Background: Globally, ovarian cancer (OC), the deadliest gynecologic malignancy, remains a major cause of mortality, with a rising number of cases in many low- and middle-income countries. Immunotherapy has been proven to be promising for OC. There is increasing awareness of the vital role that tumor mutation burden (TMB) plays in predicting the efficacy of immunotherapy. Women with a family history of OC are at higher risk of the disease due to gene mutations. However, whether these gene mutations are related to immune response and TMB remains to be explored. Methods: Our present work analyzed genetic mutation data of OC patients obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts, and we identified 11 frequently mutated genes, namely, APOB, CSMD3, DST, FAT3, FLG, HMCN1, MUC16, RYR1, TP53, TTN, and USH2A, in accordance with the overlap of two databases. Results: A statistically higher TMB was detected by whole-exome sequencing in patients with OC with CSMD3 mutation than in those with mutations in the other frequently mutated genes. Prognosis analysis performed with patients from the TCGA cohort revealed that those with CSMD3 mutation had an overall survival (OS) that was inferior to that of those with wild-type CSMD3. Gene set enrichment analysis (GSEA) and CIBERSORT analysis indicated that OC samples with CSMD3 mutations had significant involvement of pathways related to the immune response. Conclusion: In summary, we found that CSMD3 mutation is highly correlated with increased TMB and poor clinical prognosis and that it might function as a biomarker for predicting prognosis and choosing an immunotherapy regimen.

Preimplantation embryo arrest (PREMBA) is a common cause of female infertility and recurrent failure of assisted reproductive technology. However, the genetic basis of PREMBA is largely unrevealed. Here, using whole-exome sequencing data from 606 women experiencing PREMBA compared with 2,813 controls, we performed a population and gene–based burden test and identified a candidate gene, karyopherin subunit α7 (KPNA7). In vitro studies showed that identified sequence variants reduced KPNA7 protein levels, impaired KPNA7 capacity for binding to its substrate ribosomal L1 domain-containing protein 1 (RSL1D1), and affected KPNA7 nuclear transport activity. Comparison between humans and mice suggested that mouse KPNA2, rather than mouse KPNA7, acts as an essential karyopherin in embryonic development. Kpna2^–/– female mice showed embryo arrest due to zygotic genome activation defects, recapitulating the phenotype of human PREMBA. In addition, female mice with an oocyte-specific knockout of Rsl1d1 recapitulated the phenotype of Kpna2^–/– mice, demonstrating the vital role of substrate RSL1D1. Finally, complementary RNA (cRNA) microinjection of human KPNA7, but not mouse Kpna7, was able to rescue the embryo arrest phenotype in Kpna2^–/– mice, suggesting mouse KPNA2 might be a homologue of human KPNA7. Our findings uncovered a mechanistic understanding for the pathogenesis of PREMBA, which acts by impairing nuclear protein transport, and provide a diagnostic marker for PREMBA patients.

Objective: To study the influence of the previous cesarean section on the pregnancy outcomes and perinatal outcomes in single embryo transfer (SET) cycles in an in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) setting compared to those with previous vaginal delivery (VD). In addition, the association between fertility outcomes and different cesarean scar defect (CSD) sizes was studied.Method: This was a retrospective cohort study conducted in the Reproductive Center of the First Affiliated Hospital of Nanjing Medical University. A total of 4,879 patients with previous delivery history undergoing SET were included between January 2015 and April 2019. Patients were divided into the VD group and cesarean delivery (CD) group according to different modes of previous delivery. The primary outcome was live birth rate. The pregnancy outcomes of CD were analyzed as a subgroup and the relationship between pregnancy outcomes as well as the different sizes of CSD were explored by logistic regression analysis.Results: There were no significant differences in live birth rate, clinical pregnancy rate, and miscarriage rate between the CD group and VD group. The incidence rates of pregnancy complications such as pregnancy hypertension, gestational diabetes mellitus, placenta abnormalities, premature rupture of membrane, and postpartum hemorrhage were similar in the two groups. Live birth rate was significantly lower in the CSD group (23.77% vs 37.01%, aOR: 0.609, 95% CI: 0.476-0.778) comparing to patients without CSD. There were also significant differences in clinical pregnancy rate (37.52% vs 47.64%, aOR: 0.779, 95%CI: 0.623-0.973) and miscarriage rate (34.55% vs 20.59%, aOR: 1.407, 95%CI:1.03-1.923). Large size CSD significantly decreased live birth rate (13.33% vs 26.29%, aOR: 0.422, 95%CI: 0.197-0.902) and clinical pregnancy rate (25.33% vs 40.09%, aOR: 0.503, 95%CI: 0.272-0.930) compared with small size CSD.Conclusion: For women with previous cesarean sections, the pregnancy outcomes were similar to those with previous VD without increased perinatal complications following SET. The presence of CSD was associated with a marked reduction in live birth rate, especially in patients with large size CSD.