Small Cell Carcinoma of Ovary, Hypercalcemic Type Caused by Germline SMARCA4 Mutations: An Under-diagnosed Entity?

L. Witkowski¹, N. Donini², J. A. Knost², A. Berchuck³, D. L. Thull⁴, C. Lazaro⁵, M. Longy⁶, W. G. McCluggage⁷, B. A. Clarke⁸, M. Hasselblatt⁹ and W. D. Foulkes¹

1. McGill University, Montreal, QC, Canada; 2. Illinois CancerCare, Peoria, IL; 3. Duke University Medical Center, Durham, NC; 4. University of Pittsburg Medical Center, Pittsburgh, PA; 5. Catalan Institute of Oncology, Barcelona, Spain; 6. Institut Bergonie, Bordeaux, France; 7. Royal Group of Hospitals Trust, Belfast, Northern Ireland; 8. University of Toronto, Toronto, ON, Canada; 9. University of Muenster, Münster, Germany

Objectives: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most commonly diagnosed undifferentiated ovarian cancer in women below the age of 40, with a mean diagnosis age of 23.9 years. It is an aggressive tumor, with survival of early stage disease at 33%. Previously, the lack of SCCOHT-specific markers has led to its misdiagnosis as various other malignancies either arising in, or metastatic to, the ovary. Recently, we and others discovered that SCCOHT is a monogenic disease attributable to germline and/or somatic deleterious mutations in a single chromatin remodeling gene, SMARCA4. At least one germline and/or somatic mutation was found in SMARCA4 in all familial and 27/28 (96%) non-familial cases tested. Loss of the SMARCA4 protein was seen in 42/44 (95%) cases tested. Despite the lack of familial SCCOHT cases reported, half of patients with no known family history of the disease carried a germline mutation in SMARCA4. Our objective is to describe new cases studied since our publication and to outline an algorithm for the diagnosis of this aggressive disease.

Methods: Sanger and whole exome sequencing was used to identify germline and somatic mutations in cases of SCCOHT, supported by immunohistochemical staining of these tumors using an anti-SMARCA4 antibody.

Results: Since publication, we have studied two additional familial cases and four non-familial cases of SCCOHT, with loss of protein and SMARCA4 mutations seen in all cases studied. Half of non-familial cases studied carry germline SMARCA4 mutations, indicating that inherited forms of SCCOHT are more common than previously thought. This has important implications for male SMARCA4 mutation carriers whose daughters may inherit mutations, as well as affected women with young or male children who are not (yet) affected. Given the common misdiagnosis of SCCOHT as other ovarian tumors, here we propose an algorithm to aid in the proper diagnosis of SCCOHT.

Conclusions: SCCOHT is likely to be an under-reported cancer and the inherited form, caused by germline SMARCA4 mutations, is more common than previously recognized, with a likely high penetrance for these mutations. Germline DNA testing in SCCOHT patients could help the prevention of subsequent SCCOHT development in their family members.