Futagawa Mashu, Yamamoto Hideki, Kochi Mariko, Urakawa Yusaku, Sogawa Reimi, Kato Fumino, Okazawa-Sakai Mika, Ennishi Daisuke, Shinozaki Katsunori, Inoue Hirofumi, Yanai Hiroyuki, Hirasawa Akira
Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8551, Japan.
Department of Clinical Genomic Medicine, Okayama University Hospital, Okayama, Japan.
Hered Cancer Clin Pract. 2021 Nov 27;19(1):48. doi: 10.1186/s13053-021-00205-x.
RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development.
A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3'-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma.
We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.
RAD51D（RAD51旁系同源蛋白D）是原发性卵巢癌（包括输卵管癌和腹膜癌）以及乳腺癌的一种中度癌症易感基因。尽管妇科非上皮性肿瘤，如子宫肉瘤与基因组不稳定有关，包括BRCA功能受损，但尚无明确证据表明RAD51D变异与肉瘤发生风险之间的关系。
一名50多岁的日本女性在大约4年的临床过程中接受了多次手术切除以及针对起源于腹膜后并在腹膜复发的肿瘤的几种化疗方案。腹膜肿瘤经组织学诊断为平滑肌肉瘤，并通过作为癌症精准医学一部分进行的肿瘤基因分型在基因上鉴定出显示RAD51D c.904-2A>T [NM_002878] 的剪接变异。在遗传咨询后进行的验证性基因检测显示，在她肿瘤中检测到的RAD51D剪接变异是种系起源的。计算机分析支持检测到的RAD51D剪接变异可能具有致病性，由于移码导致mRNA转录预计减弱和蛋白质产生截短，这归因于RAD51D第9内含子3'端剪接受体位点的单核苷酸改变。考虑到她的不良临床结局，表现为具有RAD51D改变的平滑肌肉瘤的高度侵袭性表型，该病例为RAD51D剪接变异与恶性肿瘤发生或进展之间的关系提供了新证据。我们报告了这一罕见病例的发现，RAD51D c.904-2A>T的种系变异可能作为包括平滑肌肉瘤在内的恶性肿瘤的潜在易感因素。
我们展示了一名女性患者腹膜平滑肌肉瘤病例的发现，该患者具有RAD51D新的种系剪接变异，作为该变异致病性及其参与肉瘤病因和/或发生风险的潜在证据。据我们所知，这是第一例描述携带种系RAD51D剪接变异的平滑肌肉瘤并基于对正常转录受损和假定功能性蛋白质产生丧失的计算预测阐明其致病性的病例报告。
