Abstract B39: Exome sequencing in primary melanoma identifies novel drivers of melanoma progression

Melanoma is the most malignant and lethal among skin cancers, due to its high infiltration and invasion ability and resistance to therapy. Whereas early stages melanoma can be cured in the majority of cases by surgical excision, metastatic melanoma is a highly lethal condition. The most frequent known oncogenic mutation in melanoma is BRAF-V600E and several full exome sequencing studies have revealed numerous other alterations (Wei et al, 2011; Nikolaev et al, 2011; Stark et al, 2011; Krauthammer et al, 2012). A crucial issue in understanding melanoma progression is to identify which mutations are specifically involved in making an individual melanoma competent for metastatic spread. It is well established that this behavior is highly correlated with histological features, such as the thickness of the primary tumor and the mitotic index. Here we performed full exome sequencing of 5 thin ( 4mm in thickness) primary melanomas compared to matched-normal DNA. We confirmed recurrent somatic mutations in known melanoma-related genes, including BRAF, c-KIT, EGFR, PPP6C, MLL3 and several components of the glutamate signaling. In addition, we discovered mutations in genes not previously linked to this tumor, such as CSMD1, FGFR4 and components of the Hedgehog (HH) signaling pathway. In particular, in a thick melanoma we found an novel activating mutation in the transcription factor GLI1, one of the final effectors of the HH signaling. Notably, in the only 3 thick melanomas that produced metastasis, we identified candidate metastasis-driving mutations in six genes (ADAMTS6, ADAMTS7, CHD9, MLL3, NALCN and TSC2). Interestingly, we identified several regions of focal somatic copy-number alterations (SCNAs) that were altered at significantly higher frequency in thick compared to thin melanomas. Several gene families are comprised among these regions of focal SCNAs, including components of Notch, HH and Wnt/s-catenin signaling pathways, BRAF, c-MYC and its cofactor PIM1, several ADAMs, EGFR and the HOX genes. Our preliminary results identify potential drivers of melanoma progression, enhancing our understanding of the genomic complexity underlying melanoma. Citation Format: Valentina Montagnani, Matteo Benelli, Alessandro Apollo, Gianni Gerlini, Lorenzo Borgognoni, Barbara Stecca. Exome sequencing in primary melanoma identifies novel drivers of melanoma progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B39.