title: Mutational analysis of thirty-two double-strand DNA break repair genes in breast and pancreatic cancers.
abstract: Inactivating mutations in several genes that encode components of the DNA repair machinery have been associated with an increased risk of breast cancer. To assess whether alterations in other DNA repair genes contribute to breast cancer and to further determine the relevance of these genes to pancreatic cancer, we performed mutational analysis of 32 DNA double-strand break repair genes in genomic DNA from 38 breast tumors, 48 pancreatic tumors, and 10 non-BRCA1/BRCA2 hereditary breast cancer patients. A total of 494 coding exons were screened by denatured high-performance liquid chromatography and direct DNA sequencing. Two inactivating mutations were identified in breast tumor samples, a germline single-nucleotide deletion in POLQ (c.3605delT) and a somatic nonsense change in PRKDC (c.2408C>A, p.Ser803X). Two germline-inactivating mutations in RAD50 (c.1875C>G, p.Tyr625X and IVS14+1G>A) were also detected in separate pancreatic tumor samples. In addition, 35 novel nonsynonymous amino acid substitutions, resulting from two in-frame deletions and 33 single nucleotide alterations, were identified. Seven of these were predicted to influence protein function. A separate analysis of the CLSPN c.3839C>T (rs35490896) variant that was observed more frequently in breast tumors than in pancreatic tumors or normal controls failed to detect a significant association with breast cancer risk in a Mayo Clinic breast cancer case-control study. In conclusion, this screen of DNA repair genes implicates PRKDC and POLQ as candidate tumor suppressor genes involved in breast cancer and suggests that inactivating mutations in RAD50 predispose to pancreatic cancer as well as breast cancer.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Xianshu
authors.initials: X
authors.lastname: Wang
authors.forename: Csilla
authors.initials: C
authors.lastname: Szabo
authors.forename: Chiping
authors.initials: C
authors.lastname: Qian
authors.forename: Peter G
authors.initials: PG
authors.lastname: Amadio
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Wanguo
authors.initials: W
authors.lastname: Liu
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
mesh_terms: D017766:Acid Anhydride Hydrolases; D000483:Alleles; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D053903:DNA Breaks, Double-Stranded; D004252:DNA Mutational Analysis; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D020125:Mutation, Missense; D010190:Pancreatic Neoplasms / Q000097:blood / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics; D012680:Sensitivity and Specificity
chemical_list: D004268:DNA-Binding Proteins; D012334:RNA, Neoplasm; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes