Leora Witkowski and Jian Carrot-Zhang
PhD students in Human Genetics
Award winning publication: Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type
Published in: Nature Genetics 46, 438-443 (2014)
"Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated type of ovarian cancer diagnosed in women below the age of 40. While it is rare, with only ~400 cases described in the English literature, it is a very aggressive disease, with 5-yr survival rates for early stage diagnoses at 33%. Prior to our publication, the histogenesis of the disease remained elusive, and publications discussing the histogenesis of SCCOHT were merely speculative. Our publication confirmed for the first time that SCCOHT is a monogenic disorder and that deleterious germline mutations in the chromatin remodelling gene SMARCA4 predispose to the development of SCCOHT. Our discovery provides women with a family history of early onset ovarian cancer with the option of being tested for germline mutations in SMARCA4, and provides patients with an answer as to why the cancer developed."
Detecting that inactivating mutations in SMARCA4 are the main cause of small cell carcinoma of the ovary, hypercalcemic type represents a major discovery of a predisposition gene for a deadly cancer affecting young women. If the patients contacted for this study carried a germline mutation, their family members were tested for the mutation, thus contributing to an early prevention when possible and to effective treatments. This genetic breakthrough allows for improved survival of women below the age of 40 affected by such an aggressive cancer, the discovery of a predisposition gene being the first step in the development of targeted therapies.