Slavin Thomas P, Banks Kimberly C, Chudova Darya, Oxnard Geoffrey R, Odegaard Justin I, Nagy Rebecca J, Tsang Kar Wing Kevin, Neuhausen Susan L, Gray Stacy W, Cristofanilli Massimo, Rodriguez Angel A, Bardia Aditya, Leyland-Jones Brian, Janicek Mike F, Lilly Michael, Sonpavde Guru, Lee Christine E, Lanman Richard B, Meric-Bernstam Funda, Kurzrock Razelle, Weitzel Jeffrey N
Thomas P. Slavin, Kar Wing Kevin Tsang, Susan L. Neuhausen, Stacy W. Gray, and Jeffrey N. Weitzel, City of Hope, Duarte; Kimberly C. Banks, Darya Chudova, Justin I. Odegaard, Rebecca J. Nagy, Christine E. Lee, and Richard B. Lanman, Guardant Health, Redwood City; Razelle Kurzrock, University of California, San Diego, Moores Cancer Center, San Diego, CA; Geoffrey R. Oxnard, Dana-Farber Cancer Institute; Aditya Bardia, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA; Massimo Cristofanilli, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Angel A. Rodriguez, Houston Methodist Hospital; Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center, Houston, TX; Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Mike F. Janicek, Arizona Oncology Associates Gynecology Oncology, Scottsdale, AZ; Michael Lilly, Medical University of South Carolina, Charleston, SC; and Guru Sonpavde, The University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.
J Clin Oncol. 2018 Oct 19;36(35):JCO1800328. doi: 10.1200/JCO.18.00328.
To determine the potential for detection of incidental germline cancer predisposition mutations through cell-free DNA (cfDNA) analyses in patients who underwent solid tumor somatic mutation evaluation.
Data were evaluated from 10,888 unselected patients with advanced (stage III/IV) cancer who underwent Guardant360 testing between November 2015 and December 2016. The main outcome was prevalence of putative germline mutations identified among 16 actionable hereditary cancer predisposition genes.
More than 50 cancer types were studied, including lung (41%), breast (19%), colorectal (8%), prostate (6%), pancreatic (3%), and ovarian (2%). Average patient age was 63.5 years (range, 18 to 95 years); 43% were male. One hundred and fifty-six individuals (1.4%) had suspected hereditary cancer mutations in 11 genes. Putative germline mutations were more frequent in individuals younger than 50 years versus those 50 years and older (3.0% v 1.2%, respectively; P < .001). Highest yields of putative germline findings were in patients with ovarian (8.13%), prostate (3.46%), pancreatic (3.34%), and breast (2.2%) cancer. Putative germline mutation identification was consistent among 12 individuals with multiple samples. Patients with circulating tumor DNA copy number variation and/or reversion mutations suggestive of functional loss of the wild-type allele in the tumor DNA also are described.
Detection of putative germline mutations from cfDNA is feasible across multiple genes and cancer types without prior mutation knowledge. Many mutations were found in cancers without clear guidelines for hereditary cancer genetic counseling/testing. Given the clinical significance of identifying hereditary cancer predisposition for patients and their families as well as targetable germline alterations such as in BRCA1 or BRCA2, research on the best way to validate and return potential germline results from cfDNA analysis to clinicians and patients is needed.
确定在接受实体瘤体细胞突变评估的患者中，通过游离DNA（cfDNA）分析检测偶然的种系癌症易感突变的可能性。
对2015年11月至2016年12月期间接受Guardant360检测的10888例未经选择的晚期（III/IV期）癌症患者的数据进行评估。主要结果是在16个可操作的遗传性癌症易感基因中鉴定出的假定种系突变的患病率。
研究了50多种癌症类型，包括肺癌（41%）、乳腺癌（19%）、结直肠癌（8%）、前列腺癌（6%）、胰腺癌（3%）和卵巢癌（2%）。患者平均年龄为63.5岁（范围18至95岁）；43%为男性。156例个体（1.4%）在11个基因中存在疑似遗传性癌症突变。50岁及以下个体的假定种系突变比50岁及以上个体更常见（分别为3.0%和1.2%；P <.001）。假定种系发现率最高的是卵巢癌（8.13%）、前列腺癌（3.46%）、胰腺癌（3.34%）和乳腺癌（2.2%）患者。12例有多个样本的个体中，假定种系突变的鉴定结果一致。还描述了循环肿瘤DNA拷贝数变异和/或反转突变提示肿瘤DNA中野生型等位基因功能丧失的患者。
在没有先验突变知识的情况下，从cfDNA中检测假定种系突变在多个基因和癌症类型中是可行的。在没有明确的遗传性癌症遗传咨询/检测指南的癌症中发现了许多突变。鉴于确定患者及其家族遗传性癌症易感性以及可靶向的种系改变（如BRCA1或BRCA2）的临床意义，需要研究将cfDNA分析潜在种系结果验证并反馈给临床医生和患者的最佳方法。
