Abstract
PURPOSE: To determine the cancer risk and spectrum in patients with multilineage mosaic RASopathies with pathogenic variants (PV) in HRAS or KRAS. EXPERIMENTAL DESIGN: We conducted a systematic literature review to identify multilineage mosaic RASopathy cases with a PV in HRAS or KRAS to create a retrospective cohort. We calculated cumulative incidence, cancer-free survival, and hazard rates for cancer and standardized incidence rates (SIR). RESULTS: This study identified 69 patients. Of these, 17% had cancer, including rhabdomyosarcoma (RMS) located in the urogenital region (n = 7), skin cancer (n = 3), Wilms tumor (n = 1), and bladder cancer (n = 1). Cumulative cancer incidence by age 20 was 20% (95% confidence interval, 4%-37%). The annual cancer hazard rate peaked at 14% within the first 2 years of life. The highest SIR was found for RMS (SIR = 800; 95% confidence interval, 300-1648). CONCLUSIONS: This is the first investigation of cancer risk in KRAS or HRAS PV-positive mosaic RASopathies to date. The high incidence and SIR values found highlight the need for rigorous RMS surveillance in young children and skin cancer surveillance in adults with this high-risk condition.