“SMARCB1-deficient cancer” refers to a collection of uncommon and aggressive cancers defined not by their location, but by a specific genetic alteration: the inactivation of the SMARCB1 gene. This gene is a tumor suppressor, which prevents cells from growing and dividing uncontrollably. When both copies of the SMARCB1 gene in a cell are lost or mutated, this control is removed, leading to tumor development.
These cancers are notable because the loss of SMARCB1 is often the only major genetic mutation found, making them genetically stable compared to other cancers. This has made them a focus of research into how a single gene loss can drive such aggressive disease. The cancers linked to this deficiency appear in both children and adults and are found in various parts of the body.
The Function of the SMARCB1 Gene
The SMARCB1 gene contains instructions for a protein that is a core component of the SWI/SNF chromatin remodeling complex. This complex acts as a master regulator of gene activity within the cell’s nucleus. Its primary role is to alter the structure of chromatin—the tightly packaged combination of DNA and proteins—to control which genes can be accessed, effectively turning thousands of other genes “on” or “off.”
The genes regulated by this complex direct processes like cell growth, division, and differentiation, which is the process of a cell becoming specialized. In this capacity, the SMARCB1 protein, as part of the SWI/SNF complex, functions as a tumor suppressor. It ensures that cell growth is orderly and that cells divide only when necessary, preventing the uncontrolled proliferation that leads to tumor formation.
When the SMARCB1 protein is absent due to gene deletion or mutation, the SWI/SNF complex cannot function correctly. This malfunction leads to widespread dysregulation of gene expression, disrupting the cell’s normal checks and balances. The loss of this single protein is enough to initiate the cascade of events that results in cancer.
Types of SMARCB1-Deficient Cancers
The absence of a functional SMARCB1 protein is linked to several distinct, aggressive cancers that affect the very young. The most well-known of these are rhabdoid tumors. When these tumors arise in the brain and central nervous system, they are called Atypical Teratoid/Rhabdoid Tumors (ATRT). ATRTs are among the most common malignant brain tumors in infants and children under three.
Outside of the central nervous system, these cancers are known as Malignant Rhabdoid Tumors (MRT). MRTs can develop in various soft tissues and organs, with the kidneys being a common site. These tumors share a distinct appearance under a microscope, containing large “rhabdoid” cells with specific features that alert pathologists to the potential diagnosis.
While rhabdoid tumors are the classic examples, advanced diagnostic techniques have identified SMARCB1 loss in other cancers. These include:
- Epithelioid sarcoma, a rare soft tissue cancer that appears in young adults.
- Schwannomatosis, a condition characterized by the growth of multiple non-cancerous nerve tumors called schwannomas.
- Renal medullary carcinoma.
- Certain carcinomas of the sinuses.
Diagnosis and Genetic Confirmation
The diagnostic process for a suspected SMARCB1-deficient cancer begins with imaging studies, such as an MRI or CT scan, to identify the tumor’s location and size. Following imaging, a biopsy is performed, where a small sample of tumor tissue is surgically removed for a pathologist to examine in a laboratory.
A key diagnostic tool is immunohistochemistry (IHC), a staining method that uses antibodies to detect the presence or absence of specific proteins in cells. For these cancers, a slice of tumor tissue is treated with an antibody that binds to the SMARCB1 protein. In a normal cell, the nucleus stains, indicating the protein is present; in SMARCB1-deficient cancer cells, this staining is absent, providing strong evidence for the diagnosis.
To confirm the IHC findings, genetic testing is employed. This analysis looks directly at the SMARCB1 gene within the cancer cells’ DNA to find the exact mutation or deletion responsible for the protein’s absence. It is also important to determine if the mutation is somatic (occurred only within tumor cells) or germline (inherited and present in all body cells). This distinction helps assess the patient’s risk for other related tumors and is used for family counseling.
Treatment Strategies
Treatment for SMARCB1-deficient cancers requires a multi-modal approach, combining several therapies. The standard protocol begins with surgery to remove as much of the tumor as possible, a concept known as maximal resection. Achieving maximal resection can significantly influence patient outcomes.
Following surgery, patients undergo chemotherapy, which uses powerful drugs to kill rapidly dividing cancer cells. The specific combination of chemotherapy agents can vary based on the tumor type, location, and the patient’s age. Radiation therapy, which uses high-energy beams to destroy cancer cells, is also a common component of treatment, particularly for brain tumors like ATRT or for any residual tumor cells.
Understanding the cancer’s genetic vulnerability has led to the development of targeted therapies. The loss of SMARCB1 creates a dependency on other cellular pathways for survival, and these drugs are designed to attack these specific pathways. One prominent example is a class of drugs called EZH2 inhibitors. Research shows that when SMARCB1 is absent, cancer cells can become reliant on the EZH2 protein, so inhibiting it can selectively kill cancer cells while sparing healthy ones. These targeted drugs are being actively studied in clinical trials.
Prognosis and Current Research
The prognosis for individuals with SMARCB1-deficient cancers has historically been challenging, particularly for infants and young children affected by rhabdoid tumors. The outlook can vary widely depending on several factors. These include the specific cancer type, the patient’s age at diagnosis, the tumor’s location, and how successfully the tumor can be removed with initial surgery, as complete resection is associated with more favorable outcomes.
Advancements in treatment are paving the way for better prospects. The integration of high-dose chemotherapy, advanced radiation techniques, and targeted therapies has improved survival rates compared to previous decades. While these cancers remain difficult to treat, the prognosis is no longer as uniformly grim as it once was.
Ongoing research is focused on the molecular consequences of SMARCB1 loss to identify new therapeutic targets. Clinical trials are evaluating novel drugs, including new targeted agents and immunotherapies designed to help the patient’s own immune system fight the cancer. This progress in understanding the fundamental biology of these tumors is leading to innovative treatment strategies for more effective and less toxic therapies.