Importance  Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2, explain fewer than half of all familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C>T (p.GIn1701Ter [rs147021911]) and c.5791C>T (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending.

Objectives  To assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk.

Design, Setting, and Participants  For the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016.

Main Outcomes and Measures  FANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history.

Results  In this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27).

Conclusions and Relevance  Based on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis.

重要性  已确定的乳腺癌 (BC) 和/或卵巢癌 (OC) 中度或高度外显风险基因（包括BRCA1和BRCA2 ）中的种系突变解释了不到一半的家族性 BC 和/或 OC 病例。基于 2 个功能丧失 (LoF) 变体 c.5101C>T (p.GIn1701Ter [ rs147021911 ]) 和 c.5791C>T (p.Arg1931Ter [ rs144567652 ]) 的基因分型，FANCM基因被认为是一种新的 BC 易感基因，而对家族索引病例和地理匹配对照中FANCM基因的整个编码区的分析正在等待中。

目的评估  FANCM基因内的突变谱，并确定 FANCM 基因内的 LoF 种系突变与 BC 和/或 OC 风险的潜在关联。

设计、设置和参与者  为了鉴定和表征新的 BC 和/或 OC 易感基因，共筛选了 2047 名具有良好特征的家族性 BC 指示病例、628 名 OC 病例和 2187 名地理匹配的对照，以确定其内的 LoF 突变。 FANCM基因通过二代测序。所有患者先前的致病性BRCA1和BRCA2突变检测均为阴性。所有数据收集时间为 2013 年 6 月 1 日至 2016 年 4 月 30 日。数据分析时间为 2016 年 5 月 1 日至 2016 年 7 月 1 日。

主要结果和测量  BC 和/或 OC 患者的FANCM LoF 突变频率与地理匹配对照中的FANCM LoF 突变频率通过单变量逻辑回归进行比较。阳性关联按发病年龄和癌症家族史分层。

结果  在这项病例对照研究中，筛选了 2047 名特征良好的家族性女性 BC 指数病例、628 名 OC 病例和 2187 名地理匹配的对照以截断FANCM改变。FANCM基因中的杂合 LoF 突变与家族性 BC 风险显着相关，总体优势比 (OR) 为 2.05 (95% CI, 0.94-4.54; P  = .049)，指示病例的突变频率为 1.03%。在 51 岁之前发生 BC 的家族性患者中，观察到 OR 升高为 2.44（95% CI，1.08-5.59；P  = .02）。对于具有三阴性 BC 肿瘤表型的患者（OR，3.75；95% CI，1.00-12.85；P = .02)。对于未选择的 OC 病例，未检测到显着相关性（OR，1.74；95% CI，0.57-5.08；P  = .27）。

结论和相关性  基于杂合 LoF 突变与早发性或三阴性 BC 的显着关联，FANCM应包括在用于个体风险评估的诊断基因组测试中。需要更大规模的研究来确定 BC 的年龄依赖性疾病风险，并评估FANCM突变在 OC 发病机制中的潜在作用。