title: Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients.
abstract: Hereditary breast cancer comprises a minor but clinically meaningful breast cancer (BC) subgroup. Mutations in the major BC-susceptibility genes are important prognostic and predictive markers; however, their carriers represent only 25% of high-risk BC patients. To further characterize variants influencing BC risk, we performed SOLiD sequencing of 581 genes in 325 BC patients (negatively tested in previous BRCA1/BRCA2/PALB2 analyses). In 105 (32%) patients, we identified and confirmed 127 truncating variants (89 unique; nonsense, frameshift indels, and splice site), 19 patients harbored more than one truncation. Forty-six (36 unique) truncating variants in 25 DNA repair genes were found in 41 (12%) patients, including 16 variants in the Fanconi anemia (FA) genes. The most frequent variant in FA genes was c.1096_1099dupATTA in FANCL that also show a borderline association with increased BC risk in subsequent analysis of enlarged groups of BC patients and controls. Another 81 (53 unique) truncating variants were identified in 48 non-DNA repair genes in 74 patients (23%) including 16 patients carrying variants in genes coding proteins of estrogen metabolism/signaling. Our results highlight the importance of mutations in the FA genes' family, and indicate that estrogen metabolism genes may reveal a novel candidate genetic component for BC susceptibility.
authors.affiliation: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: F
authors.initials: F
authors.lastname: Lhota
authors.affiliation: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Zemankova
authors.affiliation: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Kleiblova
authors.affiliation: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Soukupova
authors.affiliation: Department of Oncology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Vocka
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Stranecky
authors.affiliation: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Janatova
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: H
authors.initials: H
authors.lastname: Hartmannova
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Hodanova
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Kmoch
authors.affiliation: Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. zdekleje@lf1.cuni.cz.
authors.forename: Z
authors.initials: Z
authors.lastname: Kleibl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D052240:Fanconi Anemia Complementation Group L Protein / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins; C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein
keywords: DNA repair; FANCL; SOLiD next-generation sequencing; genetic predisposition testing; hereditary breast cancer; high-throughput nucleotide sequencing; sequencing panel