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Distinct Sets of Genetic Alterations in Melanoma

ABSTRACT: We compared genome-wide DNA copy number alterations and mutational status in BRAF and RAS genes of 126 primary melanomas arising in four groups in which UV exposure differ: skin with (n=30), and without chronic sun damage (n=40); palms, soles and subungual (acral) sites (n=36) (which have very little sun exposure); and mucosa (n=20) (no sun exposure). Keywords: other

ORGANISM(S): Homo sapiens

PROVIDER: GSE2631 | GEO | 2005/11/05

SECONDARY ACCESSION(S): PRJNA92269

REPOSITORIES: GEO

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Distinct Sets of Genetic Alterations in Melanoma

Project description:We compared genome-wide DNA copy number alterations and mutational status in BRAF and RAS genes of 126 primary melanomas arising in four groups in which UV exposure differ: skin with (n=30), and without chronic sun damage (n=40); palms, soles and subungual (acral) sites (n=36) (which have very little sun exposure); and mucosa (n=20) (no sun exposure).

2010-06-09 | E-GEOD-2631 | biostudies-arrayexpress

Somatic Activation of KIT in Distinct Subtypes of Melanoma

Project description:Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogenactivated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS. Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% ofmucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels. KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden. Keywords: melanoma, oncogene, comparative genomic hybridization, KIT

2006-09-09 | GSE4747 | GEO

Anatomic position determines oncogenic specificity in melanoma

Project description:Oncogenic alterations to DNA are not transforming in all cellular contexts. This may be due to pre-existing transcriptional programs in the cell of origin. Here, we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet, or under the nails. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma but CRKL amplifications in acral melanoma. We modeled these changes in transgenic zebrafish models and found that CRKL-driven tumors predominantly formed in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin/limb melanocytes, compared to body melanocytes, revealed a positional identity gene program typified by posterior HOX13 genes. This positional gene program synergized with CRKL to drive tumors at acral sites. Abrogation of this CRKL-driven program eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

2022-01-12 | PXD027968 | Pride

Single cell characterization of the cellular landscape of acral melanoma identifies novel targets for immunotherapy

Project description:Acral melanoma is a rare subtype of melanoma that arises on the non-hair-bearing skin of the palms, soles and nail beds. In this study, we used single cell RNA-seq (scRNA-seq) to map the transcriptional landscape of acral melanoma and identify novel immunotherapeutic targets.

2022-02-14 | GSE189889 | GEO

scRNA-seq of fin and body zebrafish melanocytes

Project description:Oncogenic alterations to DNA are not transforming in all cellular contexts. This may be due to pre-existing transcriptional programs in the cell of origin. Here, we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet, or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma but CRKL amplifications in acral melanoma. We modeled these changes in transgenic zebrafish models and found that CRKL-driven tumors predominantly formed in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin/limb melanocytes, compared to body melanocytes, revealed a positional identity gene program typified by posterior HOX13 genes. This positional gene program synergized with CRKL to drive tumors at acral sites. Abrogation of this CRKL-driven program eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

2022-01-17 | GSE181748 | GEO

Gene expression changes detected in mouse melanomas after conditional genetic inactivation of ezh2 using tyr:Cre-ERT2 on a braf;pten genetic background

Project description:We use RNAseq to examine gene expression changes in braf;pten mouse melanomas after arising after conditional genetic inactivation of ezh2

2021-12-29 | GSE192491 | GEO

Acral Melanoma Targeted Sequencing Study (UCSF)

Project description:<p>Acral melanoma affects world populations irrespective of skin color. It has comparatively few single nucleotide mutations, but exhibits genomic instability characterized by structural rearrangements and amplifications. As acral melanoma harbors BRAF (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=BRAF">GeneID:673</a>) mutations at low frequencies, we searched for alternative therapeutic targets. We performed targeted deep sequencing of cancer-related genes on 37 acral melanomas and identified point mutations, structural rearrangements and copy number alterations. </p>

| phs001596 | dbGaP

Stump project-- mRNA whole tissue; Volar versus non-volar acral skin gene expression

Project description:We were interesed in defining the gene signautre of volar skin. Whole skin punch biopsies of palms, backs of hand, soles and backs of feet were submitted for Affymetrix Exon arrays. 4 replicates of each site from distinct human donors were included; total of 16 samples analyzed.

2013-07-01 | E-GEOD-34756 | biostudies-arrayexpress

Integrative molecular and clinical profiling of acral melanoma links focal amplification of chr22q11.21 to metastasis

Project description:Acral melanoma, the most common melanoma subtype among non-Caucasian individuals, is associated with poor prognosis. However, its key molecular drivers remain obscure. Here, we perform integrative genomic and clinical profiling of acral melanomas from a cohort of 104 patients treated in North America or China. We find that recurrent, late-arising amplifications of cytoband chr22q11.21 are a leading determinant of inferior survival, strongly associated with metastasis, and linked to downregulation of immunomodulatory genes associated with response to immune checkpoint blockade. Unexpectedly, LZTR1 – a known tumor suppressor in other cancers – is a key candidate oncogene in this cytoband. Silencing of LZTR1 in melanoma cell lines caused apoptotic cell death independent of major hotspot mutations or melanoma subtypes. Conversely, overexpression of LZTR1 in normal human melanocytes initiated processes associated with metastasis, including anchorage-independent growth, formation of spheroids, and increased levels of MAPK and SRC activities. Our results provide insights into the etiology of acral melanoma and implicate LZTR1 as a key tumor promoter and therapeutic target.

2021-12-14 | GSE189341 | GEO

Stump project -- mRNA fibroblasts; Volar versus non-volar acral skin gene expression

Project description:We were interested in defining the gene signature of volar skin. Dermal fibroblasts were expanded from punch biopsies of skin. We collected RNA from fibroblasts of palms, backs of hand, soles and backs of feet and submitted for Affymetrix Exon arrays. 3 replicates of each site from distinct human donors were included; because of 1 failed sample(Palm_rep2), total of 11 samples analyzed

2013-07-03 | E-GEOD-39266 | biostudies-arrayexpress

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