Abstract

. 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.

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
Journal	NATURE
Pages	354-361
Volume	604
Date	1/01/2022
Grant ID
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41586-022-04584-6