Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.
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DOI：
10.1001/jama.2017.11137
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发表时间：
2017-09-05
期刊：
影响因子：
--
通讯作者：
Offit K
中科院分区：
文献类型：
--
作者：
Mandelker D;Zhang L;Kemel Y;Stadler ZK;Joseph V;Zehir A;Pradhan N;Arnold A;Walsh MF;Li Y;Balakrishnan AR;Syed A;Prasad M;Nafa K;Carlo MI;Cadoo KA;Sheehan M;Fleischut MH;Salo-Mullen E;Trottier M;Lipkin SM;Lincoln A;Mukherjee S;Ravichandran V;Cambria R;Galle J;Abida W;Arcila ME;Benayed R;Shah R;Yu K;Bajorin DF;Coleman JA;Leach SD;Lowery MA;Garcia-Aguilar J;Kantoff PW;Sawyers CL;Dickler MN;Saltz L;Motzer RJ;O'Reilly EM;Scher HI;Baselga J;Klimstra DS;Solit DB;Hyman DM;Berger MF;Ladanyi M;Robson ME;Offit K
基于家族史的癌症基因检测指南可能会遗漏对癌症筛查或预防具有确定意义的临床可操作的基因变化。通过肿瘤和正常组织同时测序（“肿瘤-正常测序”）与基于现行指南的基因检测结果进行比较，确定遗传变异检测的比例和潜在临床意义。从2014年1月到2016年5月，在纪念斯隆凯特琳癌症中心，10336名患者同意进行肿瘤DNA测序。自2015年5月以来，1040名晚期癌症患者由肿瘤学家转介进行了76种癌症易感基因的种系分析。确定了具有临床可操作的遗传突变的患者，其基因检测结果无法通过公布的决策规则预测。对突变检测的潜在临床意义的随访一直持续到2017年5月。肿瘤和生殖系测序与基于临床指南的靶向生殖系测序预测产量的比较。通过通用肿瘤正常测序检测到的临床可操作的种系突变的比例，这些突变不会被指导测试检测到。在1040名患者中，中位年龄为58岁（四分位数范围为50.5-66岁），65.3%为男性，81.3%在基因组分析时为IV期疾病，前列腺癌、肾癌、胰腺癌、乳腺癌和结肠癌是最常见的诊断。在1040例患者中，182例（17.5%;95%CI, 15.3%-19.9%）具有具有癌症易感性的临床可操作突变，包括149例中外显率至高外显率突变；101例患者（9.7%;95%CI, 8.1%-11.7%）使用临床指南不会检测到这些突变，包括65例中等至高外显率突变。遗传突变的频率与病例组合、阶段和创始突变有关。生殖系研究结果导致38例（3.7%）患者讨论或开始改变靶向治疗，并在13个个体的家庭中进行预测性检测（1.3%），其中6个个体的遗传评估不会通过基于指南的检测进行。在这个选择晚期癌症的转诊人群中，配对生殖系和肿瘤DNA样本中广泛的癌症相关基因的普遍测序与基于当前临床指南的靶向生殖系检测预测产量的潜在临床显著遗传性突变个体的检测增加相关。了解这些额外的突变可以帮助指导治疗和预防干预，但是否所有这些干预措施都能改善癌症患者或其家庭成员的预后，还需要进一步研究。clinicaltrials.gov标识符：NCT01775072
Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention. To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue (“tumor-normal sequencing”) compared with genetic test results based on current guidelines. From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017. Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines. Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing. Of 1040 patients, the median age was 58 years (interquartile range, 50.5–66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95%CI, 15.3%–19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95%CI, 8.1%–11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing. In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study. clinicaltrials.gov Identifier: NCT01775072
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影响因子：
3.7
作者：
Pilarski, Robert;Cebulla, Colleen M.;Massengill, James B.;Rai, Karan;Rich, Thereasa;Strong, Louise;McGillivray, Barbara;Asrat, Mary-Jill;Davidorf, Frederick H.;Abdel-Rahman, Mohamed H.
通讯作者：
Abdel-Rahman, Mohamed H.
影响因子：
4.6
作者：
Abida W;Armenia J;Gopalan A;Brennan R;Walsh M;Barron D;Danila D;Rathkopf D;Morris M;Slovin S;McLaughlin B;Curtis K;Hyman DM;Durack JC;Solomon SB;Arcila ME;Zehir A;Syed A;Gao J;Chakravarty D;Vargas HA;Robson ME;Joseph V;Offit K;Donoghue MTA;Abeshouse AA;Kundra R;Heins ZJ;Penson AV;Harris C;Taylor BS;Ladanyi M;Mandelker D;Zhang L;Reuter VE;Kantoff PW;Solit DB;Berger MF;Sawyers CL;Schultz N;Scher HI
通讯作者：
Scher HI
影响因子：
50.5
作者：
Meric-Bernstam, F.;Brusco, L.;Chen, K.
通讯作者：
Chen, K.
影响因子：
11.5
作者：
Seifert, Bryce A.;O'Daniel, Julianne M.;Berg, Jonathan S.
通讯作者：
Berg, Jonathan S.
DOI：
10.1056/nejmoa1508054
发表时间：
2015-12-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Zhang J;Walsh MF;Wu G;Edmonson MN;Gruber TA;Easton J;Hedges D;Ma X;Zhou X;Yergeau DA;Wilkinson MR;Vadodaria B;Chen X;McGee RB;Hines-Dowell S;Nuccio R;Quinn E;Shurtleff SA;Rusch M;Patel A;Becksfort JB;Wang S;Weaver MS;Ding L;Mardis ER;Wilson RK;Gajjar A;Ellison DW;Pappo AS;Pui CH;Nichols KE;Downing JR
通讯作者：
Downing JR