Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Genes (Basel). 2023 Jan 20;14(2):277. doi: 10.3390/genes14020277.
was recently identified as a new candidate ovarian cancer (OC)-predisposing gene from the genetic analysis of carriers of c.1813C>T; p.L605F in OC families. Here, we aimed to investigate the molecular genetic characteristics of as they have not been described in the context of cancer. We first investigated the germline genetic landscape of two sisters with OC from the discovery c.1813C>T; p.L605F family (F1528) to re-affirm the plausibility of this candidate. As we did not find other conclusive candidates, we then performed a candidate gene approach to identify other candidate variants in genes involved in the FANCI protein interactome in OC families negative for pathogenic variants in , , , , , and , which identified four candidate variants. We then investigated in high-grade serous ovarian carcinoma (HGSC) from c.1813C>T carriers and found evidence of loss of the wild-type allele in tumour DNA from some of these cases. The somatic genetic landscape of OC tumours from c.1813C>T carriers was investigated for mutations in selected genes, copy number alterations, and mutational signatures, which determined that the profiles of tumours from carriers were characteristic of features exhibited by HGSC cases. As other OC-predisposing genes such as and are known to increase the risk of other cancers including breast cancer, we investigated the carrier frequency of germline c.1813C>T in various cancer types and found overall more carriers among cancer cases compared to cancer-free controls ( = 0.007). In these different tumour types, we also identified a spectrum of somatic variants in that were not restricted to any specific region within the gene. Collectively, these findings expand on the characteristics described for OC cases carrying c.1813C>T; p.L605F and suggest the possible involvement of in other cancer types at the germline and/or somatic level.
最近，从卵巢癌（OC）家族携带 c.1813C>T;p.L605F 者的遗传分析中，鉴定出一个新的卵巢癌易感基因 。在此，我们旨在研究 作为癌症相关基因尚未描述的分子遗传特征。我们首先研究了来自发现 c.1813C>T;p.L605F 家族（F1528）的两位 OC 姐妹的种系遗传图谱，以重新确认该候选基因的合理性。由于我们没有发现其他明确的候选基因，因此我们随后采用候选基因方法，在 OC 家族中鉴定了 、 、 、 、 和 中致病性变异阴性的 FANCI 蛋白互作组中的其他候选变异，鉴定出四个候选变异。然后，我们研究了 c.1813C>T 携带者的高级别浆液性卵巢癌（HGSC）中的 ，并在这些病例的一些肿瘤 DNA 中发现了野生型等位基因丢失的证据。为了研究 c.1813C>T 携带者的 OC 肿瘤的体细胞遗传图谱，对选定基因的突变、拷贝数改变和突变特征进行了研究，结果表明携带者肿瘤的图谱特征与 HGSC 病例的特征一致。由于其他 OC 易感基因，如 和 ，已知会增加包括乳腺癌在内的其他癌症的风险，我们研究了各种癌症类型中种系 c.1813C>T 的携带频率，并发现癌症病例中的携带者频率总体高于无癌对照（=0.007）。在这些不同的肿瘤类型中，我们还鉴定了 中不受基因内任何特定区域限制的一系列体细胞变异。总之，这些发现扩展了携带 c.1813C>T;p.L605F 的 OC 病例的描述特征，并表明 在种系和/或体细胞水平上可能涉及其他癌症类型。
