Abstract
Background: Activation in RAS pathway has been associated with cancer development. Three RAS family members, including NRAS, KRAS and HRAS are frequently mutated across various cancer types, where NRAS mutations are present in 15-20% of melanomas. NRAS-mutant melanomas (NRASm) have been extensively characterized. However, molecular and clinical implications of HRAS mutations (HRASm) in melanoma are less well understood.
Methods: A total of 6329 melanoma samples were subjected to comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq; whole exome sequencing, NovaSEQ), RNA (NovaSeq, whole transcriptome sequencing, WTS) and IHC. MPAS scores to evaluate MAPK pathway activation, IFN scores, QuantiSeq, neoantigen load (high, intermediate, low binding affinity: HBA, IBA and LBA) and GSEA were calculated from mRNA expression data. Wilcoxon, Fisher’s exact were used to determined statistical significance (p value without and q value with multi comparison correction; FDR for GSEA). The reference cohort was the entire melanoma cohort (MC).
Results: HRASm were identified in 69 (1.09%) of melanoma samples (hotspots mutations: G13, 40%; Q61, 34%; G12, 18% and others, 9%). HRASm and NRASm had different genomic landscapes: HRASm were significantly associated with a higher mutation rate of NF1 (43.2% vs 27.7%, p<.05), ARID1A (17.2% vs 6.3%, p<.05), B2M (14.3% vs 2.4%, p<.05), RAF1 (12.2% vs 1.4, p<.0001), CTNNB1 (9.1% vs 3.3%, p<.05) and higher amplifications of EMSY (11.8% vs 1.8%, p<.01), MRE11 (4.3% vs 0.5%, p<.05), whereas NRASm harbored less NF1 (14.8% vs 27.7%, q<.0001 ), BRAF (6.9% vs 39.9%, p <.0001), PTEN (3.9% vs 6.9%, q <.05), KIT (0.8% vs 4.4%, q <.0001) mutations and less amplification PDGFR (0.4% vs 1.3%, p<.05), BRAF (0.2% vs 1.4%, p<.05), KIT (0.2% vs 2.1%, q<.05) when comparing to MC. Both HRASm and NRASm had higher MPAS scores than MC (HRASm, 0.24; NRASm, 0.11; MC, -0.41, q<.001). In addition, HRASm showed higher TMB (HRASm, 68.1%; NRASm, 56.9%; MC, 50.0%, q<.05), relatively higher IFN scores (HRASm, 0.16; NRASm, -0.23; MC, -0.24, q = .16) and higher neoantigen load (HBA: HRASm, 10.5; NRASm, 4; MC, 4, p < .05; IBA: HRASm, 17.5; NRASm, 8 MC, 7, p < .05; LBA: HRASm, 37.5; NRASm, 21; MC, 19, p =.1) when compared to NRASm and MC. Lastly, suppression of angiogenesis pathway was observed in both HRASm (NES = 1.7, FDR<.05) and NRASm with respect to MC (NES = 1.4, FDR<.25).
Conclusions: The genomic landscape of HRASm are significantly different from that of NRASm, implying their distinct roles in tumorigenesis. HRASm also demonstrated higher MAPK activation, suggesting that they could potentially benefit from agents targeting on this pathway. In addition, HRASm displayed more immunogenic features, associated with down-regulation of angiogenesis pathway, revealing a potential higher susceptibility of HRASm to immunotherapy.
Citation Format: Leonel F. Hernandez-Aya, Estelamari Rodriguez, Aparna Nallagangula, Jun Yin, Phillip Walker, Joanne Xiu, Justin Moser, Gino K. In, David Spetzler, Geoffery T. Gibney, Matthew Oberley, Thuy Phung, Michael Atkins, Dave S. Hoon, Wolfgang Michael Korn, Jose Lutzky, Gilberto Lopes. Molecular and immunologic characterization of HRAS mutations in a cohort of 6,329 patients with cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5625.