PUBLICATION

Anatomic position determines oncogenic specificity in melanoma

Authors
Weiss, J.M., Hunter, M.V., Cruz, N.M., Baggiolini, A., Tagore, M., Ma, Y., Misale, S., Marasco, M., Simon-Vermot, T., Campbell, N.R., Newell, F., Wilmott, J.S., Johansson, P.A., Thompson, J.F., Long, G.V., Pearson, J.V., Mann, G.J., Scolyer, R.A., Waddell, N., Montal, E.D., Huang, T.H., Jonsson, P., Donoghue, M.T.A., Harris, C.C., Taylor, B.S., Xu, T., Chaligné, R., Shliaha, P.V., Hendrickson, R., Jungbluth, A.A., Lezcano, C., Koche, R., Studer, L., Ariyan, C.E., Solit, D.B., Wolchok, J.D., Merghoub, T., Rosen, N., Hayward, N.K., White, R.M.
ID
ZDB-PUB-220401-3
Date
2022
Source
Nature   604(7905): 354-361 (Journal)
Registered Authors
White, Richard M.
Keywords
none
Datasets
GEO:GSE181748, GEO:GSE158538
MeSH Terms
  • Transcription, Genetic
  • Hand
  • Foot
  • Skin Neoplasms*/genetics
  • Skin Neoplasms*/pathology
  • Oncogenes/genetics
  • Zebrafish/genetics
  • Nails
  • Humans
  • Melanoma*/pathology
  • Animals, Genetically Modified
  • Animals
  • Carcinogenesis/genetics
(all 13)
PubMed
35355015 Full text @ Nature
Abstract
Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes 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 and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly 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 and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme 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.
Genes / Markers
Figures
No images available
Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    		Complex
    cz3335TgTransgenic Insertion
      czt13TgTransgenic Insertion
        w2
          		Point Mutation
          zdf1
            		Point Mutation
            1 - 5 of 5
            Show
            Human Disease / Model
            Human Disease Fish Conditions Evidence
            acral lentiginous melanomaTAS
            melanomaTAS
            1 - 2 of 2
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            Sequence Targeting Reagents
            Fish
            No data available
            Antibodies
            No data available
            Orthology
            Engineered Foreign Genes
            Marker Marker Type Name
            mCherryEFGmCherry
            1 - 1 of 1
            Show
            Mapping
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            Citation
            Weiss, J.M., Hunter, M.V., Cruz, N.M., Baggiolini, A., Tagore, M., Ma, Y., Misale, S., Marasco, M., Simon-Vermot, T., Campbell, N.R., Newell, F., Wilmott, J.S., Johansson, P.A., Thompson, J.F., Long, G.V., Pearson, J.V., Mann, G.J., Scolyer, R.A., Waddell, N., Montal, E.D., Huang, T.H., Jonsson, P., Donoghue, M.T.A., Harris, C.C., Taylor, B.S., Xu, T., Chaligné, R., Shliaha, P.V., Hendrickson, R., Jungbluth, A.A., Lezcano, C., Koche, R., Studer, L., Ariyan, C.E., Solit, D.B., Wolchok, J.D., Merghoub, T., Rosen, N., Hayward, N.K., White, R.M. (2022) Anatomic position determines oncogenic specificity in melanoma. Nature. 604(7905):354-361.