The SMARCB1 gene provides instructions for creating a protein that is part of larger protein groups called SWI/SNF protein complexes. Located on chromosome 22 (22q11.2), it is a ubiquitously expressed nuclear protein, found in the nucleus of almost all cells. While its specific role is still being fully understood, its presence highlights its importance in cellular processes.
The Core Function of SMARCB1
The SMARCB1 gene is a core subunit of the SWI/SNF (SWItch/Sucrose Non-Fermentable) ATP-dependent chromatin remodeling complex. Chromatin is the tightly packaged structure of DNA and proteins within chromosomes. The SWI/SNF complex regulates gene activity by changing how tightly DNA is packaged, a process known as chromatin remodeling. Tightly packed DNA results in lower gene expression than loosely packed DNA.
SWI/SNF complexes regulate gene activity, impacting many cellular processes. They are involved in repairing damaged DNA, copying DNA, and controlling how cells grow, divide, and mature. The complex also plays a role in epigenetic regulation, which involves changes in gene activity that do not alter the DNA sequence itself, but rather how genes are expressed.
SMARCB1 and the SWI/SNF complex regulate cell cycle progression, ensuring cells divide in an orderly manner. They have both activation and repression roles in gene transcription, influencing which genes are turned on or off. This control over gene expression is important for maintaining healthy cell function.
SMARCB1’s Link to Disease
SMARCB1 acts as a tumor suppressor gene, which means it normally helps prevent uncontrolled cell growth. When mutations, deletions, or a loss of SMARCB1 function occur, it can lead to the development of various cancers. The loss of SMARCB1 can be the initiating event in certain pediatric and young adult cancers, and in some cases, it is the sole driver of the disease.
SMARCB1’s involvement in cancer was first discovered through its association with malignant rhabdoid tumors (MRTs). These are aggressive tumors of infancy that can occur in various anatomical sites, including the kidney (malignant rhabdoid tumor of the kidney, MRTK). Atypical teratoid/rhabdoid tumors (AT/RTs) are a subtype of MRTs that arise in the central nervous system. These highly malignant tumors typically affect children younger than two years of age, and loss of SMARCB1 function characterizes most of them. Biallelic loss of SMARCB1 is found in the vast majority (around 90%) of MRT cases.
SMARCB1 mutations are also linked to schwannomatosis, a genetic disorder characterized by the development of multiple benign nerve sheath tumors called schwannomas. These tumors arise from Schwann cells, which form an insulating layer around nerves. More than two dozen variants in the SMARCB1 gene have been identified in individuals with schwannomatosis, and these variants lead to a reduced but not eliminated function of the SMARCB1 protein. Germline mutations in SMARCB1 are responsible for approximately 45% of familial schwannomatosis cases.
Other cancers where SMARCB1 alterations are found include epithelioid sarcoma (ES) and renal medullary carcinoma (RMC). Epithelioid sarcomas are distinctive soft tissue tumors that affect adolescents and young adults, while RMCs are aggressive carcinomas often seen in young patients with sickle cell trait.
Current Research and Future Outlook
Research focuses on understanding how SMARCB1 dysfunction leads to cancer and developing targeted therapies. One promising area involves epigenetic therapies, which modify gene activity without changing the underlying DNA sequence. For instance, tazemetostat, an EZH2 inhibitor, has been approved for treating SMARCB1-deficient epithelioid sarcomas. This drug blocks the overactive EZH2 protein, which becomes dysregulated when SMARCB1 function is lost, helping reprogram cancer cells.
Despite initial successes, tazemetostat has not been effective for all patients, and some develop resistance. Researchers are exploring combination therapies to overcome this resistance, such as combining EZH2 inhibition with inhibitors of DNA damage repair kinases like ATR. This approach leverages synthetic lethality, where targeting two otherwise unrelated genes or pathways simultaneously leads to cell death in cancer cells but not healthy ones.
Further research includes gene therapy approaches to restore SMARCB1 function. For example, a novel tumor-targeted nanomedicine, scL-SMARCB1, is being tested to deliver a functional SMARCB1 gene to tumor cells. This nanomedicine has shown promise in preclinical models of atypical teratoid rhabdoid tumor (ATRT), inhibiting tumor growth and extending survival when used alone or in combination with chemotherapy like cisplatin. These advancements offer hope for improved diagnostic methods and more effective treatments for SMARCB1-deficient cancers.