ABSTRACT
OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and SMARCA4-deficient undifferentiated uterine sarcoma (SMARCA4-DUS) are rare and aggressive tumors, primarily affecting pre- and perimenopausal women. Inactivating SMARCA4 mutations are thought to be the driving molecular events in the majority of these tumors. Here, we report the clinical course of a family with germline SMARCA4 mutation and compare large cohorts of these rare tumor types. METHODS: We extracted clinico-pathological medical record data for the family with germline SMARCA4 mutation. Clinico-genomic data from SCCOHT and SMARCA4-DUS cohorts were retrospectively extracted from the archives of a large CLIA-certified reference molecular laboratory. RESULTS: We identified a single family with an inherited germline SMARCA4 mutation, in which two different family members developed either SCCOHT or SMARCA4-DUS, both of whom died within one year of diagnosis, despite aggressive surgical, chemotherapy and immunotherapy treatment. Retrospective comparative analysis of large SCCOHT (n = 48) and SMARCA4-DUS (n = 17) cohorts revealed that SCCOHT patients were younger (median age: 28.5 vs. 49.0) and more likely to have germline SMARCA4 alterations (37.5% vs. 11.8%) than SMARCA4-DUS patients. CONCLUSIONS: Growing understanding of the role SMARCA4 plays in the pathogenesis of these rare cancers may inform recommended genetic testing and counseling in families with these tumor types.
Subject(s)
Carcinoma, Small Cell/genetics , DNA Helicases/genetics , Germ-Line Mutation , Hypercalcemia/genetics , Nuclear Proteins/genetics , Ovarian Neoplasms/genetics , Sarcoma/genetics , Transcription Factors/genetics , Uterine Neoplasms/genetics , Adult , Carcinoma, Small Cell/pathology , Carcinoma, Small Cell/therapy , Cell Differentiation/physiology , Cohort Studies , DNA Helicases/deficiency , Female , Humans , Hypercalcemia/pathology , Hypercalcemia/therapy , Middle Aged , Nuclear Proteins/deficiency , Ovarian Neoplasms/pathology , Ovarian Neoplasms/therapy , Prognosis , Retrospective Studies , Sarcoma/pathology , Sarcoma/therapy , Transcription Factors/deficiency , Uterine Neoplasms/pathology , Uterine Neoplasms/therapyABSTRACT
Next-generation sequencing promotes identification of mutations in non-BRCA1/2 genes in hereditary cancer families. The contribution of mutations in moderate penetrance genes to hereditary cancer risk is not well established. Here, we report a family with early onset breast and fallopian tube cancer that was identified as carrying germline mutations in BARD1 and ATM genes. Loss of heterozygosity studies suggest a causative role of the BARD1 mutation in the development of primary peritoneal cancer, but fail to confirm an association between germline ATM mutations and breast cancer development in this family. Complexities in interpreting implications of mutations in moderate-risk cancer susceptibility genes are discussed.