To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3, 9q31.1) and one for endometrioid EOC (5q12.3). We then meta-analysed the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified an additional three loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a novel susceptibility gene for low grade/borderline serous EOC.

Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated amplification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2-amplified (HER2+) MC. Here, we explore HER2 amplification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/amplification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non-amplified status, and 3+ IHC with amplified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 amplification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 amplification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 amplification nor KRAS mutations.

Rhabdomyosarcoma (RMS) is the most common soft tissue tumor found in children. Up to 20% of RMS tumors in children originate in the genital tract making this the second most common site. RMS of gynecologic origin in adults is much less common. The purpose of this study was to describe the clinical and pathologic features of RMS of the adult female genital tract. We reviewed the histologic slides of women 16 years of age and older and included them in our study if they contained the classic histologic features of RMS as described by the 2002 World Health Organization classification of tumors. Rhabdomyoblastic components present in other established malignancies were not studied. We identified 15 patients, with a median age of 48 years (range, 16 to 69). Eleven (73%) of the tumors were of embryonal histology (cervix, 8; uterus, 2; and ovary, 1). Of the remaining 4 tumors, 2 were of alveolar (vulva) and 2 of pleomorphic (uterus, 1; fallopian tube, 1) histologic subtype. The majority (79%) of these patients presented with locoregional disease and had surgery as their primary intervention (73%). The median progression-free survival (PFS) and disease-specific survival was 9 months [95% confidence interval (CI), 1-24] and 21 months (95% CI, 14-28), respectively. The 5-year disease-specific survival was only 29%. There was a significant difference in PFS between cases of embryonal compared to cases with nonembryonal histology (19 vs. 3 mo, respectively) (P=0.04). Adult RMS of gynecologic origin presents with locoregional disease and most are morphologically similar to pediatric RMS; however, adult RMS behaves more aggressively, with worse overall survival. It is unclear whether these divergent outcomes are the result of differences in clinical management or because these tumors are biologically distinct.

IMPORTANCE Whether sentinel lymph node biopsy (SLNB) can replace lymphadenectomy for surgical staging in patients with high-grade endometrial cancer (EC) is unclear. OBJECTIVE To examine the diagnostic accuracy of, performance characteristics of, and morbidity associated with SLNB using indocyanine green in patients with intermediateand high-grade EC. DESIGN, SETTING, AND PARTICIPANTS In this prospective, multicenter cohort study (Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate-and High-Grade Endometrial Cancer Staging [SENTOR] study), accrual occurred from July 1, 2015, to June 30, 2019, with early stoppage because of prespecified accuracy criteria. The study included patients with clinical stage I grade 2 endometrioid or high-grade EC scheduled to undergo laparoscopic or robotic hysterectomy with an intent to complete staging at 3 designated cancer centers in Toronto