Abstract
Background: Acral lentiginous melanoma (ALM) is a rare melanoma subtype found on the palms, soles and nailbeds. Outcomes are poor for patients with advanced ALM, and novel treatment approaches are needed. Here, we seek to explore the global genomic and transcriptomic landscape of ALM.
Methods: A total of 699 primary CM (non-ALM cutaneous melanoma) and 18 primary ALM samples underwent next generation sequencing of DNA (592 Gene Panel, NextSeq, or WES, NovaSeq), and whole transcriptome sequencing (NovaSeq, WTS). Wilcoxon, Fisher’s exact test were used to determine statistical significance (displayed as p value without and q value with multi comparison correction). xCell, HLA subtyping, neoantigen load (HBA: high binding affinity; IBA: intermediate binding affinity; LBA: low binding affinity), Interferon gamma score (IFNγ), MAPK pathway activity score (MPAS), and Innate anti-PD-1 Resistance score (IPRES) were calculated by mRNA expression. Global differentially regulated genes were assessed via limma R package (C: log fold change).
Results: The most common alterations in ALM included NRAS (22.2%), NF1 (20.0%), BRAF (11.1%) and CDKN2A (11.1%) mutations, and EMSY (22.2%), ELL (11.1%), MAML2 (11.1%), MRE11(11.1%) and PIK3R2 (11.1%) amplifications. ALM had lower TMB (1.5 v 9 Mut/Mb, q<.0001), lower rates of TERT (0 v 66.7%, q<.01) and a trend towards lower BRAF (11.1 v 39.8%, p<.05) mutations, compared to CM. Neoantigen load was lower in ALM compared to CM, regardless of MHC binding affinity (HBA: 1 vs 4, q <.01; IBA: 2 vs 7, q <.001; LBA: 7 vs 18, q <.001). HLA-G RNA expression was upregulated in ALM with respect to CM (C = 1.14, q <.001). ALM showed less CD4+ T cell Th1 (C = -0.8, p <.05), B cell plasma (C = -1.8, p<.05), and γδ T cells (C = -5.9, p<.05), but more CD4+ T cell central memory cell (C = 9.7, p<.05), stroma score (C = 1.7, p<.05), and endothelial cells (C = 1.7, p<.05), versus CM. There was a trend towards lower IFNγ in ALM (-0.4 vs -0.3, p = .1), but no difference in IPRES, compared to CM (-0.09 vs 0.1, p=.9). MPAS scores were lower for ALM compared to CM (-1.6 vs -0.4, q<.001), even when stratifying by BRAF (q<.05) or NF1 (q<.05) status, but not NRAS (p = .22). Pathways related to keratinization (p <.0001) and amyloid fiber formation (p<.0001) were enriched in ALM, due to overexpression of KRT16 (C = 3.5, q <.01), KRT6B (C = 3.4, q <.01), and KRT17 (C = 3.2, q <.05), among others.
Conclusion: ALM has distinct immunologic features, including upregulation of HLA-G, as well as lower MAPK activation in ALM, compared to CM, highlighting the need for novel therapeutic approaches in the treatment of this rare subtype.
Citation Format: Gino K. In, Jun Yin, Phillip Walker, Justin Moser, Joanne Xiu, Kelsey Poorman, Geoffery T. Gibney, Matthew Oberley, Thuy Phung, Leonel F. Hernandez-Aya, Jose Lutzky, Wolfgang Michael Korn, Michael B. Atkins. Comprehensive genomic and transcriptomic profiling of acral lentiginous 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 6130.