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Mutation Frequencies in Patients With Early-Onset Colorectal Cancer
JAMA Oncology ( IF 28.4 ) Pub Date : 2017-11-01 , DOI: 10.1001/jamaoncol.2016.7089
Andrew D Beggs 1
Affiliation  

To the Editor The recent study by Pearlman et al1 raises concerns. The hypothesis of the article is laudable, that is, genetic susceptibility forms a significant part of the risk in patients with early-onset (defined as younger than 50 years) colorectal cancer (CRC). However, the data reported in the article do not correlate with what is known as being relevant in the disease mechanism of CRC.2 The authors report mutations in “nontraditional” CRC genes such as BRCA1/2, CDKN2A, PALB2, and CHEK2 in 32 of 72 patients, all of which are associated with hereditary breast cancer.3 In fact, given that CRC is a phenomenon driven primarily by dysfunctional Wnt signaling, it is difficult to understand how these germline drivers in cell cycle and DNA repair genes (which have been extensively investigated previously, in vitro and in vivo, as potential driver genes in CRC) have any relevance to this topic; they merely inflate the relevant germline variation rate reported in this study. What the article should in fact report is that a detection rate of 10% for patients with Lynch syndrome was observed, which is above what has previously been reported in other population studies and is likely to be enriched by the selection for early-onset cancer. The observed APC mutation (APC c.3920T>A, p.I1307K mutation) is almost uniquely associated with Ashkenazi Jewish ancestry,4 being associated with a multiple-tumor phenotype; it is not low penetrance and unlikely to be common outside the group of patients. In conclusion, this type of study is useful in that it highlights the role of genetic testing in early onset-cancer cases, but it should not be used to argue that there is a hidden pool of patients with relevant germline drivers. It is likely that further information from population-based whole-genome sequencing studies (eg, the UK 100 000 Genomes project) will reveal the complex landscape of rare, highly penetrant CRC driver genes.



中文翻译:

早发性结直肠癌患者的突变频率

致编辑Pearlman 等人最近的研究1引起了人们的关注。这篇文章的假设值得称赞,即遗传易感性是早发性(定义为小于 50 岁)结直肠癌 (CRC) 患者风险的重要组成部分。然而,文章中报告的数据与所谓的与 CRC 疾病机制相关的数据不相关。2作者报告了 72 名患者中有 32 名发生了“非传统”CRC 基因(如BRCA1/2、CDKN2A、PALB2CHEK2 )的突变,所有这些基因都与遗传性乳腺癌有关。3事实上,鉴于 CRC 是一种主要由功能失调的Wnt驱动的现象信号传导,很难理解细胞周期和 DNA 修复基因中的这些种系驱动因子(之前已在体外和体内广泛研究,作为 CRC 中的潜在驱动基因)与该主题有任何相关性;他们只是夸大了本研究中报告的相关种系变异率。这篇文章实际上应该报告的是,观察到林奇综合征患者的检出率为 10%,高于之前在其他人群研究中报告的检出率,并且可能会因选择早发性癌症而得到丰富。观察到的APC突变(APC c.3920T>A,p.I1307K 突变)几乎与德系犹太人血统唯一相关,4与多肿瘤表型相关;它的外显率不低,在患者群体之外不太常见。总之,这种类型的研究是有用的,因为它强调了基因检测在早发性癌症病例中的作用,但不应该用来争论存在一个隐藏的具有相关种系驱动因素的患者库。来自基于人群的全基因组测序研究(例如,UK 100 000 Genomes 项目)的进一步信息可能会揭示稀有、高渗透性 CRC 驱动基因的复杂情况。

更新日期:2017-11-10
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