Case Report: from germline to metastasis, genetic landscape of a rapidly-progressing Cutaneous Melanoma Patient. Patient_009_DNA

Cutaneous Melanoma is a skin cancer with a high-mutational burden and a high-risk metastaticrate; early genetic alterations fostering distant progression are a point of interest. In this casereport, the genetic landscape of a Cutaneous Melanoma patient with rapid clinical evolution isdescribed. Patient#009 developed a primary-tumor over a pre-existing nevus, followed byregional and distant metastases, deceasing 7-months after diagnosis. To search for the geneticcontribution to this rapid progression, whole-exome sequencing was performed on germline,precursor-nevi, primary and metastatic lymph-node biopsies. Differential SNP/INDEL and CNVgene alterations, with functional impact on key-pathways and cancer-hallmarks in each step ofevolution, were discerned. Germline-trunk SNP were detected, with stable allele-frequency from germline to metastasis;these mainly affected DNA-repair genes, promoting genome instability. Early somatic-trunkalterations, from nevi-to-metastasis, included BRAF V600E and focal CNV gene loss promotingcomplementary cancer-hallmarks; all these might have set an environment for tumortransformation. We performed an analysis of the tumor-associated nevus into two sections,finding differential SNP and CNV alterations in the tumor-associated nevus relative to the moredistant nevus. These results support that nevi are heterogeneous and rich in genetic alterations,providing a source for melanoma transformation. Upon tumor transformation, a marked increase in CNV over SNP were detected. Both the numberof SNP and CNV affected genes, including known-driver genes, increased throughoutprogression. TMB levels remained lower than expected for melanomas. Typical alterations ofBRAF V600E tumors were detected, including BRAF amplification along with loss of NF1 andPTEN; loss of CDKN2A/B and TP53 surveillance genes; and mutation of KDM5C epigeneticregulator. Finally, proper metastatic alterations were numerous and low frequency, as expected asa consequence of cumulative instability and alterations, acquiring complementary cancer-hallmarks that possibly promoted progression. In this case report, whole-exome-sequencing analysis provided us a tool to discern the differentialalterations with impact on key-pathways and cancer-hallmarks in each step of tumortransformation and progression. An integral analysis, from germline to benign and tumor lesions,was performed; revealing a sequential and cumulative pattern of genetic alterations, weregermline and early nevi somatic events have possibly contributed to its rapid clinical progression.