Abstract：
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.
摘要：
胚系BRCA1和BRCA2（BRCA）突变携带者胰腺导管腺癌（PDAC）可能受益于精准治疗，其亲属应接受量身定制的癌症预防。在这项研究中,我们比较了用PDAC识别BRCA携带者的策略。前瞻性招募PDAC事件病例进行BRCA测序。使用国家综合癌症网络（NCCN）和安大略省卫生和长期护理部（MOHLTC）指南评估了前兆。通过调查遗传咨询师并使用BRCAPRO来估计每个先证者携带突变的概率。在22/484（4.5％）先证者中检测到BRCA突变。152/484（31.2％）和16/484（3.3％）先证者符合NCCN和MOHLTC指南，分别。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之间的歧视相似（曲线下面积分别为0.755和0.775，P=0.702）。遗传咨询师普遍高估(P=0.008)，而BRCAPRO严重低估(P<0.001)，每个先证者携带突变的概率。我们的结果表明，NCCN指南和遗传咨询师准确地识别PDAC中的BRCA突变，而MOHLTC指南和BRCAPRO应该更新，以解释BRCA和PDAC之间的关联。
