Hereditary Breast and Ovarian Cancer Syndrome: looking for mutations in ERCC4 when BRCAs are not the origin. C. Velázquez Pérez 1 , E. Esteban-Cardeñosa1, M. Durán Domínguez1, M. Tascón Rodríguez, E. Lastra Aras2, G. Marcos García 3, L. Hernández Sanz1, N. Martínez Martín, M. Infante Sanz1.. 1Genética del Cáncer, Instituto de Biología y Genética Molecular (UVa-CSIC), Sanz y Forés 3, 47003 Valladolid.2 Servicio de Oncología, Complejo Hospitalario, Burgos.3 Servicio de Oncología, Hospital Río Hortega, Valladolid. [email protected]
DNA DAMAGE INTRODUCTION PARP ERCC4 is a versatile protein implicated in inhibition NUCLEOTIDE EXCISION REPAIR(NER) several DNA repair via: nucleotide excision repair (NER) pathway and Fanconi Anemia (FA) ERCC4 pathway. FA genes products are involved in mutation DNA interstrand crosslink repair. Biallelic BASE EXCISION REPAIR(BER) mutations in ERCC4 cause Fanconi Anemia subtype Q whereas monoallelic mutations DNA double-strand breaks (DSBs) contribute to inherited risk of Hereditary accumulation Synthethic Breast and Ovarian Cancer Syndrome (HBOC). Genome instability Lethality Furthermore, in a clinical scope, via NER Figure 1. PARP plays an important role in BER pathway. Cells with NER defects are more dependent on BER to alterations conferred platinum sensitivity, the maintain genome integrity. Mutations in ERCC4 leads to an increased DSBs. Synthetic lethal association between PARP inhibition in NER defective cells. standard therapy for breast and ovarian cancer.
METHODS To investigate the role of ERCC4 in HBOC we screened this gene in 125 Spanish ovarian cancer or breast cancer with ovarian cases 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 the programe CONDEL that combines tools as SIFT, Polyphen and Mutationassessor.
A.1 A.2 RESULTS Our study identified two novel variants (c.338+13A>G and c.2743A>G) and eleven A.3 A.4 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, c.2505T>C. In Silico programs predicted c.1244 G>A and c.1727G>C to be probably damaging.
CONCLUSIONS We have identified ERCC4 inactivating mutations in 0.8% of our population, which it is similar to other FA-BRCA genes. Hence, genetic testing of this gene should be considered in high risk BOC families as far as ERCC4 mutations, that compromise DNA repair, could preserve sensitivity to continuous platinum therapy.
ACKNOWLEDGEMENTS. This work was supported by grants: predoctoral fellowship de la Junta de Castilla y León (EDU1798/2014, Consejería de Educación) BIO/VA25/15 (Consejería de Sanidad) and the Cancer Prevention Program of the Regional Government of Castilla y León.