Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tumor genetic heterogeneity analysis of chronic sun-damaged melanoma.

ABSTRACT: Chronic sun-damaged (CSD) melanoma represents 10%-20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra-tumor heterogeneity (ITH) in CSD^high melanoma is still unknown. Ultra-deep targeted sequencing of 40 cancer-associated genes was performed in 72 in situ or invasive CMM, including 23 CSD^high cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in-transit metastases from one CSD^high melanoma patient. We found no significant difference in mutation frequency in melanoma-related genes or in mutational load between in situ and invasive CSD^high lesions, while this difference was observed in CSD^low lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSD^high melanomas. Sequencing of multiple specimens from one CSD^high patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSD^high and CSD^low melanomas are distinct molecular entities that progress via different genetic routes.

SUBMITTER: Sanna A

PROVIDER: S-EPMC7217060 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Tumor genetic heterogeneity analysis of chronic sun-damaged melanomas

Project description:Chronic sun-damaged (CSDhigh) melanoma represents 10-20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events, or the extent of intra-tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown. Ultra-deep targeted sequencing of 40 cancer-associated genes was performed in 73 in situ or invasive CMM, including 23 CSDhigh cases. In addition, we performed whole-exome and RNA sequencing on multiple regions of primary tumor and multiple in-transit metastases from one CSDhigh melanoma patient. We found no significant difference in mutation frequency in melanoma-related genes or in mutational load between in situ and invasive CSDhigh lesions while this difference was observed in CSDlow lesions. In addition, increased frequency of BRAF V600K, NF1 and TP53 mutations (P < 0.01, Fisher’s Exact Test) was found in CSDhigh melanomas. Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with > 95% shared mutations. Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes.

2020-05-19 | GSE139362 | GEO

Tumor genetic heterogeneity analysis of chronic sun-damaged melanomas

Project description:Tumor genetic heterogeneity analysis of chronic sun-damaged melanomas

| PRJNA579371 | ENA

Mutation analysis in individual circulating tumor cells depicts intratumor heterogeneity in melanoma

Project description:Circulating tumor DNA (ctDNA) is the cornerstone of liquid biopsy diagnostics revealing clinically relevant genomic aberrations from blood of cancer patients. Genomic analysis of single circulating tumor cells (CTCs) could provide additional insights into intra-patient heterogeneity, but it requires whole genome amplification (WGA) of DNA, which might introduce bias. Here, we describe a novel approach based on mass spectrometry for mutation detection from individual CTCs not requiring WGA and complex bioinformatics pipelines. After establishment of our protocol on tumor cell line-derived single cells, it was validated on CTCs of 33 metastatic melanoma patients and the mutations were compared to those obtained from tumor tissue and ctDNA. Although concordance with tumor tissue was superior for ctDNA over CTC analysis, a larger number of mutations were found within CTCs compared to ctDNA (p=0.039), including mutations in melanoma driver genes, or those associated with resistance to therapy or metastasis. Thus, our results demonstrate proof-of-principle data that CTC analysis can provide clinically relevant genomic information that is not redundant to tumor tissue or ctDNA analysis.

| S-SCDT-10_1038-S44321-024-00082-6 | biostudies-other

Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model.

Project description:Metastatic melanoma portends a poor prognosis and patients may present with multiple, simultaneous tumors. Despite recent advances in systemic immunotherapy, a majority of patients fail to respond, or exhibit lesion-specific responses wherein some metastases respond as others progress within the same patient. While intertumoral heterogeneity has been clinically associated with these mixed lesion-specific therapeutic responses, no clear mechanism has been identified, largely due to the scarcity of preclinical models. We developed a novel murine synchronous melanoma model that recapitulates this intertumoral genetic and microenvironmental heterogeneity. We show that genetic differences between tumors are sufficient to generate distinct tumor immune microenvironments (TIME) simultaneously in the same mouse. Furthermore, these TIMEs lead to the independent regulation of PD-1/PD-L1 (programmed cell death protein 1/PD-1 ligand), a popular axis targeted by immune checkpoint therapy, in response to ongoing anti-tumor immunity and the presence of interferon-gamma. Currently, therapeutic selection for metastatic melanoma patients is guided by a single biopsy, which may not represent the immune status of all tumors. As a result, patients can display heterogeneous lesion-specific responses. Further investigations into this synchronous melanoma model will provide mechanistic insight into the effects of intertumoral heterogeneity and guide therapeutic selection in this challenging patient population.

| S-EPMC8151632 | biostudies-literature

A single-cell analysis reveals tumor heterogeneity and immune environment of acral melanoma.

Project description:Acral melanoma is a dismal subtype of melanoma occurring in glabrous acral skin, and has a higher incidence in East Asians. We perform single-cell RNA sequencing for 63,394 cells obtained from 5 acral and 3 cutaneous melanoma samples to investigate tumor heterogeneity and immune environment. We define 5 orthogonal functional cell clusters that are involved in TGF-beta signaling, Type I interferon, Wnt signaling, Cell cycle, and Cholesterol efflux signaling. Signatures of enriched TGF-beta, Type I interferon, and cholesterol efflux signaling are significantly associated with good prognosis of melanoma. Compared with cutaneous melanoma, acral melanoma samples have significantly severe immunosuppressive state including depletion of cytotoxic CD8+ T cells, enrichment of Treg cells, and exhausted CD8+ T cells. PD1 and TIM-3 have higher expression in the exhaustive CD8+ T cells of acral melanoma. Key findings are verified in two independent validation sets. This study contributes to our better understanding of acral melanoma.

| S-EPMC9700682 | biostudies-literature

UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma.

Project description:Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade.

| S-EPMC6863386 | biostudies-literature

Interactive Beliefs about Genes and Behavior Predict Improved Sun Protection Following Melanoma Genetic Counseling.

Project description:BackgroundLittle is known about how members of cancer-prone families think about genetic determinism and whether personal behavior can amplify or counter genetic risk for disease.PurposeUnderstanding how people think about the impact of personal behavior on disease risk may inform communications about genetic risks and their management.MethodsWe assessed three sets of beliefs about the impact of behavior on genetic risk-interactive (unhealthful behaviors can amplify genetic risk), subtractive (healthful behaviors can reduce genetic risk), and deterministic (genes primarily determine health outcomes)-among 114 unaffected members of melanoma-prone families receiving genetic counseling (51.6% men, average age = 35.3). We examined whether these beliefs predicted changes in perceived control, motivation to manage melanoma risk, and sun-protection behavior one year later.ResultsParticipants strongly endorsed interactive and subtractive beliefs, but not deterministic beliefs. These beliefs generally did not change, even among those who received positive CDKN2A/p16 genetic test results conferring up to 76% lifetime melanoma risk. Controlling for age, sex, education, skin type, and genetic test result, interactive beliefs predicted sustained increases in perceptions of personal control, motivation to reduce sun exposure, use of multiple sun-protection methods, and reduction in objectively assessed tanning at the wrist one year following genetic counseling. Subtractive beliefs predicted increased personal control, motivation to manage risk, and sunscreen use, while deterministic beliefs were generally unrelated to outcomes.ConclusionsAmong people at highly elevated hereditary cancer risk, beliefs that unhealthful behaviors can amplify genetic risk seem to be especially motivating of behavioral risk-reduction efforts.

| S-EPMC9345182 | biostudies-literature

Functional heterogeneity exceeds genetic heterogeneity in chronic myelomonocytic leukemia

Project description:The respective role of genetic and epigenetic heterogeneity in the functional diversity of cells that compose human malignancies remains poorly understood. This question is addressed in chronic myelomonocytic leukemia (CMML), a myeloid neoplasm in which clinical diversity contrasts with a limited genetic heterogeneity. By reprogramming CMML-patient and healthy donor CD34-positive cells, we generated induced pluripotent cell clones (iPSC). In one of the patients, we captured a part of the genetic heterogeneity of the leukemic clone and analyzed five iPSCs with two distinct genetic backgrounds, i.e. with and without KRASG12D mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior as well as the DNA methylation pattern of hematopoietic cells derived from iPSCs with similar genetic background. Introduction of SRSF2P95H mutation in a KRAS-mutated iPSC partially suppressed the functional and epigenetic gap with the other KRAS-mutated clone. Despite the similar functional behavior of these two clones, only the SRSF2P95H clone responded to low doses of the hypomethylating agent decitabine by restoration of a more balanced production of hematopoietic cells. These analyses unravel additional levels of intraclonal heterogeneity beyond the coding mutations, which may also modulate individual cell response to treatment.

2020-04-14 | GSE114115 | GEO

Genetic Alterations among Korean Melanoma Patients Showing Tumor Heterogeneity: A Comparison between Primary Tumors and Corresponding Metastatic Lesions.

Project description:PURPOSE:Melanoma is a highly heterogeneous neoplasm, composed of subpopulations of tumor cells with distinct molecular and biological phenotypes and genotypes. In this study, to determine the genetic heterogeneity between primary and metastatic melanoma in Korean melanoma patients, we evaluated several well-known genetic alterations of melanoma. In addition, to elucidate the clinical relevance of each genetic alteration and heterogeneity between primary and metastatic lesions, clinical features and patient outcome were collected. Materials and Methods:In addition to clinical data, BRAF, NRAS, GNAQ/11 mutation and KIT amplification data was acquired from an archived primary Korean melanoma cohort (KMC) of 188 patients. Among these patients, 43 patients were included for investigation of tumor heterogeneity between primary melanoma and its corresponding metastatic lesions. RESULTS:Overall incidence of genetic aberrations of the primary melanomas in KMC was 17.6% of BRAF V600, 12.6% of NRAS mutation, and 28.6% of KIT amplification. GNAQ/11 mutation was seen in 66.6% of the uveal melanoma patients. Patients with BRAF mutation were associated with advanced stage and correlated to poor prognosis (p < 0.01). Among 43 patients, 55.8% showed heterogeneity between primary and metastatic lesion. The frequency of BRAF mutation and KIT amplification significantly increased in the metastatic lesions compared to primary melanomas. <GNAQ/11 mutation showed 100% homogeneity in uveal melanoma patients. CONCLUSION:Our data demonstrated heterogeneity between primary melanomas and corresponding metastatic lesions for BRAF, NRAS mutation and KIT amplification. However, GNAQ/11 mutation was genetically homogeneous between primary and metastatic melanoma lesions in uveal melanoma.

| S-EPMC6192908 | biostudies-literature

Intra-tumor Genetic Heterogeneity in Rectal Canger

Project description:Colorectal cancer arises in part from the cumulative effects of multiple gene lesions. Recent studies in selected cancer types have revealed significant intra-tumor genetic heterogeneity and highlighted its potential role in disease progression and resistance to therapy. We hypothesized the existence of significant intra-tumor genetic heterogeneity in rectal cancers involving variations in localized somatic mutations and copy number abnormalities. Two or three spatially disparate areas from each of six rectal tumors were dissected and subjected to next-generation whole exome DNA sequencing, Oncoscan SNP arrays, and targeted confirmatory sequencing and analysis. The resulting data were integrated to define subclones using SciClone. Mutant-allele tumor heterogeneity (MATH) scores, mutant allele frequency correlation, and mutation percent concordance were calculated, and Copy number analysis including measurement of correlation between samples was performed. Affymetrix OncoScan V3 arrays were run on all tumor samples. The OncoScan array platform consists of a set of 217k probes designed specifically for profiling tumors. The overall resolution of the assay for detecting copy number change generates data at 50-100kb resolution across a set of 891 cancer genes, and 300-400kb across the rest of the genome. Raw array florescence intensity data generated on the Affymetrix scanners in the form of CEL files were loaded into the OncoScan Console software v.1.1.0 (Affymetrix, Santa Clara, California). Quality control statistics as well as integrated OSCHP files were generated by OncoScan Console. The standard Affymetrix reference control file for OncoScan data was used for processing the arrays.

2015-09-24 | E-GEOD-73365 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data