Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53 |
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| Authors: | Suhair Lolas Hamameh Paul Renbaum Lara Kamal Dima Dweik Mohammad Salahat Tamara Jaraysa Amal Abu Rayyan Silvia Casadei Jessica B. Mandell Suleyman Gulsuner Ming K. Lee Tom Walsh Mary‐Claire King Ephrat Levy‐Lahad Moein Kanaan |
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| Affiliation: | 1. Hereditary Research Laboratory and Department of Life Sciences, Bethlehem University, Bethlehem, Palestine;2. Medical Genetics Institute, Share Zedek Medical Center, and Faculty of Medicine, Hebrew University, Jerusalem, Israel;3. Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington, Seattle, WA |
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| Abstract: | Breast cancer among Palestinian women has lower incidence than in Europe or North America, yet is very frequently familial. We studied genetic causes of this familial clustering in a consecutive hospital‐based series of 875 Palestinian patients with invasive breast cancer, including 453 women with diagnosis by age 40, or with breast or ovarian cancer in a mother, sister, grandmother or aunt (“discovery series”); and 422 women diagnosed after age 40 and with negative family history (“older‐onset sporadic patient series”). Genomic DNA from women in the discovery series was sequenced for all known breast cancer genes, revealing a pathogenic mutation in 13% (61/453) of patients. These mutations were screened in all patients and in 300 Palestinian female controls, revealing 1.0% (4/422) carriers among older, nonfamilial patients and two carriers among controls. The mutational spectrum was highly heterogeneous, including pathogenic mutations in 11 different genes: BRCA1, BRCA2, TP53, ATM, CHEK2, BARD1, BRIP1, PALB2, MRE11A, PTEN and XRCC2. BRCA1 carriers were significantly more likely than other patients to have triple negative tumors (p = 0.03). The single most frequent mutation was TP53 p.R181C, which was significantly enriched in the discovery series compared to controls (p = 0.01) and was responsible for 15% of breast cancers among young onset or familial patients. TP53 p.R181C predisposed specifically to breast cancer with incomplete penetrance, and not to other Li‐Fraumeni cancers. Palestinian women with young onset or familial breast cancer and their families would benefit from genetic analysis and counseling. |
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| Keywords: | breast cancer BRCA1 BRCA2 TP53 Palestine |
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