Whole-exome sequencing landscape of a rapidly-progressing cutaneous melanoma patient

MORDOH, ANA; CARRI, IBEL; BARRIO, MARÍA MARCELA; MORDOH, JOSÉ; ARIS, MARIANA

Congreso; LXIV Congreso de la Sociedad Argentina de Investigaciones Clínicas; 2020

Cutaneous Melanoma (CM) is a skin cancer with a high Tumor Mutational Burden (TMB) and a high-risk metastatic rate; the genetic landscape of a CM patient with rapid clinical evolution is described here.Methods: Whole-exome sequencing analyses on gDNA from germline, precursor-nevi, primary CM and lymph-node metastasis (LN-mts) microdissected-tumor biopsies were performed. Data were analyzed following GATK guidelines (GRCh37/HG19 reference). Detection algorithms: HaplotypeCaller v3.3.0 for germline SNP; Mutect2 v3.8-0 for somatic SNPs/INDELs; FACETS v0.6.0 for CNV. Differential alterations in the allelic frequency (AF) of SNP/INDELs as well as in the cellular fraction (CF) of copy-number-variation (CNV) were discerned in genes with impact on cancer hallmarks in each step of tumor transformation and progression.Results: Germline trunk mutations with known effect on susceptibility and poor-prognosis in CM were detected, early affecting genome stability (n=60). Regarding somatic gene alterations, CNV prevailed over SNP/INDELs, both showing an increasing number of affected genes in the path from nevi to metastasis. Accordingly, TMB tripled with progression (2.875X). The main somatic trunk driver was the oncogene BRAFV600E, with an increasing AF and CF in primary and LN-mts, sustaining proliferative signaling. At CNV level, deletion prevailed over gene amplification (8.42X). Metastasis-persisting genes exhibited increasing CF variation throughout progression (1.65X), supporting a functional selection of these altered-genes.Amplified genes (n=494) mainly affected cell proliferation, invasion & metastasis, angiogenesis and metabolism hallmarks. While deleted genes (n=4161) mainly affected regulation of cell proliferation, cell death and immunity hallmarks. Conclusion: in this gradual although rapidly-progressing CM case, WES analysis allowed us to disguised differential alterations with impact on cancer hallmarks in each step of tumor transformation and progression