Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen, France.
Inserm U1245, Rouen University, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
Genet Med. 2018 Dec;20(12):1677-1686. doi: 10.1038/s41436-018-0005-9. Epub 2018 Jul 10.
Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing.
Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population.
Odds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 [10.01-17.22], 8.61 [6.78-10.82], 8.22 [4.91-13.05], 4.54 [2.55-7.48], 5.23 [1.46-13.17], 3.20 [2.14-4.53], 2.49 [1.42-3.97], 1.67 [1.18-2.27], and 2.50 [1.12-4.67], respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 [5.78-19.59], 12.44 [2.94-33.30] and 3.82 [1.66-7.11]). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 [5.48-34.10]) and BARD1 PVs with triple-negative breast cancer (OR = 11.27 [3.37-25.01]). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC.
Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.
在遗传性乳腺癌和卵巢癌（HBOC）的诊断中整合基因面板需要仔细评估每个基因中检测到的致病性或可能致病性变异（PV）相关的风险。在此，我们通过下一代测序分析了 5131 例疑似 HBOC 索引病例中的 34 个基因。
使用外显子组聚集协会数据集中的 571 名个体和法国外显子组计划，我们模拟了个体从外显子组聚集协会中携带 PV 的概率，并将其与 HBOC 人群中的估计频率进行了比较。
BRCA1、BRCA2、PALB2、RAD51C、RAD51D、ATM、BRIP1、CHEK2 和 MSH6 中的 PV 所带来的比值比估计值分别为 13.22 [10.01-17.22]、8.61 [6.78-10.82]、8.22 [4.91-13.05]、4.54 [2.55-7.48]、5.23 [1.46-13.17]、3.20 [2.14-4.53]、2.49 [1.42-3.97]、1.67 [1.18-2.27]和 2.50 [1.12-4.67]。RAD51C、RAD51D 和 BRIP1 中的 PV 与卵巢癌家族史相关（OR=11.36 [5.78-19.59]、12.44 [2.94-33.30]和 3.82 [1.66-7.11]）。PALB2 PV 与双侧乳腺癌相关（OR=16.17 [5.48-34.10]），BARD1 PV 与三阴性乳腺癌相关（OR=11.27 [3.37-25.01]）。在患者和法国外显子组计划人群中进行的负担测试证实了 BRCA1、BRCA2、PALB2 和 RAD51C 的 PV 与 HBOC 相关。
我们的结果验证了 PALB2、RAD51C 和 RAD51D 纳入 HBOC 诊断的合理性，并表明其他基因参与了寡基因决定论。
