Some familial ovarian cancer (OC) could be due to rare risk alleles in genes that each account for a relatively small proportion of cases not due to BRCA1 and BRCA2, major risk genes in the homologous recombination (HR) DNA repair pathway. We report a new candidate OC risk allele, FANCI c.1813C>T in a Fanconi anemia (FA) gene that plays a role upstream of the HR DNA repair pathway. This variant was identified by whole exome sequencing of a BRCA1 and BRCA2 mutation-negative French Canadian (FC) OC family from a population exhibiting founder effects. In FCs, the c.1813C>T allele was detected in 7% (3/43) of familial and 1.6% (7/439) of sporadic OC cases; and in 3.7% (3/82) of familial breast cancer (BC) cases with a family history of OC and in 1.9% (3/158) of BC only families. This allele was significantly associated with FC BRCA1 and BRCA2 mutation-negative OC families (OR=5.6; 95%CI=1.6-19; p=0.006). Although FANCI c.1813C>T was detected in 2.5% (74/2950) of cancer-free FC females, carriers had a personal history of known OC risk reducing factors, and female/male carriers were more likely to have reported a first-degree relative with OC ("ρ" =0.037; p=0.011). Eight rare potentially pathogenic FANCI variants were identified in 3.3% (17/516) of Australian OC cases, including 10 carriers of FANCI c.1813C>T. Potentially pathogenic FANCI variants were significantly more common in AUS OC cases with a family history of OC than in isolated OC cases (p=0.027). The odds ratios (OR) were >3 for carriers of any of the seven rarest FANCI alleles, and 1.5 for c.1813C>T. Data from the OC Association Consortium revealed that the ORs for the c.1813C>T allele were highest for the most common OC subtypes. Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the FA pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level; unstable by formaldehyde or mitomycin C treatment; and exhibited sensitivity to cisplatin but not to olaparib (a poly [ADP-ribose] polymerase inhibitor). By tissue microarray analyses, FANCI protein was robustly expressed in fallopian tube epithelial cells but expressed at low-to-moderate levels in 88% (83/94) of high-grade serous carcinoma OC samples. This is the first study to describe potentially pathogenic variants in OC in a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that potentially pathogenic FANCI variants may modify OC risk in cancer families.

中文翻译：

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对北美裔后裔创始人的遗传分析表明，FANCI是候选的家族性卵巢癌危险基因

某些家族性卵巢癌（OC）可能是由于基因中罕见的风险等位基因所致，而这些基因均占相对较小比例的病例，而不是由同源重组（HR）DNA修复途径中的主要风险基因BRCA1和BRCA2引起的。我们报告一个新的候选OC风险等位基因，FANCI贫血（FA）基因中的FANCI c.1813C> T在HR DNA修复途径的上游发挥作用。通过对具有创始人效应的人群进行BRCA1和BRCA2突变阴性的法属加拿大（FC）OC家庭的全外显子组测序来鉴定此变异体。在FC中，在散发性OC病例中有7％（3/43）家族和1.6％（7/439）家族中检测到c.1813C> T等位基因；有OC家族史的家族性乳腺癌（BC）病例中占3.7％（3/82），仅BC家族中有1.9％（3/158）。该等位基因与FC BRCA1和BRCA2突变阴性的OC家族显着相关（OR = 5.6; 95％CI = 1.6-19; p = 0.006）。尽管在2.5％（74/2950）无癌的FC女性中检测到FANCI c.1813C> T，但携带者有已知的降低OC风险的个人病史，女性/男性携带者更可能报告了首次相对于OC的角度（“ρ” = 0.037； p = 0.011）。在3.3％（17/516）的澳大利亚OC病例中鉴定出8个罕见的潜在致病性FANCI变体，包括10个FANCI c.1813C> T携带者。具有家族病史的AUS OC病例中潜在致病性FANCI变体比单独的OC病例中更常见（p = 0.027）。七个最罕见的FANCI等位基因中任一个的携带者的比值比（OR）> 3，而c.1813C> T的比值比为1.5。来自OC协会协会的数据显示，对于最常见的OC亚型，c.1813C> T等位基因的OR最高。在表达p.L605F亚型的细胞中，FANCD2是FA途径中FANCI-FANCD2（ID2）结合复合体的一部分，对诱导的DNA损伤位点的定位受到严重阻碍。该同工型以降低的水平表达。甲醛或丝裂霉素C处理不稳定；对顺铂具有敏感性，但对olaparib（一种聚[ADP-核糖]聚合酶抑制剂）不敏感。通过组织微阵列分析，FANCI蛋白在输卵管上皮细胞中稳定表达，但在88％（83/94）的高度浆液性癌OC样品中以中低水平表达。这是第一项描述FA DNA修复途径ID2复合体成员中OC中潜在致病变异的研究。