Paired tumor-normal sequencing provides insights into the CDKN2A-associated tumor spectrum

Germline pathogenic variants (PV) in CDKN2A are characterized by an increased risk for melanoma, pancreatic cancer, nervous system tumors, and additional cancer types. We sought to define the tumor and clinical characteristics in a cohort of cancer patients with CDKN2A PV. Amongst 71,868 patients, 69 (0.1%) had a CDKN2A PV. Of these, 87.0% (n = 60), 7.2% (n = 5), and 5.8% (n = 4) had a PV impacting p16^INK4A, p14^ARF, or both p16^INK4A and p14^ARF, respectively. Biallelic inactivation of CDKN2A was observed in 33/47 (70.2%) of tumors assessed. Most tumors (28/38, 73.7%) in patients with p16^INK4A PV demonstrated biallelic inactivation, including non-classic tumors such as lung cancer and osteosarcoma. Approximately half (5/9, 55.6%) of tumors in patients where p14^ARF was impacted demonstrated biallelic inactivation, including peripheral nervous system tumors. This analysis supports a potential role of CDKN2A in the development of tumors beyond melanoma and pancreatic cancer and may have important implications for surveillance recommendations.