Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas.

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight 'anomalous' cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first 'anomalous' non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Bone mineral density and fractures after surgical menopause: systematic review and meta-analysis.

BACKGROUND: Oophorectomy is recommended for women at increased risk for ovarian cancer. When performed at premenopausal age oophorectomy induces acute surgical menopause, with unwanted consequences. OBJECTIVE: To investigate bone mineral density (BMD) and fracture prevalence after surgical menopause. SEARCH STRATEGY: A literature search of PubMed, EMBASE and Cochrane library was performed with no date restriction. Date of last search was March 1st, 2016. SELECTION CRITERIA: Primary studies reporting on BMD, T-scores or fracture prevalence in women with surgical menopause and age-matched control groups. DATA COLLECTION AND ANALYSIS: Data were extracted on BMD (g/cm2 ), T-scores and fracture prevalence in women with surgical menopause and control groups. Quality was assessed by an adaptation of the Downs and Black checklist. Random effects models were used to meta-analyse results of studies reporting on BMD or fracture rates. MAIN RESULTS: Seventeen studies were included, comprising 43 386 women with surgical menopause. Ten studies provided sufficient data for meta-analysis. BMD after surgical menopause was significantly lower than in premenopausal age-matched women [mean difference lumbar spine, -0.15 g/cm2 (95% CI, -0.19 to -0.11 g/cm2 ); femoral neck, -0.17 g/cm2 (95% CI, -0.23 to -0.11 g/cm2 )] but not lower than in women with natural menopause [lumbar spine, -0.02 g/cm2 (95% CI, -0.04 to 0.00 g/cm2 ); femoral neck, 0.04 g/cm2 (95% CI, -0.09 to 0.16 g/cm2 )]. Hip fracture rate was not higher after surgical menopause compared with natural menopause [hazard ratio: 0.85 (95% CI, 0.70 to 1.04)]. AUTHOR'S CONCLUSIONS: No evident effect of surgical menopause was observed on BMD and fracture prevalence compared with natural menopause. However, available studies are prone to bias and need to be interpreted with caution. TWEETABLE ABSTRACT: Bone health after menopause: no evidence for additional effect of surgical menopause on BMD and fractures.