Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity

Newell, Felicity; Wilmott, James S.; Johansson, Peter; Nones, Kátia; Addala, Venkateswar; Mukhopadhyay, Pamela; Broit, Natasa; Amato, Carol; Gulick, Robert Van; Kazakoff, Stephen H.; Patch, Ann Marie; Koufariotis, Lambros T.; Lakis, Vanessa; Leonard, Conrad; Wood, Scott; Holmes, Oliver; Xu, Qinying; Lewis, Karl D.; Medina, Theresa; González, René; Saw, Robyn P.M.; Spillane, Andrew J.; Stretch, Jonathan R.; Rawson, Robert V.; Ferguson, Peter M.; Dodds, Tristan; Thompson, John F.; Long, Georgina V.; Levesque, Mitchell P.; Robinson, William A.; Pearson, John V.; Mann, Graham J.; Scolyer, Richard A.; Waddell, Nicola; Hayward, Nicholas K.

doi:10.1038/s41467-020-18988-3

Cited by 134 publications

(207 citation statements)

References 80 publications

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“…Collectively, these results reveal somatic lesions in acral melanomas from genetically-distinct patient populations; corroborate and extend previous genomic studies 2,4,[7][8][9][10][11][12][13][14][15] , and demonstrate the integrity and high quality of our data for downstream clinical analysis.…”

Section: Genomic Characteristics Of Acral and Sun-exposed Melanomasupporting

confidence: 88%

Integrative molecular and clinical profiling of acral melanoma identifies LZTR1 as a key tumor promoter and therapeutic target

Farshidfar

Peng

Levovitz

et al. 2021

Preprint

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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.

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Section: Genomic Characteristics Of Acral and Sun-exposed Melanomasupporting

confidence: 88%

Integrative molecular and clinical profiling of acral melanoma identifies LZTR1 as a key tumor promoter and therapeutic target

Farshidfar

Peng

Levovitz

et al. 2021

Preprint

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“…In terms of mutational signatures, signatures 1 and/or 5 were present in all cases of AM, which is consistent with previous analyses (8). Signatures for ultraviolet mutagenesis, though present in 3 cases, were not the predominant contributor of the mutations, in keeping with prior observations that ultraviolet signatures, if present, are more likely to contribute to AMs of subungual origin (8,13). In addition to these observations, nearly all cases of AM in our cohort harbored CCND1 or CDK4 amplification, and or CDKN2A/2B deletion.…”

Section: Discussionsupporting

confidence: 92%

“…This KIT mutation has been previously reported to confer sensitivity to imatinib (27). In terms of mutational signatures, signatures 1 and/or 5 were present in all cases of AM, which is consistent with previous analyses (8). Signatures for ultraviolet mutagenesis, though present in 3 cases, were not the predominant contributor of the mutations, in keeping with prior observations that ultraviolet signatures, if present, are more likely to contribute to AMs of subungual origin (8,13).…”

Section: Discussionsupporting

confidence: 90%

“…Recurrent complex rearrangements were observed on chromosomes 5, 6, 7, 11 and 12, associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2. In keeping with previous reports (11,12), structural alterations including whole genome duplication, aneuploidy and complex rearrangements (such as breakage-fusion-bridge and chromotripsis) are common in AM (8). A unique form of complex rearrangement involving amplified fold-back inversions, termed "Tyfonas", were commonly observed in AM (40%) but rarely seen in cutaneous melanomas, and it has been hypothesized that they provide an alternative source of neoantigens through the generation of expressed proteincoding fusions (9).…”

Section: Discussionsupporting

confidence: 90%

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Genomic Landscapes of Acral Melanomas in East Asia

Chang

Hsieh

et al. 2021

Cancer Genomics Proteomics

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Background/Aim: Acral melanomas (AM) represent a rare subgroup of melanomas with poor clinical outcomes and are enriched in Asian populations. Recent advances in next generation sequencing have provided opportunities to apply precision medicine to AM. Patients and Methods: Here, we present a series of 13 patients with melanomas from Taiwan and Singapore, including 8 patients with AM profiled using whole exome sequencing and summarize the recent studies on the genomic landscape of AM. Results: We identified mutually exclusive mutations in BRAF, NRAS, HRAS, NF1 and KIT in 6 AM cases. In addition, recurrent copy number gains in CCND1 and CDK4, as well as recurrent deletions in CDKN2A/CDKN2B, ATM and RAD51 were observed, supporting the potential use of CDK4/6 or PARP inhibitors in the treatment of these patients. Conclusion: The genomic landscape of AM provides an important resource for applying novel targeted therapies in this rare disease.Acral melanomas (AM) are a subset of melanomas that arise from non-hair bearing glabrous skin on the palms and soles, or on the nail apparatus (1). Despite global rarity, AM is the commonest subtype of melanoma in Asian populations (2). Notably, patients with AM harbor worse prognosis as compared with cutaneous melanomas, and survival outcomes remain dismal despite modern advances in the therapeutic landscape of melanomas (3,4).Recently, next generation sequencing (NGS) technologies, involving whole exome (WES) (5-7) or genome sequencing (WGS) (8-14), have enhanced the molecular understanding of AM. At the molecular level, AM is a distinct disease as compared with cutaneous melanomas, defined by few point or indel mutations and high degrees of complex structural rearrangements and focal copy number alterations (8-10). Unlike cutaneous melanomas, the tumor mutation burden (TMB) is consequently lower and mutational signatures of ultraviolet damage are infrequent (11). At the individual gene level, hotspot mutations in BRAF and NRAS occur in over 50% of cutaneous melanomas, whereas their occurrence in AM is considerably lower (approximately 10-25%). On the other hand, mutations in NF1 and KIT, as well as oncogenic amplification of genes such as CCND1, CDK4, and TERT have been demonstrated to be common events in AM (5, 8). These unique genomic alterations harbor therapeutic implications -small molecule inhibitors of KIT and other tyrosine kinases, including imatinib, nilotinib and dasatinib, have demonstrated significant (albeit modest) efficacy against . Similarly, CDK4/6 inhibitors have also shown promising activity in AM (19). Taken together, the unique genomic landscape of AM offers an opportunity for the application of precision medicine in this rare disease and warrants further investigation.In this article, we present a series of patients with AM from Taiwan and Singapore profiled using whole exome sequencing and summarize the recent studies on the genomic landscape of AM using NGS, extending our current understanding of this Asian-prevalent subtype of melanoma.

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“…Furthermore, most of the serological and histological diagnostic markers of melanoma are based on the detection of melanocytes, rather than melanoma itself 37 . Likewise, BRAF/NRAS mutant melanoma tumors contain several high-frequency driver mutations, and therefore represent a big challenge to dermatologists or oncologists in the discovery of unique and stable upregulated oncogenic markers among highly invasive melanoma samples for an early diagnosis and targeted therapy 19 , 38 , 39 . Therefore, novel markers are mostly based on genomic markers of carcinogenetic gene mutations 40 .…”

Section: Discussionmentioning

confidence: 99%

PLA1A expression as a diagnostic marker of BRAF-mutant metastasis in melanoma cancer

Liu

Maghsoudloo

et al. 2021

Sci Rep

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BRAF and NRAS are the most reported mutations associated to melanomagenesis. The lack of accurate diagnostic markers in response to therapeutic treatment in BRAF/NRAS-driven melanomagenesis is one of the main challenges in melanoma personalized therapy. In order to assess the diagnostic value of phosphatidylserine-specific phospholipase A1-alpha (PLA1A), a potent lysophospholipid mediating the production of lysophosphatidylserine, PLA1A mRNA and serum levels were compared in subjects with malignant melanoma (n = 18), primary melanoma (n = 13), and healthy subjects (n = 10). Additionally, the correlation between histopathological subtypes of BRAF/NRAS-mutated melanoma and PLA1A was analyzed. PLA1A expression was significantly increased during melanogenesis and positively correlated to disease severity and histopathological markers of metastatic melanoma. PLA1A mRNA and serum levels were significantly higher in patients with BRAF-mutated melanoma compared to the patients with NRAS-mutated melanoma. Notably, PLA1A can be used as a diagnostic marker for an efficient discrimination between naïve melanoma samples and advanced melanoma samples (sensitivity 91%, specificity 57%, and AUC 0.99), as well as BRAF-mutated melanoma samples (sensitivity 62%, specificity 61%, and AUC 0.75). Our findings suggest that PLA1A can be considered as a potential diagnostic marker for advanced and BRAF-mutated melanoma.

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Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity

Cited by 134 publications

References 80 publications

Integrative molecular and clinical profiling of acral melanoma identifies LZTR1 as a key tumor promoter and therapeutic target

Integrative molecular and clinical profiling of acral melanoma identifies LZTR1 as a key tumor promoter and therapeutic target

Genomic Landscapes of Acral Melanomas in East Asia

PLA1A expression as a diagnostic marker of BRAF-mutant metastasis in melanoma cancer

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