Molecular effects of indoor tanning

Authors

Gerami P

Tandukar B

Deivendran D

Olivares S

Chen L

Tang J

Tan T

Sharma H

Bandari AK

Cruz-Pacheco N

Chang D

Marty A

Olshen A

Murad NF

Song J

Lee J

Yeh I

Shain AH

Doi

10.1101/2024.06.04.597225

PMID: 38895302 · DOI: 10.1101/2024.06.04.597225 · Journal: bioRxiv (2024)

TL;DR

This study investigated how indoor tanning drives melanomagenesis by performing a case-control epidemiologic analysis of 5,863 patients at Northwestern University and exome sequencing of 182 individual melanocytes from normal skin of tanning bed users versus matched controls. Tanning bed users had significantly higher melanocyte mutation burdens, a higher proportion of melanocytes harboring pathogenic mutations (particularly NF1 loss-of-function), and enrichment of COSMIC mutational signature 11 – a UV-related signature with distinct trinucleotide context. The mutagenic effect was most pronounced on body sites with low cumulative sun damage, indicating tanning beds create a broader field of mutagenized melanocytes than natural sunlight.

Cohort & data

  • Epidemiologic cohort: 2,934 patients with quantifiable tanning bed history (cases) and 2,929 age-matched controls with no tanning history, from the Northwestern University Dermatology service (32,315 total patients screened) PMID:38895302.
  • Molecular cohort: 182 melanocytes from normal skin biopsies (upper and lower back) of 11 tanning bed users, 9 matched clinical controls (control cohort 1), and 6 cadaver donors (control cohort 2) PMID:38895302.
  • Assay: Single-cell clonal expansion followed by whole-exome sequencing and RNA-seq (G&T-seq protocol), with DNA amplification via MDA or PTA. Aligned to hg19. Mutations called with MuTect and validated using RNA support and phasing PMID:38895302.
  • Cancer type: Melanoma (MEL).

Key findings

  • Tanning bed use was associated with an odds ratio of 2.0 (95% CI 1.38–2.98) for melanoma after adjusting for age, family history, and sunburn history, with a dose-dependent relationship (p < 0.0001) PMID:38895302.
  • Tanning bed users were more likely to develop melanoma on body sites with low cumulative sun damage and to have multiple primary melanomas PMID:38895302.
  • Melanocytes from tanning bed users had significantly higher mutation burdens than controls (p = 0.0128, mixed-effect model adjusting for anatomic site with random effect for subject) PMID:38895302.
  • The mutation burden difference was most prominent on the lower back (a site with low cumulative sun damage), both at the cell level and biopsy level PMID:38895302.
  • COSMIC mutational signature 11 was significantly enriched in tanning bed users (p = 0.0405, Wilcoxon; p = 0.00813, Poisson test), characterized by C>T mutations with a downstream pyrimidine, possibly attributable to the distinct UV spectrum of tanning beds PMID:38895302.
  • 40 pathogenic mutations were identified in 23 melanocytes; most activated the MAPK pathway PMID:38895302.
  • Tanning bed users had a higher fraction of melanocytes with pathogenic mutations than controls (p < 0.05, Poisson test) PMID:38895302.

Genes & alterations

  • NF1 – Most frequently mutated gene among pathogenic alterations. Multiple loss-of-function mutations observed: Q1595, V2511fs, R416, R2517, Q282, R1241*, Splice_site, E1034K. Found in both tanning and control cohorts PMID:38895302.
  • BRAF – Pathogenic mutations L597R and G466R identified in melanocytes from a tanning cohort donor PMID:38895302.
  • RAC1 – P29L hotspot mutation found in a tanning cohort melanocyte PMID:38895302.
  • PPP6C – R264C mutation observed in a control cohort melanocyte PMID:38895302.
  • ARID2 – T408I mutation found alongside NF1 co-mutation PMID:38895302.
  • RB1 – A635V mutation observed in a control cohort melanocyte PMID:38895302.
  • CDKN2A – Discussed in the context of familial melanoma predisposition (germline “hit”) PMID:38895302.

Clinical implications

  • Indoor tanning creates a melanoma risk profile resembling familial melanoma: early onset, multiple primaries, and broad field of at-risk melanocytes. This supports public health guidance opposing indoor tanning PMID:38895302.
  • The dose-dependent relationship between tanning sessions and melanoma risk (OR 2.0) reinforces that cumulative tanning bed exposure is a quantifiable risk factor PMID:38895302.
  • The distinct mutational signature (signature 11) in tanning bed users may serve as a molecular marker to distinguish tanning-bed-induced melanomas from sun-induced melanomas PMID:38895302.
  • Marketing claims that tanning beds are safer than sunlight or that pre-vacation tanning is protective are contradicted by the elevated mutation burden specifically in low-CSD body sites PMID:38895302.

Limitations & open questions

  • The molecular cohort is small (182 melanocytes from 26 donors), limiting statistical power, particularly for biopsy-level comparisons on the upper back PMID:38895302.
  • Cadaver control donors were nearly twice the age of the tanning cohort (78.3 vs 43.6 years), and their tanning bed history was unknown PMID:38895302.
  • Both study cohorts were recruited from a high-risk skin cancer clinic, limiting generalizability to the general population PMID:38895302.
  • The etiology of signature 11 remains uncertain; further work is needed to confirm it is attributable to UVA-enriched radiation from tanning beds PMID:38895302.
  • Reactive oxygen species (ROS) mutational signatures were not detected, but may be masked by the dominant UV signatures or may not reach mutagenic thresholds in vivo PMID:38895302.
  • This is a preprint (bioRxiv) that has not undergone peer review PMID:38895302.

Citations from this paper used in the wiki

  • “Tanning bed users were more likely than non-users to have melanoma on body sites with low cumulative levels of sun damage and were more likely to have multiple melanomas.” (Abstract) PMID:38895302.
  • “The melanocytes in normal appearing skin from tanning bed users had higher mutation burdens, a higher proportion of melanocytes with pathogenic mutations, and distinct mutational signatures.” (Abstract) PMID:38895302.
  • “Multiple logistic regression analysis showed tanning bed use was associated with an increased risk for melanoma (odds ratio of 2.0, 95% confidence interval 1.38, 2.98), after adjusting for age, family history of melanoma, and sunburn history.” (Results) PMID:38895302.
  • “We found 40 pathogenic mutations in 23 unique melanocytes. Most driver mutations, observed here, were predicted to activate the MAPK signaling pathway, in which loss-of-function mutations affecting the NF1 tumor suppressor gene were especially common.” (Results) PMID:38895302.
  • “Signature 11 was the only signature to reach a statistically significant difference between the cohorts.” (Results) PMID:38895302.

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