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.
Highlights
Double-strand DNA break (DSB) repair pathways are essential for the prevention of genomic instability
To identify other DNA repair genes associated with breast and pancreatic cancer, we performed a mutation screen of the coding regions of 32 genes involved in DSB signaling and repair in 38 breast tumors, 48 pancreatic tumors, and germline DNA from 10 non-BRCA1/ BRCA2 hereditary breast cancer patients
The detection rate of 96.4% for known single-nucleotide polymorphisms (SNP) indicated that the Denatured high-performance liquid chromatography (DHPLC) technique was sufficiently sensitive to detect the majority of putative diseaseassociated mutations
Summary
Double-strand DNA break (DSB) repair pathways are essential for the prevention of genomic instability. Rare inactivating mutations in several DNA damage repair and signaling genes, ATM [4], BRIP1 [5], CHEK2 [6], PALB2 [7], NBS1 [8], RAD50 [9], and TP53 [10], have been implicated in breast cancer. The recent discovery that mutations in BRCA2, FANCC, and FANCG [2, 11, 12] are associated with pancreatic cancer suggests that mutations in other repair genes may contribute to pancreatic cancer risk. We report the identification of several truncating and missense mutations
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