Abstract
Demographics for breast cancers vary widely among nations. The frequency of germline mutations in breast cancers, which reflects the hereditary cases, has not been investigated adequately and accurately in highly-consanguineous Pakistani population. In the present discovery case series, germ-line mutations in twenty-seven breast cancer candidate genes were investigated in eighty-four sporadic breast cancer patients along with the clinical correlations. The germ-line variants were also assessed in two healthy gender-matched controls. The clinico-pathological features were evaluated by descriptive analysis and Pearson χ2 test (with significant p-value <0.05). The most frequent parameters associated with hereditary cancer cases are age and ethnicity. Therefore, the analyses were stratified on the basis of age (≤40 years vs. >40 years) and ethnicity. The breast cancer gene panel assay was carried out by BROCA, which is a genomic capture, massively parallel next generation sequencing assay on Illumina Hiseq2000 with 100bp read lengths. Copy number variations were determined by partially-mapped read algorithm. Once the mutation was identified, it was validated by Sanger sequencing. The ethnic analysis stratified on the basis of age showed that the frequency of breast cancer at young age (≤40 years) was higher in Sindhis (n = 12/19; 64%) in contrast to patients in other ethnic groups. Majority of the patients had stage III (38.1%), grade III (50%), tumor size 2–5 cm (54.8%), and invasive ductal carcinoma (81%). Overall, the analysis revealed germ-line mutations in 11.9% of the patients, which was not significantly associated with younger age or any particular ethnicity. The mutational spectrum was restricted to three genes: BRCA1, BRCA2, and TP53. The identified mutations consist of seven novel germ-line mutations, while three mutations have been reported previously. All the mutations are predicted to result in protein truncation. No mutations were identified in the remaining twenty-four candidate breast cancer genes. The present study provides the framework for the development of hereditary-based preventive and treatment strategies against breast cancers in Pakistani population.
Highlights
Epidemiological studies have shown ethnic and geographic differences in breast cancer etiology
It has been estimated that half of all breast cancer cases occur in the 12% women who are at the maximum genetic risk (El Saghir et al, 2007)
Genomic analysis of known breast cancer genes revealed that 11.9% (10/84) patients carried an unambiguously pathogenic germline mutation in three genes: BRCA1, BRCA2, and TP53 (Table 2)
Summary
Epidemiological studies have shown ethnic and geographic differences in breast cancer etiology. BRCA1 and BRCA2 are high penetrant breast cancer genes These have been especially associated with hereditary breast and/or ovarian cancers. The mutations in these genes are considered to increase the life-time risks of breast cancer by 82% (Antoniou and Easton, 2006; Shiovitz and Korde, 2015). These include Sindhis, Balochis, Brahui, Makrani, and Parsis from Southern Pakistan. The other ethnicities Punjabis, Pathans, Hindko, Hazara, Kalash, Kashmiri and Burusho are from Northern Pakistan (Qamar et al, 1999; Khaliq et al, 2000) The data for these genetically distinct ethnic groups has not been incorporated in the few relevant regional-based publications on the breast cancers. The present study investigates molecular epidemiology of breast cancers from Southern Pakistan It is the first such report from this region. A panel of twenty-seven breast cancerassociated candidate genes, has been analysed in breast cancer patients belonging to genetically distinct Pakistani ethnic groups
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