Contribution of BRCA1 large genomic rearrangements to early-onset and familial breast/ovarian cancer in Pakistan.
Germline mutations in BRCA1 and BRCA2 (BRCA1/2) account for the majority of hereditary breast and/or ovarian cancers. Pakistan has one of the highest rates of breast cancer incidence in Asia, where BRCA1/2 small-range mutations account for 17% of early-onset and familial breast/ovarian cancer patients. We report the first study from Pakistan evaluating the prevalence of BRCA1/2 large genomic rearrangements (LGRs) in breast and/or ovarian cancer patients who do not harbor small-range BRCA1/2 mutations.



Both BRCA1/2 genes were comprehensively screened for LGRs using multiplex ligation-dependent probe amplification in 120 BRCA1/2 small-range mutations negative early-onset or familial breast/ovarian cancer patients from Pakistan (Group 1). The breakpoints were characterized by long-range PCR- and DNA-sequencing analyses. An additional cohort of 445 BRCA1/2 negative high-risk patients (Group 2) was analyzed for the presence of LGRs identified in Group 1.



Three different BRCA1 LGRs were identified in Group 1 (4/120; 3.3%), two of these were novel. Exon 1-2 deletion was observed in two unrelated patients: an early-onset breast cancer patient and another bilateral breast cancer patient from a hereditary breast cancer (HBC) family. Novel exon 20-21 deletion was detected in a 29-year-old breast cancer patient from a HBC family. Another novel exon 21-24 deletion was identified in a breast-ovarian cancer patient from a hereditary breast and ovarian cancer family. The breakpoints of all deletions were characterized. Screening of the 445 patients in Group 2 for the three LGRs revealed ten additional patients harboring exon 1-2 deletion or exon 21-24 deletion (10/445; 2.2%). No BRCA2 LGRs were identified.



LGRs in BRCA1 are found with a considerable frequency in Pakistani breast/ovarian cancer cases. Our findings suggest that BRCA1 exons 1-2 deletion and exons 21-24 deletion should be included in the recurrent BRCA1/2 mutations panel for genetic testing of high-risk Pakistani breast/ovarian cancer patients.
Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), 7A, Block R3, Johar Town, Lahore, Punjab, 54000, Pakistan. usmanr@skm.org.pk.|Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. usmanr@skm.org.pk.
Muhammad U
MU
Rashid
Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), 7A, Block R3, Johar Town, Lahore, Punjab, 54000, Pakistan.
Noor
N
Muhammad
Levine Cancer Institute (LCI), Carolinas Healthcare System, Charlotte, USA.
Asim
A
Amin
Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), 7A, Block R3, Johar Town, Lahore, Punjab, 54000, Pakistan.
Asif
A
Loya
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ute
U
Hamann
D000328:Adult; D017668:Age of Onset; D000368:Aged; D001483:Base Sequence; D056905:Chromosome Breakpoints; D005091:Exons; D005260:Female; D015321:Gene Rearrangement; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010154:Pakistan / Q000453:epidemiology; D010641:Phenotype; D011159:Population Surveillance; D017384:Sequence Deletion; D055815:Young Adult
BRCA1; BRCA2; Breast and/or ovarian cancer; Germline mutations; Large genomic rearrangement; Pakistan