Hereditary breast and ovarian cancer syndrome: looking for mutations in ERCC4 when BRCAs are not the origin

Abstract

ERCC4 is a versatile protein implicated in several DNA repair via: nucleotide excision repair (NER) pathway and Fanconi Anemia (FA) pathway. FA genes products are involved in DNA interstrand crosslink repair. Biallelic mutations in ERCC4 cause FA subtype Q whereas monoallelic mutations contribute to inherited risk of Hereditary Breast and Ovarian Cancer Syndrome (HBOC). In a clinical scope, via NER alterations conferred platinum sensitivity, the standard therapy for breast and ovarian cancer. To investigate the role of ERCC4 in HBOC we screened this gene for mutations in 125 Spanish ovarian cancer patients or breast cancer cases with ovarian history in their pedigrees. All samples were negatives for BRCA mutations. Mutation screening was performed by HA-CAE and subsequently Sanger Sequencing of altered pattern. Missense mutations were evaluated using CONDEL software that combines tools as SIFT, Polyphen and MutationAssessor. Our study identified two novel variants (c.338+13A>G, c.1524 A>T) and eleven previously described (c.251C>T, c.974-7A>G, c.974-53delTG, c.1244G>A, c.1251T>A, c.1563C>G, c.1727G>C, c.1812-103G>A, c.1905-35T>C, c.1905-28G>A and c.2505T>C). In Silico analysis predicted c.1244 G>A and c.1727G>C as probably damaging. We have identified ERCC4 inactivating mutations in 0.8% of our population, which is similar to other FA-BRCA genes. Hence, genetic testing of this gene should be considered in high risk HBOC families as far as ERCC4 mutations, that compromise DNA repair, could preserve sensitivity to continuous platinum therapy.