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  • 1
    Keywords: CANCER ; POPULATION ; RISK ; GENE ; SUSCEPTIBILITY ; BREAST-CANCER ; SQUAMOUS-CELL CARCINOMA ; early-onset breast cancer ; P53 MUTATIONS ; GENE-MUTATIONS ; TP53 ; BRCA2 ; FAMILIES ; CRITERIA ; HISTOLOGY ; germ line mutations ; Pakistan ; breast cancer susceptibility ; DHPLC ; FRAUMENI-SYNDROME
    Abstract: Women from Pakistan and India are more often diagnosed with early-onset breast cancer than Caucasian women. Given that only 12% of Pakistani women diagnosed with breast cancer at or before 30 years of age have previously been shown to harbor germ line mutations in the breast cancer susceptibility genes BRCA1 and BRCA2, the genetic causes of the majority of early-onset cases are unexplained. Since germ line mutations in the tumor suppressor gene TP53 predispose women to early-onset breast cancer, we assessed the prevalence of TP53 mutations in 105 early-onset breast cancer patients from Pakistan, who had previously been found to be negative for BRCA1 and BRCA2 germ line mutations. The patient group included 67 women diagnosed with early-onset breast cancer at or before age 30 with no family history of breast or ovarian cancer (EO30NFH group) and 38 women diagnosed with breast cancer at or before age 40 with one or more first- or second-degree relatives with breast or ovarian cancer (EO40FH group). Mutation analysis of the complete TP53 coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. One deleterious mutation, c.499-500delCA in exon 5, was identified in the 105 breast cancer patients (1%). This mutation is novel in the germ line and has not been described in other populations. It was detected in a 28-year-old patient with no family history of breast or ovarian cancer. This mutation is rare as it was not detected in additional 157 recently recruited non-BRCA1 and non-BRCA2-associated early-onset breast cancer patients. Our findings show that TP53 mutations may account for a minimal portion of early-onset breast cancer in Pakistan.
    Type of Publication: Journal article published
    PubMed ID: 22311583
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  • 2
    Keywords: GENE ; SUSCEPTIBILITY ; WOMEN ; HIGH-RISK ; BRCA2 MUTATIONS ; CHECKPOINT ; OVARIAN ; HEREDITARY BREAST-CANCER ; 1100DELC MUTATION ; CHEK2-ASTERISK-1100DELC VARIANT
    Abstract: BACKGROUND: Less than 20% of Pakistani women with early-onset or familial breast/ovarian cancer harbor germ line mutations in the high-penetrance genes BRCA1, BRCA2 and TP53. Thus, mutations in other genes confer genetic susceptibility to breast cancer, of which CHEK2 is a plausible candidate. CHEK2 encodes a checkpoint kinase, involved in response to DNA damage. METHODS: In the present study we assessed the prevalence of CHEK2 germ line mutations in 145 BRCA1/2-negative early-onset and familial breast/ovarian cancer patients from Pakistan (Group 1). Mutation analysis of the complete CHEK2 coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. RESULTS: Two potentially deleterious missense mutations, c.275C〉G (p.P92R) and c.1216C〉T, (p.R406C), were identified (1.4%). The c.275C〉G mutation is novel and has not been described in other populations. It was detected in a 30-year-old breast cancer patient with a family history of breast and multiple other cancers. The c.1216C〉T mutation was found in a 34-year-old ovarian cancer patient from a family with two breast cancer cases. Both mutations were not detected in 229 recently recruited BRCA1/2-negative high risk patients (Group 2). CONCLUSION: Our findings suggest that CHEK2 mutations may not contribute significantly to breast/ovarian cancer risk in Pakistani women.
    Type of Publication: Journal article published
    PubMed ID: 23806170
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  • 3
    Keywords: RISK ; OVARIAN-CANCER ; BRCA2 ; ANEMIA GENES
    Type of Publication: Journal article published
    PubMed ID: 26067930
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    Keywords: PREVALENCE ; SUSCEPTIBILITY GENE ; BRCA2 ; FAMILIES ; FANCONI-ANEMIA ; PALB2 ; HIGH-RISK BREAST ; MISSENSE VARIANTS ; BRIP1
    Abstract: RAD51C plays a key role in homologous recombination-mediated DNA repair and maintenance of genomic stability. Biallelic RAD51C mutations cause Fanconi anemia, and monoallelic mutations predispose women to breast and ovarian cancer. Genetic variability of RAD51C and its impact in Asian populations have been poorly studied. Here, we report the results of comprehensive mutational screening of the RAD51C gene in 348 BRCA1/2-negative breast and/or ovarian cancer patients from Pakistan. Mutation analysis of the complete RAD51C-coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. Three novel protein-truncating mutations, c.204T 〉 A, c.225T 〉 G, and c.701C 〉 G, were identified. c.204T 〉 A was found in one out of 22 (4.5 %) early-onset (a parts per thousand currency sign45 years of age) ovarian cancer patients and c.225T 〉 G in one out of 119 (0.8 %) patients from breast cancer only families. c.701C 〉 G was found in a 60-year-old control with no family history of breast/ovarian cancer. Furthermore, three novel in silico-predicted potentially functional mutations, a missense mutation, c.873T 〉 G, a variant in 5'UTR, c.1-34T 〉 G, and a recurrent intronic variant, c.965+21A 〉 G, were identified. The missense mutation was observed in a patient with bilateral breast cancer from a breast and ovarian cancer family (HBOC), the 5'UTR variant was noted in an early-onset breast cancer patient, and the intronic variant in one early-onset breast cancer patient and one ovarian cancer patient from a HBOC family. Five of the six mutations described were not detected in 400 healthy controls. These findings suggest that RAD51C plays a marginal role in breast and ovarian cancer predisposition in Pakistan. Reliable estimation of the clinical implications of carrying a deleterious RAD51C mutation will require identification of additional mutation-positive patients/families.
    Type of Publication: Journal article published
    PubMed ID: 24800917
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  • 6
    Keywords: OVARIAN-CANCER ; MUTATIONS ; POSTMENOPAUSAL WOMEN ; TRANSCRIPTIONAL ACTIVATION ; BONE-MINERAL DENSITY ; UK CAUCASIAN POPULATION ; AFRICAN-AMERICAN WOMEN ; D PATHWAY ; COMPREHENSIVE METAANALYSIS ; CONSANGUINEOUS MARRIAGE
    Abstract: BACKGROUND: Vitamin D is postulated to decrease the risk of breast cancer by inhibiting cell proliferation via the vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNPs) in the VDR gene, rs1544410 (BsmI) and rs2228570 (FokI), are inconsistently associated with breast cancer risk in Caucasian populations, while data for Asians are scarce. Here, we investigated the possible contribution of these SNPs to breast cancer risk in Pakistani breast cancer patients and in controls participating in a hospital-based breast cancer case-control study (PAK-BCCC). METHODS: Genotyping of the BsmI and FokI SNPs was performed by PCR-based restriction fragment length polymorphism (RFLP) analysis of 463 genetically enriched female breast cancer cases with known BRCA1/2 status and in 1,012 controls from Pakistan. The association between SNP genotypes and breast cancer risk was investigated by logistic regression adjusted for potential breast cancer risk factors and stratified by BRCA1/2 status and family history. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. RESULTS: The b allele of the BsmI was associated with an increased breast cancer risk (per b allele OR 1.28, 95% CI 1.09-1.49, P = 0.003). Subgroup analysis revealed that this effect was restricted to BRCA1/2 non-carriers (per b allele OR 1.33, 95% CI 1.11-1.59, P = 0.002) and was stronger in those who reported a positive family history of breast and/or ovarian cancer (per b allele OR 1.64, 95% CI 1.20-2.22, P = 0.002). No association with breast cancer risk was detected for the FokI SNP. CONCLUSIONS: The BsmI polymorphism in the VDR gene may be associated with an increased breast cancer risk in Pakistani women negative for BRCA1/2 germline mutations.
    Type of Publication: Journal article published
    PubMed ID: 26517870
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  • 7
    Abstract: BACKGROUND: Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS) account for a significant proportion of inherited gynecologic malignancies, mainly caused by pathogenic germline mutations in the BRCA1 and BRCA2 genes or in mismatch repair (MMR) genes, such as MLH1 and MSH2. Women harboring deleterious mutations in these genes have increased life-time risks of developing a number of malignancies including ovarian cancer. Since there is a phenotypic overlap of HBOC and LS, timely identification of individuals at-risk of a particular syndrome is crucial in order to optimize cancer risk management. CASE PRESENTATION: We report a novel pathogenic MSH2 mutation, c.2656G 〉 T, which was identified in a 67-year-old female patient with breast cancer, who had previously tested negative for a deleterious mutation in the breast cancer susceptibility genes BRCA1, BRCA2, CHEK2 or RAD51C. The patient reported a personal history of endometrial cancer diagnosed at age 48, and a strong family history of breast and ovarian cancer, as well as several other malignancies within the spectrum of LS. The novel mutation was also found in the index patient's daughter and a niece, who were diagnosed with endometrial and ovarian cancer, respectively. Breast and endometrial tumors from c.2656G 〉 T mutation carriers showed loss of MSH2 and MSH6 protein expression. The mutation was absent in the control population. CONCLUSIONS: Our finding suggests that testing for MMR genes may be of benefit to BRCA1/2 negative families with overlapping HBOC and LS phenotype in Pakistan. It is clinically significant to identify individuals harboring mutations in genes linked with a particular syndrome so that they can benefit from targeted life-saving cancer surveillance and preventive strategies.
    Type of Publication: Journal article published
    PubMed ID: 27413415
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  • 8
    Abstract: BACKGROUND: Women harboring BRCA1/2 germline mutations have high lifetime risk of developing breast/ovarian cancer. The recommendation to pursue BRCA1/2 testing is based on patient's family history of breast/ovarian cancer, age of disease-onset and/or pathologic parameters of breast tumors. Here, we investigated if diagnosis of triple-negative breast cancer (TNBC) independently increases risk of carrying a BRCA1/2 mutation in Pakistan. METHODS: Five hundred and twenty-three breast cancer patients including 237 diagnosed 〈/= 30 years of age and 286 with a family history of breast/ovarian cancer were screened for BRCA1/2 small-range mutations and large genomic rearrangements. Immunohistochemical analyses were performed at one center. Univariate and multiple logistic regression models were used to investigate possible differences in prevalence of BRCA1/2 mutations according to patient and tumor characteristics. RESULTS: Thirty-seven percent of patients presented with TNBC. The prevalence of BRCA1 mutations was higher in patients with TNBC than non-TNBC (37 % vs. 10 %, P 〈 0.0001). 1 % of TNBC patients were observed to have BRCA2 mutations. Subgroup analyses revealed a larger proportion of BRCA1 mutations in TNBC than non-TNBC among patients 1) diagnosed at early-age with no family history of breast/ovarian cancer (14 % vs. 5 %, P = 0.03), 2) diagnosed at early-age irrespective of family history (28 % vs. 11 %, P = 0.0003), 3) had a family history of breast cancer (49 % vs. 12 %, P 〈 0.0001), and 4) those with family history of breast and ovarian cancer (81 % vs. 28 %, P = 0.0005). TNBC patients harboring BRCA1 mutations were diagnosed at a later age than non-carriers (median age at diagnosis: 30 years (range 22-53) vs. 28 years (range 18-67), P = 0.002). The association between TNBC status and presence of BRCA1 mutations was independent of the simultaneous consideration of family phenotype, tumor histology and grade in a multiple logistic regression model (Ratio of the probability of carrying BRCA1/2 mutations for TNBC vs. non-TNBC 4.23; 95 % CI 2.50-7.14; P 〈 0.0001). CONCLUSION: Genetic BRCA1 testing should be considered for Pakistani women diagnosed with TNBC.
    Type of Publication: Journal article published
    PubMed ID: 27553291
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  • 9
    Abstract: BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
    Type of Publication: Journal article published
    PubMed ID: 27826754
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  • 10
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