Normal Skin Melanocytes and Keratinocytes (2024)

Overview

Single-cell resolution clonal genomic study of normal skin cells (keratinocytes, melanocytes, fibroblasts) from 15 donors, combined with a matched cSCC-actinic keratosis (AK) cohort, to map the genetic evolution from normal keratinocytes to cutaneous squamous cell carcinoma. Data deposited in dbGaP (phs001979.v1.p1, phs003683.v2.p1, phs003282.v2.p1) and cBioPortal as normal_skin_melanocytes_2024. PMID:39091884

Composition

  • Normal skin cells: 137 keratinocytes, 131 melanocytes, and 23 fibroblasts from 22 biopsies across 15 donors (ages 35–95), profiled via clonal expansion and whole-exome sequencing (~95X coverage). PMID:39091884
  • cSCC-AK cohort: 16 archival tissue cases with cSCC immediately adjacent to actinic keratosis (AK), sequenced with a cancer gene panel at ~380X depth. PMID:39091884

Assays / panels (linked)

  • Clonal expansion and whole-exome sequencing (~95X) for normal cells. PMID:39091884
  • Cancer gene panel sequencing (~380X) for cSCC-AK cohort. PMID:39091884
  • 10X Visium spatial transcriptomics on 5 cSCC-AK cases. PMID:39091884

Papers using this cohort

  • PMID:39091884 — Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma.
  • PMID:39975212 — Tandukar et al. 2025: Clonal joint DNA/RNA profiling of 297 single melanocytes from 58 skin biopsies of 31 donors identifies two coexisting subpopulations (HighMut and LowMut) with distinct UV mutational burdens, transcriptional states, and spatial niches; spatial Xenium profiling validates hair follicle as a UV-protected melanocyte stem-cell reservoir.

Notable findings derived from this cohort

  • Keratinocytes have lower mutation burdens (median 1.14 mut/Mb) vs. melanocytes (3.91 mut/Mb) despite shared UV exposure in basal epidermis. PMID:39091884
  • Pathogenic mutations — especially dominant-negative TP53 missense mutations — break UV repair capacity, producing the highest mutation burdens (up to 49.71 mut/Mb). PMID:39091884
  • Cell-type-specific mutational signatures: keratinocytes show higher clock-like (SBS1, SBS5) vs. UV (SBS7a) signatures compared to melanocytes/fibroblasts. PMID:39091884
  • AK-to-cSCC progression model: TERT promoter and CDKN2A mutations emerged early (AK trunk), while ARID2 loss-of-function and RTK-RAS-MAPK activation marked the cSCC transition. PMID:39091884
  • Within sun-damaged skin, HighMut melanocytes (UV signature SBS7-dominated, dendritic, differentiated) reside in the interfollicular epidermis; LowMut melanocytes (clock-like SBS1/SBS5-dominated, smaller, stem-like, neural-crest transcriptome) are concentrated in hair follicles — consistent with a model of follicular UV-protected stem-cell replenishment PMID:39975212.
  • HighMut melanocyte transcriptome upregulates pigmentation/metabolism genes (HMOX1, ABCC2, MC1R, HERC2) and antigen-presentation markers; LowMut melanocytes upregulate neural-crest lineage genes (VCAN, TAGLN, SEMA3C, TCF4), aligning with MSC signatures from hair-follicle fetal atlases PMID:39975212.
  • 297 single melanocytes were profiled by clonal joint DNA/RNA amplification (G&T-Seq + SMART-Seq2) with whole-exome sequencing; a custom 360-gene spatial Xenium panel validated subpopulation spatial niche separation on FFPE skin in situ PMID:39975212.

Sources

  • cBioPortal study normal_skin_melanocytes_2024 PMID:39091884.
  • Tandukar et al. single-melanocyte atlas, with data at dbGaP phs001979.v1.p1 / phs003683.v2.p1 (single-cell DNA/RNA) and GEO GSE286964 (Xenium spatial) PMID:39975212.

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