Ayub Shiekh Gazalla, Rasool Shabhat, Ayub Taha, Khan Saquib Naveed, Wani Khursheed Alam, Andrabi Khurshid Iqbal
Department of Biotechnology, University of Kashmir, Kashmir 190006, India.
Government Medical College, Srinagar 190010, India.
Mol Med Rep. 2014 Feb;9(2):749-53. doi: 10.3892/mmr.2013.1862. Epub 2013 Dec 13.
Breast cancer demonstrates geographical and ethnic variation in its incidence reflecting the effect of local environmental conditions and lifestyle. The genesis of the disease has further been complexed by the involvement of a number of genes with small effects and above all by population heterogeneity. Accordingly, variations in genes, including breast cancer 1, early onset (BRCA1)/breast cancer 2, early onset (BRCA2), that have been markedly associated with the breast cancer phenotype exhibit a scattered mutational pattern in different populations. The present study was aimed to analyze the sequence variations in BRCA2 gene in a case control manner in ethnically pure Kashmiri population using PCR. Sequencing of BRCA2 exons revealed the presence of five sequence variations, four of which present in exon 11 alone were somatic and one was germline located in the U-terminal region (UTR) of exon 2. Out of these, the two somatic mutations comprised of substitutions, one representing a missense mutation leading to an amino-acid substitution at codon 991 and the other was a silent mutation at codon 1131, whereas the other two mutations located in exon 11 represented a loss of polymorphism. Codons for amino acid position 846 and 868 were demonstrated to be heterozygous polymorphic variants in 66% of the normal breast tissue samples, whereas the heterozygous polymorphic variant codons at the two loci were replaced by a homozygous genotype in associated tumor tissue in 88% of cases. These two mutations were always linked. Germline variation observed in exon 2 was located in the UTR region at contig position 13870572 (rs1799943). Other screened exons of BRCA2 did not demonstrate any sequence variation. These variations may contribute to breast cancer susceptibility along with variations in other low penetrating genes in sporadic types of breast cancer in this cohort of the population.
乳腺癌的发病率存在地理和种族差异，这反映了当地环境条件和生活方式的影响。多种效应较小的基因参与其中，尤其是人群异质性，使得该疾病的发病机制更加复杂。因此，与乳腺癌表型显著相关的基因变异，包括乳腺癌1号基因（早发型）（BRCA1）/乳腺癌2号基因（早发型）（BRCA2），在不同人群中呈现出分散的突变模式。本研究旨在以病例对照的方式，利用聚合酶链反应（PCR）分析纯种克什米尔人群中BRCA2基因的序列变异。BRCA2外显子测序显示存在五个序列变异，其中仅在外显子11中出现的四个变异是体细胞变异，一个是位于外显子2的U末端区域（UTR）的种系变异。其中，两个体细胞突变包括替换，一个是错义突变，导致密码子991处的氨基酸替换，另一个是密码子1131处的沉默突变，而位于外显子11中的另外两个突变代表多态性缺失。在66%的正常乳腺组织样本中，氨基酸位置846和868的密码子被证明是杂合多态性变体，而在88%的病例中，相关肿瘤组织中这两个位点的杂合多态性变体密码子被纯合基因型取代。这两个突变总是连锁的。在外显子2中观察到的种系变异位于重叠群位置13870572（rs1799943）的UTR区域。BRCA2的其他筛选外显子未显示任何序列变异。这些变异可能与该人群中散发性乳腺癌的其他低 penetrance 基因变异一起，导致乳腺癌易感性增加。
