Dataset Information

Case Report: early contribution of germline and nevi genetic alterations to a rapidly-progressing Cutaneous Melanoma Patient

ABSTRACT: Background. Cutaneous Melanoma is a skin cancer with a high mutational burden and a high metastatic rate. Early genetic alterations and biomarkers of distant progression are a point of interest. Adding to germline-susceptibility loci, almost 30% of melanomas arise from precursor benign nevi lesions, constituting a source for malignant transformation. Case Presentation. Patient#009 developed a primary tumor over a pre-existing nevus, followed by regional and distant metastases, deceasing 7 months after diagnosis. To search for the genetic contribution to this rapid progression, longitudinal whole-exome sequencing analysis was performed on germline, nevi, primary tumor, and a metastatic lymph node. Tumor-associated nevus was analyzed splitted into two sections, adjacent and distant to the tumor. Differential SNP/INDEL and CNV gene alterations, with functional impact on key pathways and cancer hallmarks in each step of evolution, were discerned. Germline-trunk SNP were detected with stable allele-frequency from germline to metastasis; mainly affecting DNA-repair genes, promoting genomic instability. Early somatic-trunk alterations, detected in nevi and persisting in primary tumor and metastasis, included BRAFV600E and focal CNV with copy loss of several genes involved in DNA repair, cytoskeleton regulation, intercellular connections, chemokines and vesicular transport, acquiring additional cancer-hallmarks. Adjacent and distant nevi were rich in alterations, presenting differential SNP and CNV alterations. Upon tumor transformation, a marked increase in CNV over SNP alterations were detected. Both the number of SNP and CNV-affected genes, including known driver genes, increased throughout progression, although TMB levels remained lower than expected for melanomas. Typical alterations of BRAFV600E tumors related to intrinsic resistance to BRAF-inhibitors were detected, including BRAF amplification and loss of NF1, PTEN, CDKN2A/B and TP53 surveillance genes. Finally, numerous metastatic alterations were detected, further promoting tumor progression. Conclusions. In this patient, a longitudinal WES analysis was performed, from germline to benign and tumor lesions, revealing 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 that nevi can be genetically heterogeneous entities, providing a fertile precursor for melanoma transformation and progression, in which prognostic biomarkers should be further studied.

PROVIDER: EGAS00001006459 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Similar Datasets

Project description:The breast tumor microenvironment plays an active role in tumorigenesis. Molecular alterations, including epigenetic modifications to DNA, and changes in RNA and protein expression have been identified in tumor-associated stroma; however, there is considerable debate as to whether the stroma is characterized by genomic instability or whether detection of chromosomal alterations in the breast stroma is a reflection of technological artifact rather than the true genomic content of the tumor microenvironment. Methods: Surgically-removed breast stroma specimens from 112 women undergoing reductive mammoplasty (n=15), prophylactic mastectomy (N=6) or mastectomy for a diagnosis of breast disease (n=92) were frozen in optimal cutting temperature medium. Allelic imbalance (AI) analysis was performed in 484 stromal specimens from 98 women using a panel of 52 microsatellite markers; SNP data was generated from a subset of 86 stromal specimens using 250K SNP arrays (Affymetrix). Copy number alterations were identified using Partek Genomics Suite. Results: AI was not detected in 92% (444/484) of stroma specimens. When compared to previously generated AI data from 77 formalin-fixed, paraffin-embedded stroma specimens (Ellsworth et al., Ann Surg Oncol 2004), 32 (42%) of which harbored at least one detectable AI event, the frequency of AI in the FFPE specimens (4.62%) was significantly higher (P<0.0001) than that found in frozen specimens (0.45%). Of the stroma specimens assayed using SNP arrays 95% (82/86) had no detectable alterations and the 11 copy number changes were small and not shared between specimens. Conclusions: The data presented here support a model in which the tumor microenvironment is genetically stable. The direct comparison of copy number alterations between FFPE and frozen research-grade specimens using identical methodologies suggests that past reports of significant AI in breast stroma, both adjacent to and distant from the tumor, reflects artifact in the archival specimens caused by formalin-fixation, paraffin-embedding and tissue storage. 250K STY data was generated for 86 breast stromal specimens. The tissue specimens were analyzed by paired analysis to the SNP data from matched genomic (blood) DNAs

Project description:Circulating tumor cells (CTCs) are critical in the development of distant organ tumor metastasis, and are associated with advanced cancer stage and poor patient outcome. Here, we present the first genome-wide nucleotide-level characterization of CTCs. Our single-nucleotide polymorphism (SNP) analysis in patients with melanoma involved: 1) global comparative genomic analysis of CTCs and matched regional metastases, 2) identification of key genomic aberrations in CTCs, 3) verification of these target genes in aggressive distant tumor metastases, and 4) evidence of selective expression and functional consequence of CTC-associated genes in melanomas. We report 131 aberrant loci in CTCs that are potentially pro-metastatic, and show that such expression of a 5-marker gene panel (CSMD2, CNTNAP5, FLJ14051, ADAM6, TRPM2) in melanomas confers prognostic utility. Successful treatment of melanoma requires understanding of the metastatic process and identification of patients with tumors most likely to develop aggressive metastatic disease. Melanomas are heterogeneous, and CTCs have long been recognized as vehicles for cancer spread, representing particularly aggressive tumor clones that can evolve into successful clinical metastases. Elucidation of genomic aberrations in CTCs will aid in the development of prognostic biomarkers and therapeutic strategies to target CTCs to prevent or control distant cancer spread. This study provides the first detailed genomic confirmation of the close relation between CTCs and tumor metastases, and illustrates how CTCs can be utilized as a novel approach and rational source for identification of pro-metastatic genes in cancer research. Three individual patient cohorts were utilized in the study. CNV and LOH loci were evaluated initially in metastatic melanoma patients (n=13) in a discovery cohort. SNP loci that harbored CNV/LOH in CTCs were then separately verified for: (a) presence in distant organ metastasis (AJCC Stage IV melanoma) (n=27), and (b) relevance to prognosis in regional melanoma metastasis (AJCC Stage III melanoma) (n=35). The first discovery patient cohort group was utilized for capture of CTCs, and consisted of peripheral blood mononuclear cell (PBMC) and tumor specimens from metastatic melanoma patients (n=13). CTC-related loci were verified in a second cohort of patients with Stage IV distant organ metastases (n=27), including 15 brain, 4 lung, and 8 gastrointestinal (bowel, liver) metastases. The third patient cohort consisted of early passage (<12) established melanoma cell lines derived from 35 regional melanoma metastases (Stage III) for evaluation of the prognostic utility of the CTC-associated aberrant loci.

Dataset Information

Case Report: early contribution of germline and nevi genetic alterations to a rapidly-progressing Cutaneous Melanoma Patient

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets