title: Molecular and in silico analysis of BRCA1 and BRCA2 variants.
abstract: Germline mutations of high penetrant BRCA1 and BRCA2 genes have been associated to hereditary breast cancer risk, while polymorphic variants of the two genes still have an unknown role in breast pathogenesis. The aim of our study was to characterize BRCA1 and BRCA2 genes polymorphic variants in familial breast cancer. 110 patients affected by familial breast and/or ovarian cancer have been consecutively enrolled according to family history and BRCA mutation risk. All of them have been screened for BRCA1 and BRCA2 pathogenetic mutations, SNPs and intronic variants. In silico analysis have been also performed using different computational methods to individualize genetic variations that can alter the two genes expression and function. BRCA1 resulted mutated in 14% while BRCA2 in 3% of cases, while 80% of patients presented at least one polymorphism. A neural network splicing prediction model individualized one BRCA1 and one BRCA2 intronic variants able to determine alternative splicing. Furthermore, Q356R BRCA1 and N289H BRCA2 appear to show a possible harmful role also due to their location in functional regions of the two genes. However, in silico data are not always consistent with biological evidences. In conclusion, SNPs profile provides a basis for DNA-based cancer risk classification and help to define the gene alterations that could influence biochemistry activity protein or could modify drug sensitivity.
authors.affiliation: National Cancer Institute "Giovanni Paolo II"- v. Hahnemann 10, 70126 Bari, Italy. s.tommasi@oncologico.bari.it
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
authors.forename: Brunella
authors.initials: B
authors.lastname: Pilato
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Pinto
authors.forename: Alessandro
authors.initials: A
authors.lastname: Monaco
authors.forename: Michele
authors.initials: M
authors.lastname: Bruno
authors.forename: Marco
authors.initials: M
authors.lastname: Campana
authors.forename: Maria
authors.initials: M
authors.lastname: Digennaro
authors.forename: Francesco
authors.initials: F
authors.lastname: Schittulli
authors.forename: Rosanna
authors.initials: R
authors.lastname: Lacalamita
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
mesh_terms: D000328:Adult; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites
chemical_list: D022821:RNA Splice Sites