1] Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3].
1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [3].
Nat Genet. 2014 May;46(5):438-43. doi: 10.1038/ng.2931. Epub 2014 Mar 23.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.
卵巢小细胞癌，高钙血症型（SCCOHT）是 40 岁以下女性最常见的未分化卵巢恶性肿瘤。我们对三个 SCCOHT 家族的六名个体进行了外显子组测序。在三个家族中均发现了 SMARCA4 种系中分离的有害突变后，我们测试了第四个受影响家族的 DNA，该家族也携带了分离的 SMARCA4 种系突变。所有测序的家族性肿瘤均存在体细胞突变或野生型等位基因丢失。对这些病例以及其他家族性和非家族性病例的免疫组化分析显示，总体上有 38/40 例肿瘤存在 SMARCA4（BRG1）蛋白缺失。对有可用 DNA 的病例进行测序，在 32 例中有 30 例至少发现了一个种系或体细胞有害的 SMARCA4 突变。此外，SCCOHT 细胞系 BIN-67 在 SMARCA4 中存在双等位基因有害突变。我们的研究结果确定了 SMARCA4 的改变是 SCCOHT 的主要原因，这可能导致遗传咨询的改善和新的治疗方法。
