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Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53
Author(s) -
Lolas Hamameh Suhair,
Renbaum Paul,
Kamal Lara,
Dweik Dima,
Salahat Mohammad,
Jaraysa Tamara,
Abu Rayyan Amal,
Casadei Silvia,
Mandell Jessica B.,
Gulsuner Suleyman,
Lee Ming K.,
Walsh Tom,
King MaryClaire,
LevyLahad Ephrat,
Kanaan Moein
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30771
Subject(s) - breast cancer , palb2 , chek2 , medicine , penetrance , family history , cancer , genetic counseling , oncology , aunt , mutation , genetics , germline mutation , biology , gene , sociology , anthropology , phenotype
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.