Variable Genomic Landscapes of Advanced Melanomas with Heavy Pigmentation

Abstract

Background In the current study, we examined the real-world prevalence of highly pigmented advanced melanomas (HPMel) and the clinicopathologic, genomic, and ICPI biomarker signatures of this class of tumors. Materials and Methods Our case archive of clinical melanoma samples for which the ordering physician requested testing for both PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP) was screened for HPMel cases, as well as for non-pigmented or lightly pigmented advanced melanoma cases (LPMel). Results Of the 1268 consecutive melanoma biopsies in our archive that had been submitted for PD-L1 IHC, 13.0% (165/1268) were HPMel and 87.0% (1103/1268) were LPMel. In the HPMel cohort, we saw a significantly lower tumor mutational burden (TMB, median 8.8 mutations/Mb) than in the LPMel group (11.4 mut/Mb), although there was substantial overlap. In examining characteristic secondary genomic alterations (GA), we found that the frequencies of GA in TERTp, CDKN2A, TP53, and PTEN were significantly lower in the HPMel cases than in LPMel. A higher rate of GA in CTNNB1, APC, PRKAR1A, and KIT was identified in the HPMel cohort compared with LPMel. Conclusions In this study, we quantified the failure rates of melanoma samples for PD-L1 testing due to high melanin pigmentation and showed that CGP can be used in these patients to identify biomarkers that can guide treatment decisions for HPMel patients. Using this practical clinical definition for tumor pigmentation, our results indicate that HPMel are frequent at 13% of melanoma samples, and in general appear molecularly less developed, with a lower TMB and less frequent secondary GA of melanoma progression.

Molecular Characterization of Advanced-Stage Melanomas in Clinical Practice Using a Laboratory-Developed Next-Generation Sequencing Panel

“…In fact, although the data demonstrate that this panel was able to identify mutations in almost all advanced melanoma, in 10% of these, no alterations were identified. In these samples, it might be worth investigating other markers, such as using a panel for fusion genes (e.g., ALK fusions) [28] or a Comprehensive Genomic Profiling (CGP) panel [29,30], allowing the identification of mutations in uncommonly altered genes. With our panel, the primary and metastatic samples showed the same molecular structure; however, the extension to other markers could also be performed to understand whether there are any acquired variants in the metastases that are not present in the primary lesion.…”

Immunohistochemical Expression of Programmed Cell Death Ligand 1 (PD-L1) in Human Cutaneous Malignant Melanoma: A Narrative Review with Historical Perspectives

“…The paper by Huan R.S.P. et al [ 29 ] is very interesting, in which the authors analysed 1268 melanoma samples for which an IHC investigation for PD-L1 was requested and which were divided into high-pigmented melanoma (HPMel) and low-pigmented melanoma (LPMel), constituting 13.0% and 87.0% of the sample, respectively. In terms of TMB, in the HPMel cohort, TMB was significantly lower (median 8.8 mutations/Mb) than in the LPMel group (11.4 mutations/Mb), while secondary molecular alterations such as TERTp, CDKN2A, TP53, and PTEN were lower in HPMel cases than in LPMel ones.…”