Introduction:
Rare small cell carcinoma of the ovary is one of the aggressive types of ovarian cancer, with unique histology, and is associated with a poor prognosis. This cancer is linked to a genetic mutation in the SMARCA4 (SWI/SNF [switch/sucrose non-fermentable]-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene, which encodes a protein called SMARCA4, also known as BRG1 (Brahma-related gene 1). SMARCA4 is involved in the SWI/SNF chromatin remodeling complex. This article delves into the molecular pathogenesis and implications of these genetic mutations involved in this rare small-cell carcinoma.
What Is Small Cell Carcinoma of the Ovary?
Small cell carcinoma of the ovary is one of the rare and aggressive types of cancer with a poor prognosis. It usually affects young females and is associated with hypercalcemia, characterized by increased levels of calcium in the body. The management of this cancer includes radical surgery, which involves the extensive surgical removal of the affected tissue, followed by adjuvant therapy such as chemotherapy, radiation therapy, or immunotherapy. The mean survival of patients diagnosed with this type is approximately 5.7 years. It consists of two subtypes, which include:
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Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT): This is the more common type, characterized by small round cells and associated with high levels of calcium. It primarily affects younger females.
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Pulmonary-Type Small Cell Carcinoma of the Ovary (PSCCO): This is the rarest form and resembles small cell carcinoma of the lung under a microscope. It primarily affects older women and is not associated with increased levels of calcium.
Both forms of cancer are aggressive and have a poor prognosis.
What Is SWI/SNF Chromatin Remodeling Complex, and Is SMARCA4 Gene Related?
These are a group of proteins involved in the regulation of gene expression and maintenance of chromatin which is the DNA (deoxyribonucleic acid)-protein complex forming chromosomes inside the nucleus within the cells. The complex consists of core subunits such as INI1 /SMARCB1, BAF155/SMARCC1, and BAF170/SMARCC2, as well as helicases such as BRM/SMARCA2 and BRG1/SMARCA4. The SMARCA4 gene provides instructions for the BRG1 protein. This chromatin remodeling complex uses energy produced from ATP (adenosine triphosphate) hydrolysis to facilitate interactions between histone proteins and DNA. This process is essential during DNA transcription (a process by which an RNA [ribonucleic acid] molecule is created by using a DNA template), repair, replication, and recombination. Abnormalities in this complex can lead to the development of cancer, with about 20 percent of cancers showing mutations in the subunits of the SWI/SNF chromatin remodeling complex. The cancers that occur due to abnormalities in this complex are referred to as SWI/SNFomas and are usually found in pediatric tumors, such as leukemia (a cancer of bone marrow and blood) and brain tumors, as well as in adult cancers, such as non-small cell carcinoma and Burkitt lymphoma (cancer that occurs from the lymphatic system). Studies have shown a strong relationship between SMARCA4 mutations and the aggressive form of ovarian cancer.
What Is the Molecular Pathogenesis of Small Cell Carcinoma of the Ovary?
Molecular pathogenesis is the study of mechanisms involved in the development of a disease. It helps to understand how specific molecules (genes, proteins, and other components of the cell) are implicated in the disease's progression. Small cell carcinoma of the ovary contains small round cells with a minimal amount of cytoplasm (a gel-like substance surrounding the cell membranes) under the microscope. The molecular pathogenesis of small cell carcinoma of the ovary includes:
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This tumor is associated with a mutation in the SMARCA4 gene, making it also known as SMARCA4-deficient ovarian neoplasm. The discovery of this mutation has led to the development of antibodies helpful in diagnosis and differentiation from other cancers.
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The mutations can be either inherited or acquired in affected individuals.
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The most common feature of the SMARCA4 gene mutation is the loss of the SMARCA4 protein. Some cases have also shown deleterious mutations and biallelic mutations (where both gene copies are affected).
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In cases with one mutated gene, the underlying mechanisms include epigenetic changes (changes in the gene expression without change in the sequence of the DNA) and loss of heterozygosity (loss of one copy of the gene due to mutation or deletion).
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In some cases, there are also mutations in the subunits of the SWI/SNF chromatin remodeling complex, including SMARCB1 or ARID1A.
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Familial SCCOHT is inherited in an autosomal dominant pattern, where a mutation in one gene is enough for the development of the disease. In some cases, there have been mutations in the TP53 gene, resulting in a high number of p53 proteins.
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SCCOHT shows high expression of programmed death ligand-1 (PD-L1), indicating a potential response to immune checkpoint inhibitors. This is associated with T-cell infiltration.
What Is the Management of Rare Small Cell Carcinomas of the Ovary?
According to studies, loss of BRG1 expression is highly sensitive in the diagnosis of SCCOHT, with approximately 94 percent of cases showing this loss, while other cases involve deficiencies in other parts of the SWI/SNF chromatin remodeling complex. In some instances, the dual loss of BRM (SMARCA2) and BRG1 expression is the diagnostic hallmark of SCCOHT. Around 43 percent of SCCOHT cases have germline mutations in the SMARCA4 gene, leading to diagnoses at a very young age. Genetic testing, using next-generation sequencing, can be employed for diagnosis. Family members should also undergo genetic testing and counseling. Prophylactic bilateral oophorectomy (removal of ovaries) is recommended in these cases, performed at a young age. The treatment approaches include:
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Survival in stage 1 SCCOHT is poor. For some cases, gene expression profiling has suggested treatment options like Pazopanib, 5-Azacytidine, Bortezomib, and PARP (Poly [ADP-ribose] polymerase) inhibitors.
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Other approaches include high-dose chemotherapy along with stem cell rescue.
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Immunotherapy with anti-PD-L1 treatment has shown promising results in some cases.
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Targeted therapies have shown excellent results with SMARCA4 mutations and the loss of SMARCA2 expression.
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In cases of SWI/SNF complex-deficient tumors, inhibitors targeting EZH2 (enhancer of zeste homolog 2) have shown promising results.
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RTK (receptor tyrosine kinase) inhibitors, such as Ponatinib, have demonstrated cell suppression in SCCOHT.
Conclusion:
The discovery of SMARCA4 mutations has significantly improved the diagnosis and management of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The dual loss of BRM (SMARCA2) and BRG1 expression is considered the diagnostic hallmark of SCCOHT. Genetic tests can aid in identifying these mutations, enabling clinical screening and prophylactic treatment.
