Unifying cancer genetics.
Unifying cancer genetics.
复制标题
统一癌症遗传学。
DOI：
10.1097/gim.0b013e31820d5e87
复制
发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Plon SE
中科院分区：
文献类型：
--
作者：
Plon SE
在过去的几十年里，癌症遗传学领域实际上是两个领域。医学遗传学家和遗传咨询师使用该术语来描述遗传性癌症易感性和识别传递这种风险的体质突变。或者，许多病理学家、肿瘤学家和分子生物学家使用该术语来描述肿瘤细胞本身发生的大量遗传变化。即使在美国医学遗传学委员会的实验室专业中，分子诊断学家也专注于遗传突变，例如，从血液中测序肿瘤抑制基因突变，而细胞遗传学家和分子病理学家则专注于肿瘤标本中的易位、拷贝数变化和特定致癌错义突变。像癌症遗传学中的大多数事情一样，人们总是可以从视网膜母细胞瘤开始。确定单侧视网膜母细胞瘤患者是否具有遗传形式是基于对肿瘤标本的分析，以鉴定两种RB 1失活事件。1该信息随后用于通知血液分析，例如，如果RB 1启动子经历双等位基因甲基化，则不指示血液分析。来自癌症基因组解剖项目（TCGA）的胶质母细胞瘤分析的大量数据显示，易感基因（如RB 1）的体细胞突变比最初意识到的更频繁。随着下一代测序技术的日益普及，所有类型的从业者在做出临床决策时都需要考虑体质和癌症基因组。这里描述的是医学遗传学家如何开始将癌症基因组数据纳入临床实践的一些例子。对相对罕见的胃肠道肿瘤的分析证明了同一信号通路中基因之间的相互作用。分子病理学家已经证明，肝母细胞瘤和硬纤维瘤的很大一部分都含有影响WNT信号传导的突变。3在大多数情况下，这些突变是编码β-连环蛋白的CTNNB 1基因中的特异性外显子3错义突变。[4]相反，对遗传性肿瘤的研究表明，即使家族性腺瘤性息肉病的其他临床特征尚不明显，也有一部分患者（约10-15%）存在APC基因的种系突变。5因此，对所有患有这些肿瘤的儿童建议进行APC突变的血液诊断测序。APC和β-连环蛋白在APC调节β-连环蛋白可用性的相同途径中起作用。最近，已经建立了硬纤维瘤和肝母细胞瘤中体细胞CTNNB 1突变和组成性APC突变之间的反比关系。4，6如果肿瘤包含CTNNB 1的体细胞突变，则未发现构成性APC突变。因此，现在当我被转介为患有这些肿瘤之一的儿童时，
For the past several decades, the field of cancer genetics has really been two fields. Medical geneticists and genetic counselors use the term to describe inherited susceptibility to cancer and the identification of constitutional mutations, which convey this risk. Alternatively, many pathologists, oncologists, and molecular biologists use the term to describe the multitude of genetic changes that occur in the tumor cell itself. Even among the American Board of Medical Genetics laboratory specialties, molecular diagnosticians have focused on inherited mutations, eg, sequencing DNA from blood for tumor suppressor gene mutations, whereas cytogeneticists and molecular pathologists characterize translocations, copy number changes, and specific oncogenic missense mutations in tumor specimens.This dichotomy is breaking down. Like most things in cancer genetics, one can always start with retinoblastoma. The determination as to whether a patient with unilateral retinoblastoma has the hereditary form is founded on analysis of the tumor specimen to identify both RB1 inactivating events. 1 This information is then used to inform analysis of the blood, eg, if the RB1 promoter undergoes biallelic methylation, then analysis of the blood is not indicated. The wealth of data from the Cancer Genome Anatomy project (TCGA) analysis of glioblastoma reveals that somatic mutations in susceptibility genes like RB1 are more frequent than first realized. 2 As next generation sequencing becomes increasingly available, practitioners of all types will need to consider both the constitutional and cancer genome when making clinical decisions. Described here are some examples of how medical geneticists are beginning to incorporate cancer genome data into clinical practice. Analysis of relatively rare gastrointestinal tumors demonstrates the interaction between genes in the same signaling pathway. Molecular pathologists have demonstrated that a substantial portion of both hepatoblastoma and desmoid tumors contain mutations that impact WNT signaling. 3 In the majority of cases, these mutations are specific exon 3 missense mutations in the CTNNB1 gene encoding ß-CATENIN. 4 In contrast, work on hereditary tumors has demonstrated that a subset of patients with these tumors (perhaps 10–15%) harbor germline mutations in the APC gene even if other clinical features of familial adenomatous polyposis are not yet evident. 5 Thus, diagnostic sequencing of the blood for mutations in APC has been recommended for all children with these tumors. 5 APC and ß-CATENIN proteins function in the same pathway where APC regulates the availability of ß-CATENIN. More recently, an inverse relationship between somatic CTNNB1 mutation and constitutional APC mutation in desmoid and hepatoblastoma tumors has been established. 4, 6 If the tumor contains a somatic mutation in CTNNB1, then constitutional APC mutations are not found. So now when I am referred a child with one of these tumors,