A case of hereditary breast and ovarian cancer syndrome of initially presented as cancer of unknown primary with lymph node metastases unveiled by genetic analysis.

Cancer of unknown primary (CUP) is a heterogeneous disease concept involving various malignant tumors. Understanding its pathophysiology is often difficult, together with its treatment. Here, we present a case of CUP with abdominal lymph node enlargement and elevated carbohydrate antigen 125 levels. It initially resembled a favorable prognosis type similar to ovarian cancer, but metastases were observed in cervical lymph nodes, indicating a somewhat atypical CUP compared to the typical ovarian cancer-like CUP. We identified a germline Breast Cancer 1 (BRCA1) p.L63* variant through a family history inquiry and BRCA analysis, indicating hereditary breast and ovarian cancer syndrome. The patient achieved near-complete remission with platinum-based therapy followed by poly (ADP-ribose) polymerase (PARP) inhibitor. The variant has shown sensitivity in both clinical and pathogenic reports in the ClinVar database of the National Institutes of Health. No clinical studies reported on the efficacy of PARP inhibitors specific to this variant, but our case demonstrated the sensitivity of platinum-based therapy followed by PARP inhibitor. Reports of CUP in hereditary breast and ovarian cancer syndrome are very rare, with only a single report in the literature.

Shape of the first mitotic spindles impacts multinucleation in human embryos.

During human embryonic development, early cleavage-stage embryos are more susceptible to errors. Studies have shown that many problems occur during the first mitosis, such as direct cleavage, chromosome segregation errors, and multinucleation. However, the mechanisms whereby these errors occur during the first mitosis in human embryos remain unknown. To clarify this aspect, in the present study, we image discarded living human two-pronuclear stage zygotes using fluorescent labeling and confocal microscopy without microinjection of DNA or mRNA and investigate the association between spindle shape and nuclear abnormality during the first mitosis. We observe that the first mitotic spindles vary, and low-aspect-ratio-shaped spindles tend to lead to the formation of multiple nuclei at the 2-cell stage. Moreover, we observe defocusing poles in many of the first mitotic spindles, which are strongly associated with multinucleation. Additionally, we show that differences in the positions of the centrosomes cause spindle abnormality in the first mitosis. Furthermore, many multinuclei are modified to form mononuclei after the second mitosis because the occurrence of pole defocusing is firmly reduced. Our study will contribute markedly to research on the occurrence of mitotic errors during the early cleavage of human embryos.