Wade Isaac, Witkowski Leora, Ahmed Afrida, Rowlands Charlie F, Banerjee Susana, Pressey Joseph G, McVeigh Terri P, Tischkowitz Marc D, Foulkes William D, Turnbull Clare
Institute of Cancer Research, London, UK.
Cancer Research Program and the SCCOHT/SMARCA4 Registry and Biobank, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Genet Med. 2025 Jan;27(1):101287. doi: 10.1016/j.gim.2024.101287. Epub 2024 Oct 2.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an extremely rare, highly aggressive cancer (mean age of onset, 24 years). Nearly all cases are associated with somatic or germline pathogenic variants (GPVs) in SMARCA4. Early bilateral oophorectomy is recommended for unaffected females with a SMARCA4 GPV. However, the penetrance of SMARCA4 GPVs for SCCOHT is highly uncertain and subject to ascertainment bias.
Leveraging the early-onset, sex-specific, highly morbid nature of SCCOHT, we hypothesized that the penetrance for SCCOHT could be quantified from the deficit in SMARCA4 GPVs in females compared with males in UK Biobank, a population cohort for which recruitment was restricted to those age 40 to 69. We also analyzed pedigrees ascertained internationally by the Montreal-based SCCOHT-SMARCA4 Registry.
We observed SMARCA4 GPVs in 8/210,182 (0.0038%) female and 18/179,210 (0.0100%) male participants in UK Biobank (P = .028), representing a male:female odds ratio of 2.64 (95% CI 1.09-7.02), implying a penetrance of 62% for SCCOHT (given the absence of other SMARCA4-related female-specific early morbid diseases). A deficit of GPVs in females in UK Biobank was also demonstrated for BRCA1 and TP53.
Our findings support bilateral oophorectomy in early adulthood as a rational choice for at-risk females with SMARCA4 GPVs.
卵巢高钙血症型小细胞癌（SCCOHT）是一种极其罕见、侵袭性很强的癌症（平均发病年龄为24岁）。几乎所有病例都与SMARCA4基因的体细胞或种系致病性变异（GPV）相关。对于携带SMARCA4基因GPV的未患病女性，建议早期行双侧卵巢切除术。然而，SMARCA4基因GPV对SCCOHT的外显率高度不确定，且存在确诊偏倚。
利用SCCOHT早发、性别特异性、高致病性的特点，我们假设可以通过英国生物银行中女性与男性相比SMARCA4基因GPV的不足来量化SCCOHT的外显率，英国生物银行是一个人群队列，招募对象仅限于40至69岁的人群。我们还分析了由位于蒙特利尔的SCCOHT - SMARCA4登记处国际确定的家系。
在英国生物银行中，我们在210182名女性参与者中的8名（0.0038%）和179210名男性参与者中的18名（0.0100%）中观察到SMARCA4基因GPV（P = 0.028），男性与女性的优势比为2.64（95%可信区间1.09 - 7.02），这意味着SCCOHT的外显率为62%（假设不存在其他与SMARCA4相关的女性特异性早期疾病）。英国生物银行中女性的BRCA1和TP53基因GPV也存在不足。
我们的研究结果支持成年早期双侧卵巢切除术是携带SMARCA4基因GPV的高危女性的合理选择。
