutations. Constitutive epimutations are usually present in varying percentages of cells in normal tissues and most likely represent stochastic and/or environmentally induced methylation errors during early development.
Hansmann T, Pliushch G, Leubner M, Kroll P, Endt D, Gehrig A, Preisler-Adams S, Wieacker P, Haaf T. Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer. Hum. Mol. Genet. 21, 4669-4679 (2012).
Galetzka D, Hansmann T, El Hajj N, Weis E, Irmscher B, Ludwig M, Schneider-Raetzke B, Kohlschmidt N, Beyer V, Bartsch O, Zechner U, Spix C, Haaf T. Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer. Epigenetics 7, 47-54 (2012).
Weis E, Schoen H, Victor A, Spix C, Ludwig M, Schneider-Raetzke B, Kohlschmidt N, Bartsch O, Gerhold-Ay A, Boehm N, Grus F, Haaf T, Galetzka D. Reduced mRNA and protein expression of the genomic caretaker RAD9A in primary fibroblasts of individuals with childhood and independent second cancer. PLoS ONE 6(10):e25750 (2011).