SMARCA4 and SMARCA2 co-deficiency: An uncommon molecular signature defining a subset of rare, aggressive and undifferentiated malignancies associated with defective chromatin remodeling

Genetic mutations and epigenetic modifications affecting multiple cancer-related genes occur synergistically to drive tumorigenesis. Across a wide spectrum of cancers, pathogenic changes have been identified in members of the SWItch/Sucrose Non-Fermentable complex including its two catalytic subunits, SMARCA4 and SMARCA2. During cancer development, it is not uncommon to lose the function of either SMARCA4 or SMARCA2, however, loss of both together has been reported to be synthetic lethal and therefore unexpected. Co-deficiency of SMARCA4 and SMARCA2 occurs as a pathognomonic feature of the early-onset ovarian cancer Small-cell carcinoma of the ovary, hypercalcemic type. The loss of both catalytic subunits is also described in other rare undifferentiated neoplasms including Thoracic SMARCA4 -deficient undifferentiated tumors, Malignant rhabdoid tumors and dedifferentiated or undifferentiated carcinomas, predominantly of lung, gastrointestinal, and endometrial origin. This review provides the first extensive characterization of cancers with concurrent SMARCA4 and SMARCA2 loss through the discussion of shared clinical and molecular features. Further, we discuss the mechanisms triggering the loss of catalytic activity, the cellular processes that are dysfunctional as a consequence, and finally, current therapeutic candidates which may selectively target these cancers. • Dual loss of SMARCA4/2 links to a spectrum of aggressive tumors with poor prognosis. • Dual loss of SMARCA4/2 is not synthetic lethal in a defined group of cancers. • Distinct cell types and tissues of origin can display dual loss of SMARCA4/2. • 3 newly defined groups of rare cancers over the lifespan show loss of SMARCA4/2. • Immunotherapy and targeting chromatin modifiers have potential in dual loss tumors.