Center for Familial Breast and Ovarian Cancer and Center for Integrated Oncology, Medical Faculty, University Hospital Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
JAMA Oncol. 2017 Sep 1;3(9):1245-1248. doi: 10.1001/jamaoncol.2016.5592.
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.
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.
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.
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).
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.
已确立的中度或高度外显率乳腺癌（BC）和/或卵巢癌（OC）风险基因（包括 BRCA1 和 BRCA2）中的种系突变解释了不到所有家族性 BC 和/或 OC 病例的一半。基于对 2 种失活（LoF）变体 c.5101C>T（p.Gln1701Ter [rs147021911]）和 c.5791C>T（p.Arg1931Ter [rs144567652]）的基因分型，FANCM 基因已被提议为一种新的 BC 易感性基因，而 FANCM 基因全长编码区在家族性指数病例和地理匹配对照中的分析仍在进行中。
评估 FANCM 基因内的突变谱，并确定 FANCM 基因内 LoF 种系突变与 BC 和/或 OC 风险的潜在关联。
设计、地点和参与者：为了鉴定和表征新的 BC 和/或 OC 易感性基因，共对 2047 名特征明确的家族性 BC 指数病例、628 例 OC 病例和 2187 名地理匹配对照进行了下一代测序，以筛选 FANCM 基因中的 LoF 突变。所有患者之前均检测为致病性 BRCA1 和 BRCA2 突变阴性。所有数据收集均在 2013 年 6 月 1 日至 2016 年 4 月 30 日之间进行。数据分析于 2016 年 5 月 1 日至 2016 年 7 月 1 日进行。
通过单变量逻辑回归比较了 BC 和/或 OC 患者的 FANCM LoF 突变频率与地理匹配对照的 FANCM LoF 突变频率。阳性关联按发病年龄和癌症家族史进行分层。
在这项病例对照研究中，对 2047 名特征明确的家族性女性 BC 指数病例、628 例 OC 病例和 2187 名地理匹配对照进行了筛选，以确定截断 FANCM 改变。FANCM 基因中的杂合 LoF 突变与家族性 BC 风险显著相关，总体优势比（OR）为 2.05（95%CI，0.94-4.54；P=0.049），指数病例中的突变频率为 1.03%。在 BC 发病年龄在 51 岁之前的家族性患者中，观察到更高的 OR 为 2.44（95%CI，1.08-5.59；P=0.02）。对三阴性 BC 肿瘤表型的患者观察到更明显的关联（OR，3.75；95%CI，1.00-12.85；P=0.02）。未检测到对未选择的 OC 病例的显著关联（OR，1.74；95%CI，0.57-5.08；P=0.27）。
基于杂合 LoF 突变与早发性或三阴性 BC 的显著关联，FANCM 应纳入个体风险评估的诊断基因面板检测中。需要更大的研究来确定 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。
