After a brief summary of the current status of poly-ADP ribose polymerase (PARP) inhibitors for ovarian cancer, we summarize the current status of PARP inhibitors for BRCA wild type ovarian cancer, especially regarding gene alterations other than BRCA, homologous recombination deficiency (HRD), and combinations. Discussion of gene alterations other than BRCA include the results of multiple gene panels studying homologous recombination repair deficiency genes and cancer susceptibility genes, and influences of these alterations on efficacy of PARP inhibitors and cancer susceptibility. Discussions of HRD include the results of phase three trials using HRD assay, the definition of HRD assays, and the latest assays. Discussions of combinations include early phase trial results and ongoing trials combining PARP inhibitors with immune checkpoint inhibitors, anti-angiogenic agents, and triplets.
Background Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. Case presentation Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. Conclusions Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.
Background 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. Case presentation 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. Conclusions 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.
With the rapid expansion of genomic medicine, citizens are compelled to think about genetics in daily life. Therefore, this study aims to explore appropriate types of educational media and methods of enlightenment activities for genetics and hereditary cancer. For this purpose, we launched the public awareness project, planned and run by genetic medicine experts. In this study, we presented an 18-minute YouTube video on genetics and hereditary cancer to participants at Science Agora 2020, and administered a web questionnaire to investigate their opinions about when and how citizens should start learning about genetics and hereditary cancer. We recruited 133 participants who watched the video. Among them, only 35 (26.3%) responded to the questionnaire. Most of the respondents understood and appreciated the contents of the video. They identified websites, videos, manga, and books as suitable learning media, irrespective of sex, age, or profession. Moreover, they highlighted upper elementary school or junior high school as appropriate educational stages to start learning about genetics and hereditary cancer to facilitate collecting their own genetic information by themselves. Our findings show that educational institutions should provide opportunities to learn about genetics and hereditary cancers, especially for upper elementary school and junior high school students, using learning media, such as videos, depending on their level or demand.
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