Ajaz Sadia, Zaidi Sani-E-Zehra, Ali Saleema, Siddiqa Aisha, Memon Muhammad Ali
Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi, Pakistan.
Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan.
Front Genet. 2022 Mar 9;13:820610. doi: 10.3389/fgene.2022.820610. eCollection 2022.
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 χ 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 ( = 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: , , and . 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.
各国乳腺癌的人口统计学特征差异很大。在高度近亲结婚的巴基斯坦人群中，尚未对反映遗传性病例的乳腺癌种系突变频率进行充分且准确的调查。在本发现病例系列中，对84例散发性乳腺癌患者的27个乳腺癌候选基因的种系突变及其临床相关性进行了研究。还在两名性别匹配的健康对照中评估了种系变异。通过描述性分析和Pearson χ检验（显著p值<0.05）评估临床病理特征。与遗传性癌症病例相关的最常见参数是年龄和种族。因此，分析根据年龄（≤40岁与>40岁）和种族进行分层。乳腺癌基因检测面板由BROCA进行，这是一种在Illumina Hiseq2000上进行的基因组捕获、大规模平行下一代测序检测，读长为100bp。通过部分映射读算法确定拷贝数变异。一旦鉴定出突变，便通过桑格测序进行验证。基于年龄分层的种族分析表明，信德族中年轻女性（≤40岁）的乳腺癌发病率较高（=12/19；64%），而其他种族的患者发病率较低。大多数患者处于III期（38.1%）、III级（50%）、肿瘤大小为2 - 5cm（54.8%），且为浸润性导管癌（81%）。总体而言分析显示，11.9%的患者存在种系突变，这与年轻年龄或任何特定种族均无显著关联。突变谱局限于三个基因： 、 和 。鉴定出的突变包括七个新的种系突变，而此前已报道过三个突变。所有突变预计都会导致蛋白质截短。在其余24个候选乳腺癌基因中未鉴定出突变。本研究为制定针对巴基斯坦人群乳腺癌的基于遗传的预防和治疗策略提供了框架。
