Hedau Suresh, Jain Neeraj, Husain Syed A, Mandal Ashish K, Ray Gibanananda, Shahid M, Kant Ravi, Gupta Vishal, Shukla Nootan K, Deo Suryanarayan S V, Das Bhudev C
Division of Molecular Oncology, Institute of Cytology and Preventive Oncology (ICMR), Maulana Azad Medical College Campus, New Delhi, 110 002, India.
Breast Cancer Res Treat. 2004 Nov;88(2):177-86. doi: 10.1007/s10549-004-0593-8.
Mutations in breast cancer susceptibility genes, BRCA1 and BRCA2 account for more than 80% of hereditary breast and ovarian cancers. p53 tumor suppressor gene that controls cellular growth and differentiation is also known to be mutated in more than 50% of human cancers including breast cancer. We have carried out a study on BRCA1 and BRCA2 along with p53 gene mutations in both sporadic as well as familial breast cancer patients from India where breast cancer is fast emerging as a major cancer among premenopausal urban women. We examined 124 untreated primary breast cancer patients comprising 100 sporadic and 24 familial cases including 56 age-matched healthy controls for the presence of BRCA1, BRCA2 and the p53 gene mutations using PCR-SSCP and direct nucleotide sequencing. Certain frequently mutated exons such as 2, 5, 11, 13 and 20 of BRCA1, exons 2, 9, 11 (for 6174delT), 18 and 20 of BRCA2 and 4-9 exons of p53 gene were analyzed in sporadic breast cancer while all 22 coding exons of BRCA1 including its flanking intronic regions along with above mentioned exons of BRCA2 and p53 gene were analyzed in familial breast cancer patients. We identified six patients (25%) with BRCA1 mutation of which three were found to be of novel type one in exon 16 (4956insG) and two in exon 7 (Lys110Thr) (Ser114Pro) out of 24 familial breast cancer patients studied from two different geographic regions/populations of India. Two sisters from a single family (12.5%) out of eight families from Goa with Portuguese colonial origin showed presence of founder Ashkenazi Jewish BRCA1 mutation (185delAG) along with (IVS7 561-34T>C; IVS18 5271 + 66G > A). While from New Delhi, four (25%) of 16 breast cancer families showed BRCA1 mutations; a frame shift protein truncating (4956insG), a transition nonsense (Gln1395Stop) and two amino acid substitutions (Lys110Thr) and (Ser114Pro). Only one (4%) p53 mutation (Val97Ile) in its exon 4 along with BRCA1 mutation (4956insG) could be detected. No major sequence variation in BRCA2 gene was observed except for G203A at 5' UTR of exon 2, a common population polymorphism in two Goan patients who also showed silent nucleotide change for amino acid serine at codon 1436 of BRCA1 gene. None of the 100 sporadic breast cancer patients revealed any protein truncating or deleterious BRCA1 or BRCA2 gene mutation. Interestingly, three (3%) p53 mutations in its exon 5 were detected in sporadic breast cancer patients. Although three novel BRCA1 mutations including a founder Ashkenazi Jewish BRCA1 mutation were recorded in Indian women with familial breast cancer, the overall prevalence of BRCA gene mutations in Indian women with a family history of breast cancer appears to be low.
乳腺癌易感基因BRCA1和BRCA2的突变占遗传性乳腺癌和卵巢癌的80%以上。已知控制细胞生长和分化的p53肿瘤抑制基因在包括乳腺癌在内的50%以上的人类癌症中也会发生突变。我们对来自印度的散发性和家族性乳腺癌患者的BRCA1、BRCA2以及p53基因突变进行了研究，在印度，乳腺癌正迅速成为绝经前城市女性中的主要癌症。我们使用PCR-SSCP和直接核苷酸测序法，对124例未经治疗的原发性乳腺癌患者进行了检测，其中包括100例散发性病例和24例家族性病例，以及56例年龄匹配的健康对照，以检测BRCA1、BRCA2和p53基因突变的存在。在散发性乳腺癌中分析了BRCA1的某些频繁突变外显子，如2、5、11、13和20外显子，BRCA2的2、9、11（针对6174delT）、18和20外显子以及p53基因的4-9外显子；而在家族性乳腺癌患者中分析了BRCA1的所有22个编码外显子及其侧翼内含子区域，以及BRCA2和p53基因的上述外显子。在从印度两个不同地理区域/人群研究的24例家族性乳腺癌患者中，我们鉴定出6例（25%）BRCA1突变患者，其中3例在外显子16中发现为新型（4956insG），2例在外显子7中（Lys110Thr）（Ser114Pro）。来自果阿有葡萄牙殖民起源的8个家族中的一个家族的两姐妹（12.5%）显示存在始祖阿什肯纳兹犹太BRCA1突变（185delAG）以及（IVS7 561-34T>C；IVS18 5271 + 66G > A）。而在新德里，16个乳腺癌家族中有4个（25%）显示BRCA1突变；一个移码蛋白截短突变（4956insG）、一个转换无义突变（Gln1395Stop）以及两个氨基酸替换（Lys110Thr）和（Ser114Pro）。仅检测到1例（4%）p53基因外显子4中的突变（Val97Ile）以及BRCA1突变（4956insG）。除了外显子2的5'UTR处的G203A（这是两名果阿患者中的常见群体多态性，他们在BRCA1基因的密码子1436处也显示了氨基酸丝氨酸的沉默核苷酸变化）外，未观察到BRCA2基因的主要序列变异。100例散发性乳腺癌患者中均未发现任何蛋白截短或有害的BRCA1或BRCA2基因突变。有趣的是，在散发性乳腺癌患者中检测到3例（3%）p53基因外显子5中的突变。尽管在有家族性乳腺癌的印度女性中记录到3种新型BRCA1突变，包括一种始祖阿什肯纳兹犹太BRCA1突变，但有乳腺癌家族史的印度女性中BRCA基因突变的总体患病率似乎较低。
