Abstract 3618: Gene mutation and protein co-expression in melanoma and colorectal cancer by BRAF V600 mutation status
Authors: Carnell Matthew A. , Feldman Rebecca , Atkins Michael B. , El-Deiry Wafik S. , Pishvaian Michael J. , Salem Mohamed E. , VanderWalde Ari M. 
Published: August 2018

BRAF V600 oncogenic mutations are targetable in the treatment of melanoma but are more difficult to treat in colorectal cancer (CRC). The difference in the biological profile of BRAF V600 mutant melanoma and CRC compared to BRAF V600 wildtype melanoma and CRC has not been established. 5,139 tumor samples (CRC, 4007 and Mel, 1132) submitted for IHC (protein expression), ISH (gene amplification), and NGS sequencing of between 44 and 592 genes between 2009 and 2015 at a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) were retrospectively studied. Of these, 270 colorectal (6.7%) and 334 melanoma (29.5%) samples had BRAF V600 mutations. Genes or proteins with more than 100 samples in each BRAF wildtype and mutant group were tested for co-expression or co-mutation in each malignancy and correlations with a p-value &lt;0.01 were reported. The rate of co-mutations/expression in BRAF V600 mutant melanoma compared to BRAF wildtype melanoma was lower for 5 genes: KRAS (0% vs 3%), NRAS (0% vs 37 %), HNF1A (1% vs 2%), c-KIT (1% vs 7%), and GNAQ (0% vs 4%), and 3 proteins: MGMT by IHC (23% vs 31%), PTEN by IHC (64% vs 81%), and TOPO1 by IHC (44% vs 53%). The rate of co-mutations/expression in BRAF V600 mutant CRC compared to BRAF wildtype CRC was lower for 3 genes: KRAS (0% vs 52%), NRAS (0% vs 4%), and APC (26% vs 61%), and 2 proteins: MLH1 (66% vs 98%), PMS2 (65% vs 97%); and higher for 10 genes: HNF1A (7% vs 1%), JAK2 (2% vs 0%), MPL (1% vs 0%), AKT1 (3% vs 1%), EGFR (4% vs 1%), SMARCB1 (2% vs 0%), ATM (8% vs 4%), STK11 (3% vs 1%), PTEN (8% vs 3%), BRCA2 (18% vs 9%), and 5 proteins: EGFR (77% vs 60%), PD-1 (61% vs 42%), PD-L1 (10% vs 2%), RRM1 (63% vs 44%), and TS (58% vs 32%), and MSI by fragment analysis (35% vs 4%). In melanoma, all 8 proteins and gene mutations with significantly different expression were expressed less frequently in BRAF V600 mutants compared to wildtype. However, in CRC, 16 of 21 gene mutations and proteins were expressed more frequently among BRAF V600 mutants compared to wildtype. HNF1A was expressed more frequently in BRAF mutant CRC than in wildtype CRC but less frequently in BRAF mutant melanoma compared to BRAF wildtype melanoma. BRAF V600 mutations are associated with a biological profile that is distinct from BRAF V600 wildtype in both melanoma and colorectal cancer. Furthermore, BRAF mutant melanoma tends to have different genes and proteins co-mutated/expressed than colorectal cancer which supports previous findings suggesting differential activation of protective feedback loops. These differences in expression of gene mutations and proteins may play a role in the different responses to therapies between BRAF V600 mutant melanoma and BRAF V600 mutant colorectal cancer.

Citation Format: Matthew A. Carnell, Rebecca Feldman, Michael B. Atkins, Wafik S. El-Deiry, Michael J. Pishvaian, Mohamed E. Salem, Ari M. VanderWalde. Gene mutation and protein co-expression in melanoma and colorectal cancer by BRAF V600 mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3618.