The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas

Abstract

Purpose: Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes. Experimental Design: Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression. Results: For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance. Conclusions: In 4 patients who received immunotherapy, we found 1–3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.

Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies

“…However, Luo et al. reported the difference between JAK1 and JAK2 , with JAK1 deficiency being able to mediate resistance to anti-PD-L1 immunotherapy while JAK2 could not ( 82 ), consistent with a recent report that metastases with JAK2 loss-of-function might be regressing under immunotherapy ( 83 ). As for the LOH or heterozygous mutations of the IFN-γ signaling genes, retaining a wide type allele, the tumors are still under effective immune attack ( 84 , 85 ).…”

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

“…Much of the existing postmortem melanoma research has been limited to bulk DNA sequencing data (8,10,11). The inclusion of additional data modalities, namely transcriptomics and single-cell sequencing data in our study, revealed novel findings with clinical and technical implications.…”

“…Our study expands on previous multilesional metastatic melanoma analyses (8)(9)(10)(11)62) by increasing the number of patients studied, the number of samples per patient and the breadth of represented sites of metastases, as well as the breadth of multiomic data generated. We observe a number of different evolutionary routes to lethality.…”

“…The research autopsy has emerged as a method to overcome the limitations of tumour sampling during life (7), with several examples in melanoma (8)(9)(10)(11). However, various areas remain hitherto unexplored, including the genotype to phenotype link via the analysis of transcriptomic and radiological data; the application of an extensive multi-regional sampling design, shown to reveal subclones that are missed from single samples (12)(13)(14); as well as phylogenetic analyses that utilise clone-based trees rather than sample trees (15).…”

Organ Specific Copy Number Variations in Visceral Metastases of Human Melanoma

“…Skin melanoma is among the most metastatic human cancers and is also among those with the highest tumor mutation burden (TMB~10 3 ) due to UV-induced carcinogenesis [ 1 ]. Furthermore, chromosomal instability (CIN) results in a high frequency of copy number variations (CNV) in a similar range as TMB as determined by the highest resolution technologies such as whole genome sequencing (WGS) or whole exome sequencing (WES) [ 2 ]. Meanwhile the TMB and CNV of melanoma are not strictly tightened together [ 3 ].…”