Abstract 87: Clustered somatic mutations are frequent in transcription factor binding motifs in melanoma and other cutaneous malignancies

Abstract

Abstract We sought to explore the etiology, frequency and clinicopathologic associations of clustered noncoding hotspot mutations in cutaneous malignancies (melanoma, basal cell carcinoma (BCC) and Merkel cell carcinoma (MCC)). We did so by applying a sliding window approach which identified clusters in melanoma whole exome and genome sequencing data. These regions were then evaluated for recurrence in other skin malignancies by using whole exome data from BCC and MCC samples; motifs were extracted using a maximum expectation algorithm. We then sequenced 170 annotated melanoma clinical samples using a targeted amplicon panel which permitted analysis of clinicopathological correlations. Numerous recurrent clustered hotspot mutations were identified in melanoma whole exome and genome data sets in proximal promoters, with some gene-associated clusters present in up to 25% of cases. Mutations were clustered around canonical ETS and SP1 transcription factor binding sites and had a clear UV signature. These promoter mutations correlated with overall mutation load and NF1 mutation status, and showed significant enrichment in specific melanoma subtypes (desmoplastic and lentigo maligna melanoma), sun exposed anatomical locations, male gender, ulceration and increasing age. Identical clusters were identified in BCC and MCC samples, including several previously annotated in melanoma. In conclusion, we identify a novel class of mutation in cutaneous malignancies which rather than being defined by a particular genomic position are related to a position in a transcription factor binding motif. These mutations are also independent of cell of origin. Clinicopathologic correlation and mutation analysis support an etiologic role for chronic UV irradiation. Citation Format: Andrew J. Colebatch, Leon di Stefano, Stephen Q. Wong, Anthony T. Papenfuss, Grant A. McArthur. Clustered somatic mutations are frequent in transcription factor binding motifs in melanoma and other cutaneous malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 87.