Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis

Farshad Farshidfar, Kahn Rhrissorrakrai, Chaya Levovitz, Cong Peng, James Knight, Antonella Bacchiocchi, Juan Su, Mingzhu Yin, Mario Sznol, Stephan Ariyan, James Clune, Kelly Olino, Laxmi Parida, Joerg Nikolaus, Meiling Zhang, Shuang Zhao, Yan Wang, Gang Huang, Miaojian Wan, Xianan Li, Jian Cao, Qin Yan, Xiang Chen (), Aaron M. Newman () and Ruth Halaban ()
Additional contact information
Farshad Farshidfar: Stanford University
Kahn Rhrissorrakrai: IBM Research
Chaya Levovitz: IBM Research
Cong Peng: Central South University
James Knight: Yale University
Antonella Bacchiocchi: Yale University School of Medicine
Juan Su: Central South University
Mingzhu Yin: Central South University
Mario Sznol: Yale University School of Medicine
Stephan Ariyan: Yale University School of Medicine
James Clune: Yale University School of Medicine
Kelly Olino: Yale University School of Medicine
Laxmi Parida: IBM Research
Joerg Nikolaus: Yale University School of Medicine
Meiling Zhang: Yale University School of Medicine
Shuang Zhao: Central South University
Yan Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Gang Huang: Affiliated Tumor Hospital of Xiangya Medical School of Central South University
Miaojian Wan: Sun Yat-sen University
Xianan Li: Affiliated Tumor Hospital of Xiangya Medical School of Central South University
Jian Cao: Yale University School of Medicine
Qin Yan: Yale University School of Medicine
Xiang Chen: Central South University
Aaron M. Newman: Stanford University
Ruth Halaban: Yale University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Acral melanoma, the most common melanoma subtype among non-White 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 104 patients treated in North America (n = 37) or China (n = 67). We find that recurrent, late-arising focal amplifications of cytoband 22q11.21 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 causes apoptotic cell death independent of major hotspot mutations or melanoma subtypes. Conversely, overexpression of LZTR1 in normal human melanocytes initiates processes associated with metastasis, including anchorage-independent growth, formation of spheroids, and an increase in 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.

Date: 2022
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DOI: 10.1038/s41467-022-28566-4

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