Merajver S D, Frank T S, Xu J, Pham T M, Calzone K A, Bennett-Baker P, Chamberlain J, Boyd J, Garber J E, Collins F S
Departments of Internal Medicine, Pathology, and Human Genetics, and the Human Genome Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Clin Cancer Res. 1995 May;1(5):539-44.
The BRCA1 gene on human chromosome 17q21 is responsible for an autosomal dominant syndrome of inherited early onset breast/ovarian cancer. It is estimated that women harboring a germline BRCA1 mutation incur an 85% lifetime risk of breast cancer and a greatly elevated risk of ovarian cancer. The BRCA1 gene has recently been isolated and mutations have been found in the germline of affected individuals in linked families. Previous studies of loss of heterozygosity (LOH) in breast tumors have been carried out on sporadic tumors derived from individuals without known linkage to BRCA1 and on tumors from linked families. Loss of large regions of chromosome 17 has been observed, but these LOH events could not be unequivocally ascribed to BRCA1. We have studied 28 breast and 6 ovarian tumors from families with strong evidence for linkage between breast cancer and genetic markers flanking BRCA1. These tumors were examined for LOH using genetic markers flanking and within BRCA1, including THRA1, D17S856, EDH17B1, EDH17B2, and D17S183. Forty-six percent (16/34) of tumors exhibit LOH which includes BRCA1. In 8 of 16 tumors the parental origin of the deleted allele could be determined by evaluation of haplotypes of associated family members; in 100% of these cases, the wild-type allele was lost. In some of these families germline mutations in BRCA1 have been determined; analyses of tumors with LOH at BRCA1 have revealed that only the disease-related allele of BRCA1 was present. These data strongly support the hypothesis that BRCA1 is a tumor suppressor gene.
人类17号染色体q21区域上的BRCA1基因与遗传性早发性乳腺癌/卵巢癌的常染色体显性综合征有关。据估计，携带BRCA1种系突变的女性患乳腺癌的终生风险为85%，患卵巢癌的风险也大幅升高。BRCA1基因最近已被分离出来，并且在相关家族中受影响个体的种系中发现了突变。先前对乳腺肿瘤杂合性缺失（LOH）的研究是在散发性肿瘤上进行的，这些肿瘤来自与BRCA1无已知连锁关系的个体以及来自相关家族的肿瘤。已观察到17号染色体大片段的缺失，但这些LOH事件不能明确归因于BRCA1。我们研究了来自乳腺癌与BRCA1侧翼遗传标记之间有强连锁证据的家族的28例乳腺肿瘤和6例卵巢肿瘤。使用BRCA1侧翼和内部的遗传标记，包括THRA1、D17S856、EDH17B1、EDH17B2和D17S183，对这些肿瘤进行LOH检测。46%（16/34）的肿瘤表现出包含BRCA1的LOH。在16例肿瘤中的8例中，缺失等位基因的亲本来源可通过评估相关家族成员的单倍型来确定；在这些病例中，100%野生型等位基因丢失。在其中一些家族中，已确定BRCA1的种系突变；对BRCA1处有LOH的肿瘤分析显示，仅存在与疾病相关的BRCA1等位基因。这些数据有力地支持了BRCA1是一种肿瘤抑制基因的假说。
