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

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.

Comprehensive Analysis of Genomic Alterations in Hepatoid Adenocarcinoma of the Stomach and Identification of Clinically Actionable Alterations

“…There were 32 regions specifically amplificated or deleted in HAS ( Figure S7C,D ), and the amplification of chr22q11.21 and deletions of chr1p36.21, chr7q11.21, chr7q22.1, chr9q12 as well as chr12q24.33 predicted a tendency of shorter OS. Intriguingly, Farshidfar et al demonstrated that chr22q11.21 amplification in melanoma was strongly associated with inferior survival, metastasis, and downregulation of immunotherapy response-related genes [ 38 ], indicating its important role in HAS. Additionally, chr10q21.2 amplification was linked with precursor B-cell acute lymphoblastic leukemia of childhood [ 39 ], and in this study we found it was associated with local vascular invasion.…”

Single-cell Genome-and-Transcriptome sequencing without upfront whole-genome amplification reveals cell state plasticity of melanoma subclones

“…Moreover, a 22q11.21 focal amplification is found in 10% of the CCLE skin cancer cell lines (e.g. Hs294-T and COLO679 BRAF(V600) mutant cell lines), 22q11.21 was also identified as recurrently amplified in a pan-cancer analysis (Zack et al, 2013), and was recently associated with inferior survival in acral melanoma (Farshidfar et al, 2022). Subclonal differences in the presence, size and copy number were observed for the majority of the focal amplifications on chr13 (Fig.…”

Clinical features, molecular pathology, and immune microenvironmental characteristics of acral melanoma

“…Farshidfar et al have found that recurrent, late-arising focal amplifications of cytoband 22q11.21 associated with limbic melanoma metastasis was a major determinant of poor clinical outcome and was related to the downregulation of immunomodulatory genes associated with immunotherapeutic response. For example, LZTR1 and CRKL are two important genes associated with 22q11.21 amplification in limbic melanoma, and LZTR1 can be a viable therapeutic target [ 64 ].…”

“…For example, a study has previously determined mutations associated with AM invasion and metastasis, including EP300, ANO1, CPEB1, INADL, MAP1B, MAP7D1, MARCH 6, NETO1, PRKCE, SBK1, TNRC6A, USP13, WDR74, and ZNF827 [63] of poor clinical outcome and was related to the downregulation of immunomodulatory genes associated with immunotherapeutic response. For example, LZTR1 and CRKL are two important genes associated with 22q11.21 amplification in limbic melanoma, and LZTR1 can be a viable therapeutic target [64].…”