Rosman Diana S, Kaklamani Virginia, Pasche Boris
Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Curr Treat Options Oncol. 2007 Feb;8(1):61-73. doi: 10.1007/s11864-007-0021-5.
The combined observation that 20-30% of all patients with breast cancer have a family history of the disease and the results from twin studies showing that 25% of breast cancer cases are heritable, indicate that this malignancy is one of the most commonly inherited cancers. Discovery of the BRCA1 and BRCA2 genes more than a decade ago has had a tremendous impact on patient care allowing for early detection and prevention of breast cancer. However, deleterious mutations within the BRCA1 and BRCA2 genes cause at most 3-8% of all breast cancer cases. New data indicate that genomic rearrangements within the same genes may occasionally identify additional carriers of nonfunctional BRCA1 and BRCA2 genes. Such genomic rearrangements are missed by conventional sequencing. The remainder of the unexplained familial risk is presumably due to other yet unidentified high penetrance genes, but polygenic mechanisms and high frequency low penetrance tumor susceptibility genes are likely to account for a greater proportion of familial breast cancers. In this regard, there is growing evidence that a common variant of the type I TGF-ss receptor, TGFBR1*6A, may account for approximately 5% of all breast cancer cases, a fraction similar to that attributable to BRCA1 and BRCA2. Such genes may also modify the penetrance of the BRCA1 and BRCA2 genes. In the next decade, screening for combinations of high and low penetrance genes will likely permit the identification of a large fraction of inherited breast cancer cases and will further reduce the burden of familial breast cancer.
综合观察发现，所有乳腺癌患者中有20%-30%有家族病史，双胞胎研究结果显示25%的乳腺癌病例具有遗传性，这表明这种恶性肿瘤是最常见的遗传性癌症之一。十多年前BRCA1和BRCA2基因的发现对患者护理产生了巨大影响，使得乳腺癌能够早期检测和预防。然而，BRCA1和BRCA2基因中的有害突变最多导致所有乳腺癌病例的3%-8%。新数据表明，同一基因内的基因组重排偶尔可能会识别出非功能性BRCA1和BRCA2基因的其他携带者。这种基因组重排会被传统测序遗漏。其余无法解释的家族性风险可能归因于其他尚未确定的高 penetrance 基因，但多基因机制和高频低 penetrance 肿瘤易感性基因可能在家族性乳腺癌中占更大比例。在这方面，越来越多的证据表明，I型TGF-β受体的一个常见变体TGFBR1*6A可能占所有乳腺癌病例的约5%，这一比例与BRCA1和BRCA2所致比例相似。此类基因也可能改变BRCA1和BRCA2基因的 penetrance。在未来十年，对高 penetrance 和低 penetrance 基因组合进行筛查可能会识别出很大一部分遗传性乳腺癌病例，并将进一步减轻家族性乳腺癌的负担。
