Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance
Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance
复制标题
DOI：
10.1200/jco.18.01512
复制
发表时间：
2019-05-01
影响因子：
45.3
通讯作者：
Goggins, Michael
中科院分区：
文献类型：
--
作者：
Abe, Toshiya;Blackford, Amanda L.;Goggins, Michael
比较生殖系突变状态与无已知生殖系突变家族史的肿瘤进展风险方法在约翰霍普金斯医院胰腺癌筛查项目中的464名高危个体中，119人在胰腺癌易感基因中存在已知的有害生殖系突变; 345人符合胰腺监测的家族史标准，但不知道是否存在生殖系突变。我们使用下一代测序技术来鉴定这345名个体中以前未被识别的种系突变。我们比较了胰腺癌、高度异型增生或临床上令人担忧的特征的发展，调整了竞争性死亡率，在所有生殖系突变携带者中，在一个没有已知生殖系突变的队列中有进展风险。在345名被归类为具有家族性风险的个体中，有4.3%的人具有先前未被识别的胰腺癌易感基因突变。（9例涉及ATM，2例BRCA 2，1例BRCA 1，1例PALB 2，1例TP 53和1例CPA 1）。胰腺癌、高度异型增生或胰腺影像学上令人担忧的特征的累积发生率在生殖系突变风险组（n = 134）中显著高于家族性风险组（n = 330 [胰腺癌，风险比，2.85; 95% CI，1.0至8.18;结论胰腺癌易感基因中具有可识别的有害生殖系突变的个体的胰腺癌累积发病率显著高于具有强家族史但未识别突变的个体。根据家族史对符合胰腺监测标准的个体进行基因检测，可以更好地确定肿瘤进展风险最高的个体。(C)2019年美国临床肿瘤学会
PURPOSE To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance.METHODS Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation.RESULTS Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]).CONCLUSION The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression. (C) 2019 by American Society of Clinical Oncology