In women under 40 years old, small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated type of ovarian cancer—in other words, the most common ovarian cancer in which the cells are more primitive and do not resemble ovarian cells. Although SCCOHT is a rare cancer overall, it is devastating, with an average age of onset of 24 years and a low rate of survival.
In 2014, it was discovered that deleterious mutations in SMARCA4, which encodes the SMARCA4 protein (also called BRG1), leads to the development of SCCOHT.1,2,3 SMARCA4 is the key component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, a protein complex whose most well-studied function is in controlling how genes are expressed. While many genes in this complex are mutated in multiple tumor types, germline mutations that predispose to the development of cancers have only been found in a few of these genes, including SMARCA4.
Occasionally, SCCOHT has been seen to occur in families, and cases of affected sisters, cousins, and mother–daughter pairs have all been reported. While these cases gave the first clue that SCCOHT can be hereditary, patients with sporadic SCCOHT have also been found to carry germline mutations, either de novo in the patient or inherited from the paternal side.
While some mutations are somatic and therefore do not pose a risk for any relatives of the patient, it is estimated that up to half of patients with no family history of the disease may carry a germline mutation. Despite the rarity of SCCOHT, its association with SMARCA4 is important, as germline mutations in this gene can also predispose to an inherited cancer syndrome called rhabdoid tumor predisposition syndrome type 2 (RTPS2). Patients with RTPS2 are at higher risk of developing malignant rhabdoid tumors (MRTs), which are aggressive pediatric soft tissue tumors that most commonly occur in the brain and kidney, but can develop in other tissues. Histologically and genetically, SCCOHT and MRTs are quite similar, and it has therefore been proposed that SCCOHT should really be referred to as a malignant rhabdoid tumor of the ovary.4
This connection between SMARCA4 and SCCOHT is valuable not only as a preventive screening tool, but as a diagnostic tool as well. SCCOHT has a broad differential diagnosis and there are several tumors with which it can be mistaken, including germ cell tumors, granulosa cell tumors, and even metastases to the ovary from small cell carcinoma of the lung. The specificity of deleterious SMARCA4 mutations in SCCOHT and subsequent loss of expression of its protein make it a useful diagnostic tool.
Any patient diagnosed with SCCOHT should be tested for mutations in SMARCA4. While the penetrance of these mutations is still unknown, the number of patients who carry germline mutations with no family history of SCCOHT, along with the severity and early age of onset of these tumors, make SMARCA4 testing an invaluable resource for SCCOHT patients and their families.
1Witkowski, L, et al. Nat Genet. 2014;46(5):438–443.
2Ramos, P, et al. Nat Genet. 2014;46(5):427–429.
3Jelinic, P, et al. Nat Genet. 2014;46(5):424–426.
4Foulkes, WD, et al. J Pathol. 2014;233(3):209–214.