Early contribution of germline and nevi genetic alterations to a rapidly-progressing cutaneous melanoma patient: a case report

Abstract

Background: Cutaneous melanoma is the skin cancer with the highest mutational burden and metastatic rate. Early genetic alterations and biomarkers of distant progression are a point of interest. In addition to germline-susceptibility loci, almost 30% of melanomas arise from precursor benign nevi lesions, providing a source for malignant transformation.

Case presentation: Patient#009 developed a cutaneous melanoma over a nevus, followed by progression to regional and distant metastases in months, unresponsive to targeted therapy. To search for the genetic contribution to this rapid progression, a longitudinal analysis was performed through WES of germline, nevi, primary tumor, and a metastatic lymph node. Differential SNP/INDEL and CNV gene alterations, with functional impact on key pathways and cancer hallmarks in each step of evolution, were discerned. Tumor-associated nevus was, for the first time, split into two sections, distant and adjacent to the primary tumor, to study its heterogeneity. Shared SNP alterations, with stable allele fraction from germline to metastasis were detected, mainly affecting DNA repair genes and promoting genome instability. Early somatic alterations, shared by nevi and primary and metastatic tumors, included BRAF^V600E and focal copy-loss of several genes, acquiring additional cancer hallmarks. Phylogenetic analyses revealed that these common somatic alterations would provide a "bridge", allowing progression from a benign to a malignant state. Distant and adjacent nevi were rich in alterations, presenting differential SNP and CNV alterations. Upon tumor transformation, a marked increase in CNV over SNP alterations was determined. Both the number of SNP and CNV-affected genes, including known driver genes, increased throughout progression, although TMB levels remained lower than expected for melanoma. Typical alterations in BRAF^V600E tumors related to intrinsic resistance to targeted therapy were found, including BRAF amplification and loss of PTEN, CDKN2A/B, and TP53 surveillance genes. Finally, numerous metastatic alterations were detected, further promoting tumor progression.

Conclusions: In this patient, longitudinal WES analysis revealed a sequential and cumulative pattern of genetic alterations, where germline and nevi somatic events contributed early to its rapid clinical progression. In this case report, we found tumor-associated nevi as genetically heterogeneous precursor entities, in which potential prognostic biomarkers should be studied prospectively.

Keywords: Cancer hallmarks; Cancer pathways; Case report; Cutaneous melanoma; Germline alterations; Nevi heterogeneity; Somatic alterations; Tumor progression; Whole-exome sequencing.

Fig. 1

Patient#009 timeline and genetic landscape. A Clinical evolution of patient#009 including the main events. Biopsies analyzed in this case report are indicated with a green box, and representative HE-histology images at low magnification are shown: (I) adjacent nevus and primary-CM (2 mm), distal nevus (2 mm), and LN-mts (500 µm). B Longitudinal WES analysis of patient#009 throughout cancer progression, with differential SNP/CNV alterations at each step of clinical evolution: shared germline alterations, including germline alterations present in all tissue samples; shared somatic alterations, including somatic alterations common to all tissue samples; adjacent nevus alterations, including alterations present in the adjacent nevus and not in the distal nevus; melanoma alterations, including common tumor alterations to primary-CM and LN-mts; and LN-mts alterations, including only alterations proper of the metastasis. All analyses performed are fully described under Methods (Additional file 1)

Fig. 2

Cancer driver genes throughout the progression of patient#009. Oncoprint representation of selected driver genes throughout the progression of patient#009 are shown, indicating SNP/INDEL alterations in green, CNV amplifications in red and CNV deletions in blue. In the right axis, the total number of hits or alterations on each gene throughout progression is shown. Subsets: shared germline alterations (SHR germline ALT), shared somatic alterations (SHR somatic ALT), adjacent nevus alterations, CM alterations, LN-mts alterations

Fig. 3

Key pathways throughout the progression of patient#009. A Heatmap representing hierarchical clustering of each step of progression (columns) and KEGG cancer-related pathways (rows), analyzed by functional enrichment. The color key and histogram related to p-values are indicated in the upper box. A p-value adjusted by FDR of 0.05 has been selected as a significant threshold. B Tree visualization of phylogenetic distances between each step of progression, according to their SNP and CNV alterations. Subsets: shared germline alterations (SHR germline ALT), shared somatic alterations (SHR somatic ALT), adjacent nevus alterations, CM alterations, LN-mts alterations. All analyses performed are fully described under Methods (Additional file 1)