Abstract 1722: Spectrum of solid malignancies associated with mutations in CYLD gene

Abstract Introduction: The CYLD gene product is a de-ubiqutinating enzyme involved in regulation of NF-kappaB signaling. Inactivating germline mutations in CYLD are the cause of Brooke-Spiegler syndrome characterized by multiple cutaneous tumors (cylindromas, trichoepitheliomas and spiradenomas) and tumors of salivary glands. Little is known about the role of CYLD in the development of solid organ malignancies. Methods: We retrospectively analyzed CYLD gene mutations detected in a large database of solid tumors genetically profiled (NGS of 592 genes) at a reference laboratory (Caris Life Science, Phoenix, AZ). Results: CYLD pathogenic mutations were identified in 235 tumor samples (0.4% of the tumors analyzed). The most common primary sites included lung (60), endometrium (15) and anus (10). Histologically, the majority of the tumors were classified as squamous (71) and adenocarcinoma (59). A number of mutations were identified, most commonly affecting codons p.N722fs (27), p.S371* (16) and p.P771S/p.P771L (12). 38 cases had only CYLD mutations detected, while the majority of associated mutations occurred in TP53 (45%). Numerous co-occurring pathogenic mutations were present in oncogenes (e.g. PIK3CA in 41, KRAS in 33, BRAF 17) and/or tumor suppressor genes (e.g. APC in 40, PTEN in 36, BRCA2 in 25, RB1 in 23). Conclusion: Our study provides the largest database analysis of CYLD gene mutations in solid tumors and shows the distribution in numerous primary tumor sites previously unrecognized in association with CYLD. Additional studies may reveal unexpected germ-line associations and will be pursued in the future. Citation Format: Michelle Ellis, Jeff Swensen, Zoran Gatalica. Spectrum of solid malignancies associated with mutations in CYLD gene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1722.