Abstract 1094: Deciphering driver mechanisms for tumorigenesis in BRAF/NRAS double wild-type melanoma through integration of heterogeneous genome-wide datasets

In cutaneous melanoma, the most lethal form of skin cancer, BRAF is mutated in ∼45% of cases and NRAS in a further ∼20% of cases. The lack of known drivers in the remaining proportion of samples represents a challenge for personalized medicine. We hypothesize that the BRAF/NRAS double wild-type (WT) samples are a heterogeneous group driven by multiple events that arise independently. We performed whole exome sequencing (WES) and complimentary RNA-seq of 23 tumor tissue samples from 21 patients. Six of these tumors were WT for BRAF and NRAS, so we studied these cases further. The SNV load in the WT samples is more variable than the BRAF or NRAS driven melanomas. The median number of SNVs/Mb (± SD) for BRAF mutant (n = 9), NRAS mutant (n = 7) and BRAF WT/ NRAS WT (n = 6) samples were: 12.2 ± 8.0, 42.2 ± 82.7 and 12.6 ± 90.2 respectively. Next we analyzed the TCGA cutaneous melanoma cohort where there are 154 BRAF and 92 NRAS mutated and 76 BRAF WT/NRAS WT samples. The median numbers of SNVs (± SD) were 374 ± 638.3, 577 ± 518.3 and 146.5 ± 1221.6 respectively. The p-value for the comparisons BRAF vs. WT and NRAS vs. WT were 0.087 and 0.002 respectively (two-tailed Mann-Whitney test). We identified the somatic mutations that are specifically enriched for double wild-type samples and observed that the top two hits, NF1 (30.2% in double WT vs. 5.7% otherwise) and KIT (15.8% in double WT vs. 0.8% otherwise) are known driver gene candidates for wild-type melanomas, but we also find other novel candidate driver genes. Thus, we present a framework for identification of driver mutations and therapeutic targets in double wild-type melanomas and integration of these types of data with other large datasets such as those derived from RNA-seq and RPPA will assist in the development of approaches to stratify double wild-type patients for targeted or immune-therapies. Citation Format: Amit Mandal, Maria Romina Girotti, Amaya Viros, Gabriela Gremel, Elena Galvani, Rebecca Lee, Kok Haw Jonathan Lim, Simon J. Furney, Paul Lorigan, Richard Marais. Deciphering driver mechanisms for tumorigenesis in BRAF/NRAS double wild-type melanoma through integration of heterogeneous genome-wide datasets. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1094. doi:10.1158/1538-7445.AM2015-1094