Valarmathi Mani T, Sawhney Meenakshi, Deo Suryanarayana S V, Shukla Nootan K, Das Satya N
Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India.
Department of Surgical Oncology, Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
Hum Mutat. 2004 Feb;23(2):205. doi: 10.1002/humu.9213.
The two major hereditary breast/ovarian cancer predisposition tumor suppressor genes, BRCA1 and BRCA2 that perform apparently generic cellular functions nonetheless cause tissue-specific syndromes in the human population when they are altered, or mutated in the germline. However, little is known about the contribution of BRCA1 and BRCA2 mutations to breast and/or ovarian cancers in the Indian population. We have screened for mutations the entire BRCA1 and BRCA2 coding sequences, and intron-exon boundaries, as well as their flanking intronic regions in sixteen breast or breast and ovarian cancer families of Indian origin. We have also analyzed 20 female patients with sporadic breast cancer regardless of age and family history, and 69 unrelated normal individuals as control. Thus a total of 154 samples were screened for BRCA1 and BRCA2 mutations using a combination of polymerase chain reaction-mediated site directed mutagenesis (PSM), polymerase chain reaction-single stranded conformation polymorphism assay (PCR-SSCP) and direct DNA sequencing of PCR products (DS). Twenty-one sequence variants including fifteen point mutations were identified. Five deleterious pathogenic, protein truncating frameshift and non-sense mutations were detected in exon 2 (c.187_188delAG); and exon 11 (c.3672G>T) [p.Glu1185X] of BRCA1 and in exon 11 (c.5227dupT, c.5242dupT, c.6180dupA) of BRCA2 (putative mutations - four novel) as well as fourteen amino acid substitutions were identified. Twelve BRCA1 and BRCA2 missense variants were identified as unique and novel. In the cohort of 20 sporadic female patients no mutations were found.
两种主要的遗传性乳腺癌/卵巢癌易感肿瘤抑制基因BRCA1和BRCA2，尽管执行明显的一般细胞功能，但当它们在种系中发生改变或突变时，却会在人群中导致组织特异性综合征。然而，关于BRCA1和BRCA2突变对印度人群乳腺癌和/或卵巢癌的影响知之甚少。我们筛查了16个印度裔乳腺癌或乳腺癌和卵巢癌家族中BRCA1和BRCA2的整个编码序列、内含子-外显子边界及其侧翼内含子区域的突变。我们还分析了20名散发性乳腺癌女性患者，无论其年龄和家族史如何，并将69名无关的正常个体作为对照。因此，使用聚合酶链反应介导的定点诱变（PSM）、聚合酶链反应-单链构象多态性分析（PCR-SSCP）和PCR产物直接DNA测序（DS）相结合的方法，对总共154个样本进行了BRCA1和BRCA2突变筛查。共鉴定出21个序列变异，包括15个点突变。在BRCA1的外显子2（c.187_188delAG）和外显子11（c.3672G>T）[p.Glu1185X]以及BRCA2的外显子11（c.5227dupT、c.5242dupT、c.6180dupA）（推定突变——4个新突变）中检测到5个有害的致病性蛋白质截短移码和无义突变，以及14个氨基酸替换。鉴定出12个BRCA1和BRCA2错义变异为独特的新变异。在20名散发性女性患者队列中未发现突变。
