Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis
Heterogenic loss of the wild-type BRCA allele in human breast tumorigenesis
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DOI：
10.1245/s10434-007-9372-1
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发表时间：
2007-09-01
影响因子：
3.7
通讯作者：
Boyd, Jeff
中科院分区：
文献类型：
--
作者：
King, Tari A.;Li, Weiwei;Boyd, Jeff
背景资料：对于通过突变BRCA等位基因遗传而易患乳腺癌和卵巢癌的个体，影响野生型等位基因的体细胞杂合性缺失被认为是癌症发生和/或进展的必然原因。然而，有几条证据表明，表型效应可能会导致BRCA haploinsufficient.Methods：档案固定和包埋组织标本的生殖系有害突变BRCA 1或BRCA 2的妇女进行了鉴定。病理学检查后，从14例BRCA 1相关和9例BRCA 2相关乳腺癌中发现了正常乳腺上皮、非典型导管增生、导管原位癌和浸润性导管癌的病灶区域。10 BRCA连锁预防性乳房切除术标本和12 BRCA连锁浸润性卵巢癌也进行了研究。激光弹射显微切割用于分离细胞从各种病理病变和相应的正常组织。DNA分离后，实时聚合酶链反应测定被用来定量的比例野生型突变BRCA等位基因在每个组织samples.Results：定量等位基因分型的microdissected细胞揭示了高层次的异质性，在杂合性丢失内和之间的浸润性病变和浸润性癌症从BRCA 1和BRCA 2杂合子与乳腺癌。相反，所有BRCA相关的卵巢癌显示野生型BRCA等位基因的完全丢失。结论：这些数据表明，野生型BRCA等位基因的丢失是不需要BRCA相关的乳腺肿瘤发生，这将有重要的影响BRCA肿瘤抑制的遗传机制，并为临床管理这一患者群体。
Background: For individuals genetically predisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss of heterozygosity affecting the wild-type allele is considered obligatory for cancer initiation and/or progression. However, several lines of evidence suggest that phenotypic effects may result from BRCA haploinsufficiency.Methods: Archival fixed and embedded tissue specimens from women with germ line deleterious mutations in BRCA1 or BRCA2 were identified. After pathologic review, focal areas of normal breast epithelium, atypical ductal hyperplasia, ductal carcinoma-in-situ, and invasive ductal carcinoma were identified from 14 BRCA1-linked and 9 BRCA2-linked breast cancers. Ten BRCA-linked prophylactic mastectomy specimens and 12 BRCA-linked invasive ovarian carcinomas were also studied. Laser catapult microdissection was used to isolate cells from the various pathologic lesions and corresponding normal tissues. After DNA isolation, real-time polymerase chain reaction assays were used to quantitate the proportion of wild-type to mutant BRCA alleles in each tissue sample.Results: Quantitative allelotyping of microdissected cells revealed a high level of heterogeneity in loss of heterozygosity within and between preinvasive lesions and invasive cancers from BRCA1 and BRCA2 heterozygotes with breast cancer. In contrast, all BRCA-associated ovarian cancers displayed complete loss of the wild-type BRCA allele.Conclusions: These data suggest that loss of the wild-type BRCA allele is not required for BRCA-linked breast tumorigenesis, which would have important implications for the genetic mechanism of BRCA tumor suppression and for the clinical management of this patient population.