Grant Robert C, Holter Spring, Borgida Ayelet, Dhani Neesha C, Hedley David W, Knox Jennifer J, Akbari Mohammad R, Zogopoulos George, Gallinger Steven
Division of Medical Oncology, University of Toronto, Toronto, Canada.
Ontario Institute for Cancer Research, Toronto, Canada.
J Genet Couns. 2018 Aug;27(4):988-995. doi: 10.1007/s10897-018-0212-1. Epub 2018 Feb 13.
Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.
携带生殖系BRCA1和BRCA2（BRCA）突变的胰腺导管腺癌（PDAC）患者可能从精准治疗中获益，其亲属应接受针对性的癌症预防。在本研究中，我们比较了识别PDAC患者中BRCA携带者的策略。前瞻性招募PDAC新发病例进行BRCA测序。根据美国国立综合癌症网络（NCCN）和安大略省卫生与长期护理部（MOHLTC）指南对先证者进行评估。通过咨询遗传咨询师并使用BRCAPRO估计每个先证者携带突变的概率。在484名先证者中检测到22例（4.5%）BRCA突变。分别有152/484（31.2%）和16/484（3.3%）的先证者符合NCCN和MOHLTC指南。NCCN指南的敏感性高于MOHLTC指南（0.864对0.227，P<0.001），但特异性较低（0.712对0.976，P<0.001）。119名遗传咨询师完成了调查。遗传咨询师和BRCAPRO之间的鉴别能力相似（曲线下面积：分别为0.755和0.775，P=0.702）。遗传咨询师通常高估了（P=0.008），而BRCAPRO严重低估了（P<0.001）每个先证者携带突变的概率。我们的结果表明，NCCN指南和遗传咨询师能准确识别PDAC中的BRCA突变，而MOHLTC指南和BRCAPRO应更新以考虑BRCA与PDAC之间的关联。
