Anatomic position determines oncogenic specificity in melanoma

Oncogenic alterations to DNA are not transforming in all cellular contexts . 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...

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Bibliographic Details
Published in:Nature (London) 2022-04, Vol.604 (7905), p.354-361
Main Authors: Weiss, Joshua M, Hunter, Miranda V, Cruz, Nelly M, Baggiolini, Arianna, Tagore, Mohita, Ma, Yilun, Misale, Sandra, Marasco, Michelangelo, Simon-Vermot, Theresa, Campbell, Nathaniel R, Newell, Felicity, Wilmott, James S, Johansson, Peter A, Thompson, John F, Long, Georgina V, Pearson, John V, Mann, Graham J, Scolyer, Richard A, Waddell, Nicola, Montal, Emily D, Huang, Ting-Hsiang, Jonsson, Philip, Donoghue, Mark T A, Harris, Christopher C, Taylor, Barry S, Xu, Tianhao, Chaligné, Ronan, Shliaha, Pavel V, Hendrickson, Ronald, Jungbluth, Achim A, Lezcano, Cecilia, Koche, Richard, Studer, Lorenz, Ariyan, Charlotte E, Solit, David B, Wolchok, Jedd D, Merghoub, Taha, Rosen, Neal, Hayward, Nicholas K, White, Richard M
Format: Article
Language:English
Subjects:
Amplification
Animals
Animals, Genetically Modified
Cancer
Carcinogenesis - genetics
Deoxyribonucleic acid
DNA
Fins
Foot
Genes
Growth factors
Hand
Humans
Insulin
Insulin-like growth factors
Melanocytes
Melanoma
Melanoma - pathology
Melanoma, Cutaneous Malignant
Mutation
Nails
Nucleotide sequence
Oncogenes - genetics
Patients
Skin
Skin Neoplasms - genetics
Skin Neoplasms - pathology
Transcription, Genetic
Tumors
Zebrafish
Zebrafish - genetics
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Summary:Oncogenic alterations to DNA are not transforming in all cellular contexts . 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 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 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-022-04584-6