Whole Genome Sequencing in Cancer Clinics.
Whole Genome Sequencing in Cancer Clinics.
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DOI：
10.1016/j.ebiom.2014.12.007
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发表时间：
2015-01
期刊：
影响因子：
11.1
通讯作者：
Meric-Bernstam, Funda
中科院分区：
文献类型：
--
作者：
Chen, Ken;Meric-Bernstam, Funda
具有癌症家族史的患者正在用单基因或基因组测试进行评估（LaDuca等人，2014年）。降低成本和提供全面遗传风险评估的潜力使全基因组测序（WGS）成为了解癌症遗传风险的有吸引力的工具（柯林斯和汉堡，2013）。尽管有这样的潜力，WGS在癌症遗传学诊所的经验价值是未知的：WGS是否可以复制以前的单/多基因检测结果，以及它是否会增加识别率。在EBioMedicine的这一期，Foley等人描述了他们从分析两组癌症遗传学患者血液样本的WGS数据中获得的结果：具有BRCA 1/2突变的那些（n= 176）和没有BRCA 1/2突变的那些（n= 82）（Foley等人，2015年-在这个问题上）。在他们的分析中，他们专注于一组163个临床相关基因，包括美国医学遗传学学院推荐的商业癌症易感基因面板上的基因（绿色等人，2013），以及可能影响生殖决策的因素（Dorschner等人，2013年）。他们发现，在每个BRCA 1/2患者中，平均有6.8-6.9个潜在致病性变异（PPV），定义为正常人群中等位基因频率b1%的非同义变异（ESP 6500）。所有先前已知的BRCA 1/2突变都被检测到，证明了WGS的灵敏度。正如预期，这些PPV中的大多数是错义变体，根据现有知识，其中大多数将被归类为意义未知的变体（VUS）（Biesecker，2012）。为了便于诊断，Foley等人进一步将分析仅限于功能丧失（LoF）PPV，包括无义、非终止单核苷酸变体（SNV）和移码插入缺失（Foley等人，2015年-在这个问题上）。在6名患者中，他们在4个显性癌症相关基因（CHEK 2，ATM，RAD 50和CDKN 2B）中鉴定出LoF PPV，以及最初临床诊断的BRCA 1/2突变。这些携带额外癌症风险的变异可能用于咨询，然后筛选患者的家庭成员。有趣的是，他们发现先前报道的几个基因中的致病性错义变异与他们预测的疾病无关。例如，错义变体CREBBP p.N1978S先前被报道为Rubenstein Taybi综合征（RTS）的致病性和诊断性（Roelfsema和Peters，2007）。然而，携带这种变异的患者及其携带这种变异的家庭成员没有症状
Patients with a family history of cancer are being evaluated with single-gene or gene panel tests (LaDuca et al., 2014). The decreasing cost and potential to provide comprehensive genetic risk assessment makes whole genome sequencing (WGS) an attractive tool for understanding the genetic risk for cancer (Collins and Hamburg, 2013). Despite such potential, the empirical value of WGS in cancer genetics clinics is unknown: whether WGS can replicate previous findings in single/multi-gene testing, and whether it will increase the rate of identification.In this issue of EBioMedicine, Foley et al. describes their results obtained from analyzing the WGS data from the blood samples of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n= 176) and those without (n= 82)(Foley et al., 2015-in this issue). In their analysis, they focus on a set of 163 clinically relevant genes, including those on commercial cancer-susceptibility gene panels, recommended by American College of Medical Genetics (Green et al., 2013), and those that might impact reproductive decision-making (Dorschner et al., 2013). They find that in each BRCA1/2 patient there is an average of 6.8–6.9 potentially pathogenic variants (PPVs), defined as nonsynonymous variants with allele frequency b1% in a normal human population (ESP6500). All the previously known BRCA1/2 mutations are detected, proving the sensitivity of WGS. As anticipated, most of these PPVs are missense variants, the majority of which will be classified as variants of unknown significance (VUS) based on existing knowledge (Biesecker, 2012). To facilitate diagnoses, Foley et al. further restrict analyses to only loss-of-function (LoF) PPVs, including nonsense, nonstop single nucleotide variants (SNVs) and frameshift indels (Foley et al., 2015-in this issue). In six patients, they identify LoF PPVs in four dominant cancer-associated genes (CHEK2, ATM, RAD50, and CDKN2B), in addition to original clinically diagnosed BRCA1/2 mutations. These variants that carry additional cancer risk may be of use for counseling and then screening of the patient's family members. Interestingly, they find that previously reported pathogenic missense variants in several genes do not associate with their predicted diseases. For example, the missense variant CREBBP p. N1978S is previously reported as pathogenic and diagnostic for Rubenstein Taybi syndrome (RTS)(Roelfsema and Peters, 2007). However, a patient carrying this variant and her family members that carried the variant have no symptoms
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影响因子：
6.2
作者：
Roelfsema, Jeroen H.;Peters, Dorien J. M.
通讯作者：
Peters, Dorien J. M.
DOI：
10.1038/gim.2014.40
发表时间：
2014-11
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
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DOI：
10.1038/gim.2013.73
发表时间：
2013-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
9.8
作者：
Dorschner, Michael O.;Amendola, Laura M.;Jarvik, Gail P.
通讯作者：
Jarvik, Gail P.
影响因子：
14.9
作者：
Landrum MJ;Lee JM;Riley GR;Jang W;Rubinstein WS;Church DM;Maglott DR
通讯作者：
Maglott DR