Integrative molecular and clinical profiling of acral melanoma links focal amplification of chr22q11.21 to metastasis

Acral melanoma, the most common melanoma subtype among non-Caucasian individuals, is associated with poor prognosis. However, its key molecular drivers remain obscure. Here, we perform integrative genomic and clinical profiling of acral melanomas from a cohort of 104 patients treated in North America or China. We find that recurrent, late-arising amplifications of cytoband chr22q11.21 are a leading determinant of inferior survival, strongly associated with metastasis, and linked to downregulation of immunomodulatory genes associated with response to immune checkpoint blockade. Unexpectedly, LZTR1 – a known tumor suppressor in other cancers – is a key candidate oncogene in this cytoband. Silencing of LZTR1 in melanoma cell lines caused apoptotic cell death independent of major hotspot mutations or melanoma subtypes. Conversely, overexpression of LZTR1 in normal human melanocytes initiated processes associated with metastasis, including anchorage-independent growth, formation of spheroids, and increased levels of MAPK and SRC activities. Our results provide insights into the etiology of acral melanoma and implicate LZTR1 as a key tumor promoter and therapeutic target. We applied single-cell RNA-seq to characterize acral melanomas from 4 patients treated in the United States comparing expression differences of patients with 22q11.21 amplification (n = 1) and without 22q11.21 amplificaiton (n = 3). >>> Due to patient privacy concerns, raw data have been submitted to dbGaP (phs000933.v3.p1). <<<