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The genomic landscapes of individual melanocytes from human skin.

ABSTRACT: Every cell in the human body has a unique set of somatic mutations, but it remains difficult to comprehensively genotype an individual cell¹. Here we describe ways to overcome this obstacle in the context of normal human skin, thus offering a glimpse into the genomic landscapes of individual melanocytes from human skin. As expected, sun-shielded melanocytes had fewer mutations than sun-exposed melanocytes. However, melanocytes from chronically sun-exposed skin (for example, the face) had a lower mutation burden than melanocytes from intermittently sun-exposed skin (for example, the back). Melanocytes located adjacent to a skin cancer had higher mutation burdens than melanocytes from donors without skin cancer, implying that the mutation burden of normal skin can be used to measure cumulative sun damage and risk of skin cancer. Moreover, melanocytes from healthy skin commonly contained pathogenic mutations, although these mutations tended to be weakly oncogenic, probably explaining why they did not give rise to discernible lesions. Phylogenetic analyses identified groups of related melanocytes, suggesting that melanocytes spread throughout skin as fields of clonally related cells that are invisible to the naked eye. Overall, our results uncover the genomic landscapes of individual melanocytes, providing key insights into the causes and origins of melanoma.

SUBMITTER: Tang J

PROVIDER: S-EPMC7581540 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The genomic landscapes of individual melanocytes from human skin.

Tang Jessica J Fewings Eleanor E Chang Darwin D Zeng Hanlin H Liu Shanshan S Jorapur Aparna A Belote Rachel L RL McNeal Andrew S AS Tan Tuyet M TM Yeh Iwei I Arron Sarah T ST Judson-Torres Robert L RL Bastian Boris C BC Shain A Hunter AH

Nature 20201007 7830

Every cell in the human body has a unique set of somatic mutations, but it remains difficult to comprehensively genotype an individual cell<sup>1</sup>. Here we describe ways to overcome this obstacle in the context of normal human skin, thus offering a glimpse into the genomic landscapes of individual melanocytes from human skin. As expected, sun-shielded melanocytes had fewer mutations than sun-exposed melanocytes. However, melanocytes from chronically sun-exposed skin (for example, the face) ...[more]

PMID: 33029006

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Project description:BackgroundThis study aims to screen the key genes and possible signaling pathways involved in the differentiation and proliferation of human melanocytes (MCs) by in vitro culture of mixed skin cells. This will be helpful to further study the mechanisms and treatment strategies of pigment-related diseases such as vitiligo.MethodsMixed skin cells were obtained by digesting and separating normal human foreskin tissues. Ribonucleic acid (RNA) was extracted from sorting cells and high-throughput transcriptome sequencing was performed at different culture time points. Differentially expressed genes (DEGs) were obtained by comparing the expression abundance of genes at different culture time points. Then the key genes and signaling pathways involved in the differentiation and proliferation of MCs were screened and verified by real-time quantitative polymerase chain reaction (qPCR) test.ResultsTwenty one DEGs were finally screened for further qPCR validation, mainly involved in 4 signaling pathways. The expressions of Wnt5A, Wnt5B, FZD2 and FZD3 in Wnt pathway were continuously up-regulated, and that of Wnt4 gene was continuously down-regulated, however, all the above hadn't been verified by qPCR. The expressions of COL5A2, COL6A3, ITGB1, ITGA4, ITGAV, AKT3, PIK3CD, PIK3R1 and PIK3R2 in phosphoinositide 3-kinase (PI3K) pathway were continuously up-regulated, of which PIK3CD, PIK3R2, COL5A2, ITGA4, ITGAV and AKT3 were verified by qPCR. PDGFB and GRB2 gene expressions were down-regulated in platelet-derived growth factor (PDGF) pathway, while PDGFRB was continuously up-regulated, of which PDGFB and PDGFRB were verified. The DHRS3, DHRS9, RDH10 and SDR16C5 genes in retinol metabolic pathway were continuously down-regulated and verified by qPCR.ConclusionWe suggested that Wnt5A gene in Wnt/β-catenin classical pathway, integrin combining with extracellular matrix through PI3K signaling pathway, retinoic acid catabolism-related genes could promote the differentiation and proliferation of MCs; however, PDGFB gene might have a negative regulatory effect on the growth of MCs.

Project description:The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are coaltered in RAS-mutant tumors, we analyzed targeted next-generation sequencing data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutation burden and mutational signatures on comutation patterns. These analyses revealed differential RAS prevalence and comutations with non-RAS genes in a cancer lineage-dependent and context-dependent manner, with differences across age, sex, and ethnic groups. Allele-specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non-small cell lung cancer. Integrated multiomic analyses of 10,217 tumors from The Cancer Genome Atlas (TCGA) revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS-mutant tumors. The distinct genomic tracks discovered in RAS-mutant tumors reflected differential clinical outcomes in TCGA cohort and in an independent cohort of patients with KRAS G12C-mutant non-small cell lung cancer that received immunotherapy-containing regimens. The RAS genetic architecture points to cancer lineage-specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS-mutant allele-directed therapies with targeted therapies and immunotherapy.SignificanceThe complex genomic landscape of RAS-mutant tumors is reflective of selection processes in a cancer lineage-specific and context-dependent manner, highlighting differential therapeutic vulnerabilities that can be clinically translated.

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The genomic landscapes of individual melanocytes from human skin.

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The genomic landscapes of individual melanocytes from human skin.

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