Lowstuter Katrina, Espenschied Carin R, Sturgeon Duveen, Ricker Charité, Karam Rachid, LaDuca Holly, Culver Julie O, Dolinsky Jill S, Chao Elizabeth, Sturgeon Julia, Speare Virginia, Ma Yanling, Kingham Kerry, Melas Marilena, Idos Gregory E, McDonnell Kevin J, Gruber Stephen B
Katrina Lowstuter, Duveen Sturgeon, Charité Ricker, Julie O. Culver, Julia Sturgeon, Yanling Ma, Marilena Melas, Gregory E. Idos, Kevin J. McDonnell, and Stephen B. Gruber, University of Southern California, Los Angeles; Carin R. Espenschied, Rachid Karam, Holly LaDuca, Jill S. Dolinsky, Elizabeth Chao, and Virginia Speare, Ambry Genetics, Aliso Viejo; and Kerry Kingham, Stanford University School of Medicine, Stanford, CA.
JCO Precis Oncol. 2017 Nov;1:1-12. doi: 10.1200/PO.16.00021.
Mutations in the gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management.
This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate mutation prevalence and associated clinical phenotypes. mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative.
In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria.
The majority of mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of -positive patients and families and provide opportunities for early detection and risk reduction.
该基因的突变会使患弥漫性胃癌的终生风险高达80%，患小叶性乳腺癌的终生风险高达60%。对于符合国际胃癌连锁联盟（IGCLC）指南的个体，建议进行该基因突变检测。然而，对于不符合IGCLC标准或没有遗传性弥漫性胃癌表型提示的患者中检测到的意外基因突变进行解读在临床上具有挑战性。本研究旨在描述通过多基因检测板检测（MGPT）鉴定出的该基因突变携带者的表型，并为医疗管理提供明智的建议。
这项横断面患病率研究纳入了2012年3月至2014年9月期间在一家商业实验室（n = 26,936）和一家学术医疗中心癌症遗传学诊所（n = 318）接受MGPT的所有患者，以估计该基因突变患病率及相关临床表型。该基因突变携带者被分为IGCLC阳性（符合标准）、IGCLC部分表型和IGCLC阴性。
在实验室队列中，26,936例患者中有16例（0.06%）被鉴定为具有致病性该基因突变。在临床队列中，318例中有4例（1.26%）具有致病性该基因突变。总体而言，65%的基因突变携带者不符合2015年发布的修订检测标准。所有接受了降低风险胃切除术的3例该基因突变携带者，尽管不符合IGCLC标准，但均有弥漫性胃癌的病理证据。
在MGPT上鉴定出的大多数该基因突变是意外发现的，且存在于不符合公认诊断检测标准的个体中。这些检测结果改变了该基因阳性患者及其家族的医疗管理，并为早期检测和降低风险提供了机会。
