The differential diagnosis of a TP53 genetic testing result.
The differential diagnosis of a TP53 genetic testing result.
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DOI：
10.1038/gim.2017.250
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Maxwell KN
中科院分区：
文献类型：
--
作者：
MacFarland SP;Maxwell KN
Li-Fraumeni癌症易感综合征（LFS, MIM 151623）最初被描述为一种常染色体显性遗传综合征，以儿童肉瘤和多种其他癌症类型为特征，通常是由于TP53基因的种系突变。1基于早发性肉瘤表型的经典LFS诊断标准对TP53突变的特异性超过90%；然而，灵敏度只有40%。因此，更广泛的标准（Chompret标准）被用于预测生殖系TP53突变的存在，包括“核心癌”（肉瘤、绝经前乳腺癌、脑癌、白血病或肾上腺皮质癌）和/或多发性原发恶性肿瘤和/或患有早发性癌症的家庭成员的诊断。3这些标准对TP53突变的敏感性超过90%，但特异性较低，在15%到52%之间，2可能是由于基因座异质性，与TP53突变相关的表型谱比最初认识的更广泛，以及新生突变的存在。鉴于与种系TP53突变相关的表型异质性，在目前用于癌症易感性评估的临床应用中，几乎所有的多重检测面板上都发现了TP53。考虑到大多数被检测个体突变的预测概率较低，TP53错义突变的优势具有不同的致病性支持，以及低渗透或不完全渗透TP53突变的潜力，在当前的多重面板检测时代，解释TP53突变存在许多挑战。最近，由于人们越来越认识到大规模平行测序（MPS）检测循环血细胞中与杂合或纯合突变不一致的等位基因部分的TP53突变，种系TP53突变检测变得更加复杂。这些所谓的“马赛克突变”一直存在；然而，传统的基于桑格测序的基因检测可能错过了绝大多数病例。虽然罕见，但马赛克TP53结果产生了重大的临床难题，因为这些结果的病因学解释具有不同的临床意义。在这一期的《医学遗传学》中，Weitzel及其同事分析了来自临床检测实验室的数据，并使用辅助测试来解决马赛克TP53结果的频率和可能的病因这一重要的临床问题。6
The Li-Fraumeni cancer predisposition syndrome (LFS, MIM 151623) was originally described as an autosomal dominantly inherited syndrome characterized by childhood sarcomas and multiple other cancer types and is often due to germ-line mutations in the TP53 gene. 1 Classic LFS diagnostic criteria based on the early-onset sarcoma phenotype are over 90% specific for TP53 mutations; however, sensitivity is only 40%. 2 Therefore, more expansive criteria (Chompret criteria) were developed to predict the presence of a germ-line TP53 mutation, including diagnosis of a “core cancer”(sarcoma, premenopausal breast, brain, leukemia, or adrenocortical carcinoma) and/or multiple primary malignancies and/or family members with early-onset cancer. 3 These criteria are over 90% sensitive for TP53 mutations, but specificity is low, ranging from 15 to 52%, 2 probably owing to locus heterogeneity, a broader phenotypic spectrum associated with TP53 mutations than originally appreciated, and the existence of de novo mutations. In view of the phenotypic heterogeneity associated with germ-line TP53 mutations, TP53 is found on nearly all multiplex panels in current clinical use for cancer predisposition evaluation. There are many challenges in interpreting a TP53 mutation in this current era of multiplex panel testing, given the low pretest probability of a mutation in the majority of individuals being tested, the preponderance of missense mutations in TP53 with variable support of pathogenicity, and the potential for low or incompletely penetrant TP53 mutations.Recently, germ-line TP53 mutation testing has become further complicated by the increasing recognition that massively parallel sequencing (MPS) detects mutations in TP53—among other genes—in circulating blood cells at allelic fractions inconsistent with a heterozygous or homozygous mutation. 4 These so-called “mosaic mutations” have always existed; 5 however, traditional Sanger sequencing-based genetic testing probably missed the vast majority of cases. Although rare, mosaic TP53 results are creating significant clinical conundrums as the interpretation of the etiology of these results has differing clinical implications. In this issue of Genetics in Medicine, Weitzel and colleagues analyze data from a clinical testing laboratory and use ancillary testing to address the important clinical question of the frequency and possible etiologies of mosaic TP53 results. 6
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DOI：
10.6004/jnccn.2017.0003
发表时间：
2017-01-01
影响因子：
13.4
作者：
Daly, Mary B.;Pilarski, Robert;Darlow, Susan
通讯作者：
Darlow, Susan
影响因子：
56.9
作者：
MALKIN, D;LI, FP;FRIEND, SH
通讯作者：
FRIEND, SH
影响因子：
82.9
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--
影响因子：
28.4
作者：
Swisher EM;Harrell MI;Norquist BM;Walsh T;Brady M;Lee M;Hershberg R;Kalli KR;Lankes H;Konnick EQ;Pritchard CC;Monk BJ;Chan JK;Burger R;Kaufmann SH;Birrer MJ
通讯作者：
Birrer MJ
DOI：
10.1126/science.aag1381
发表时间：
2017-02-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fuster JJ;MacLauchlan S;Zuriaga MA;Polackal MN;Ostriker AC;Chakraborty R;Wu CL;Sano S;Muralidharan S;Rius C;Vuong J;Jacob S;Muralidhar V;Robertson AA;Cooper MA;Andrés V;Hirschi KK;Martin KA;Walsh K
通讯作者：
Walsh K