oa Genomic analysis of inherited breast cancer among Palestinian women

In the Middle East, breast cancer incidence among Palestinian women has historically been low, but with increased education and later initiation of child bearing among Palestinian young women, is now rapidly increasing. Furthermore, perhaps because of its historically low incidence, breast cancer among Palestinian women is strikingly familial. We explored the genetic bases of this familial risk in the context of providing culturally appropriate genetic counseling services to high-risk women. Participants were 274 Palestinian with breast cancer, most either with a positive family history of breast or ovarian cancer (116 subjects) or diagnosed at age 40 or younger (130 subjects). Genomic DNA was tested by BROCA, which enables the capture and simultaneous multiplex sequencing of all coding, regulatory, and intronic regions of 30 known breast and ovarian cancer genes. Considering only unambiguously damaging mutations (i.e. truncations, complete deletions, splice mutations leading to a mutant message, and missenses proven experimentally to be damaging), 29 of the 274 subjects (11%) carried a mutation responsible for their breast cancer. These included 22 of the 116 familial subjects (19%), 8 of the 130 young-onset-nonfamilial subjects (6%), and 0 of the 29 subjects not meeting either criterion. The damaging mutations included 7 in BRCA1, 10 in BRCA2, 2 in ATM, 2 in BARD1, and 1 each in TP53, CHEK2, CDH1, PALB2, ATR, BRIP1, and XRCC2. With two exceptions (BRCA2 p.E2229X and BRCA2 c.6462delTC), all mutations were different. Also, two subjects had two mutations each: in CHEK2 and BARD1; and in CHEK2 and ATM. Multiple variants potentially altering splicing and missenses potentially damaging to function are still in process of evaluation and remain good candidates. Based on the historical demography of the region, we anticipated that the spectrum of mutations predisposing to breast cancer in the Palestinian population would be broad, with multiple individually rare, highly localized mutations, rather than a small number of founder alleles; that is, a European pattern rather than an Ashkenazi Jewish pattern. This proved to be true. Breast cancer among Palestinian women is generally diagnosed at late stages, and consequently has poor prognosis. If Palestinian women at genetically high risk were provided the opportunity to undertake special scrutiny, staging and mortality could be substantially improved.