Integrative Molecular and Clinical Profiling of Acral Melanoma Identifies LZTR1 as a Key Tumor Promoter and Therapeutic Target

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 performed integrative genomic and clinical profiling of acral melanomas from a cohort of 104 patients treated in North America or China. We found 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 new insights into the etiology of acral melanoma and implicate LZTR1 as a key tumor promoter and therapeutic target. Keywords: Expression profiling by high throughput sequencing We applied whole exome (tumor/normal) and RNA sequencing to characterize acral melanomas from 104 patients treated in the United States (n = 37) and China (n = 67), most of whom had long-term follow-up data available. Through comparative genomic analysis with 157 sun-exposed melanomas, we identified novel molecular features of acral melanoma; generated the first prognostic map linking highly recurrent somatic aberrations in acral melanoma to risk of death; and found that late-arising focal amplifications in chr22q11.21 are associated with lymph node involvement and distant metastasis, leading to poor outcomes. Within chr22q11.21, we identified LZTR1 – a known tumor suppressor in other cancers – as a key candidate driver of metastasis. Our findings reveal novel molecular insights of acral melanoma pathogenesis and designate LZTR1 as a new therapeutic target. ------------------------------------- Authors state "We will submit the raw data to dbGAP."