Re: Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative.
Re: Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative.
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回复：亲属遗传性癌症风险的级联基因检测：在线倡议的结果。
DOI：
10.1093/jnci/djz028
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Schwartz,MarcD
中科院分区：
文献类型：
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作者：
Peshkin,BethN;Isaacs,Claudine;Schwartz,MarcD
我们饶有兴趣地阅读了 Caswell-Jin 等人关于对有遗传性癌症风险的亲属进行级联检测的报告 (1)。他们指出，在患有癌症易感致病性变异 (PV) 的 1084 名一级亲属中，在接受多基因癌症小组检测 (MCPT) 时，4.9% 的人在其家族中存在的基因以外的基因中检测出 PV 呈阳性。这些数据之所以重要有两个原因。首先，针对 MCPT 的现场特定测试已成为标准做法，国家指南不建议在亲属中进行 MCPT (2)。其次，尽管已发表的报告表明一个家庭中发现了多个 PV，包括通过 MCPT 发现的那些 (3)，但这是第一个也是最大的描述在亲属中系统使用此类测试的研究。鉴于 MCPT 的成本已大幅下降（美国一些实验室为 250 美元或更低），因此更频繁地提供这种检测也就不足为奇了——不仅针对索引患者，还针对他们的亲属。 MCPT 可以为有家族性 PV 风险的亲属带来好处。例如，家族史可能不是识别不同 PV 的可靠预测因素。亲属可能有家族史，但没有已知的 PV。而且，一些已识别的 PV（本报告中约占 20%）将存在于高度渗透且可操作的综合征基因中。 MCPT 也存在相关风险和限制。在这份报告中，在 4.9% 的参与者中，除了指示患者中发现的 PV 以外，大约 80% 的参与者存在低外显率等位基因或中度风险基因的变异。由于针对患有此类真性红斑狼疮的个体几乎没有基于证据的管理指导，因此这些结果的临床效用尚不清楚 (4)。此外，当评估多个基因时，识别一种或多种具有不确定意义的变异的可能性会升高（当前报告中为 16.8%），这可能会引起关注，并且需要在重新分类时进行后续跟踪 (5)。
We read with interest Caswell-Jin et al.’s report regarding cascade testing in relatives at-risk for hereditary cancer (1). They noted that of 1084 first-degree relatives of individuals with a cancer predisposing pathogenic variant (PV) who underwent multigene cancer panel testing (MCPT), 4.9% tested positive for a PV in a gene other than the one present in their family. These data are important for two reasons. First, site-specific testing versus MCPT has been the standard practice, and MCPT in relatives is not recommended by national guidelines (2). Second, although there are published reports of more than one PV identified in a family, including those identified from MCPT (3), this is the first and largest study describing systematic use of such testing in relatives. Given that the cost of MCPT has dropped considerably ($250 or less in some US labs), it is not surprising that this testing is being offered more often—not only to index patients but also to their relatives. There are benefits conferred by MCPT in relatives at risk for a familial PV. For example, family history may not be a reliable predictor of identifying a different PV. Relatives may have a suggestive history on the side of the family without the known PV. And, some identified PVs (about 20% in this report) will be in highly penetrant and actionable syndromic genes. There are also risks and limitations associated with MCPT. In this report, of the 4.9% of participants with a PV other than the one identified in the index patient, about 80% had a variant in a low-penetrance allele or moderate risk gene. As there is little evidence-based management guidance for individuals with these types of PVs, the clinical utility of these results is unclear (4). In addition, the likelihood of identifying one or more variants of uncertain significance is elevated when multiple genes are assessed (16.8% in the current report), which may cause concern and the need for future follow-up as these are reclassified (5).