Integrated genomic analyses reveal frequent <i>TERT</i> aberrations in acral melanoma

Liang, Winnie S.; Hendricks, William P.D.; Kiefer, Jeffrey; Schmidt, Jessica; Sekar, Shobana; Carpten, John D.; Craig, David W.; Adkins, Jonathan; Cuyugan, Lori; Manojlovic, Zarko; Halperin, Rebecca F.; Helland, Adrienne; Nasser, Sara; Legendre, Christophe; Hurley, Laurence H.; Sivaprakasam, Karthigayini; Johnson, Douglas B.; Crandall, Holly; Busam, Klaus J.; Zismann, Victoria; DeLuca, Valerie; Lee, Jeeyun; Sekulić, Aleksandar; Ariyan, Charlotte E.; Sosman, Jeffrey A.; Trent, Jeffrey M.

doi:10.1101/gr.213348.116

Cited by 117 publications

(170 citation statements)

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“…By undertaking unsupervised hierarchical clustering of gene expression profiles, Jönsson and collaborators were able to categorise melanomas into four biologically relevant subgroups; MITFlow/proliferative, high-immune response, MITF-high/ pigmentation and normal-like [19]. Importantly, the MITF-low/proliferative subtype, characterised by an absence of the expression of immune-response genes, had only BRAF/NRAS-mutated samples and more ∼5-10% [3,4] rarely seen [13,43] ∼3-36% [44,46,47,52] ∼11% [53] ∼7-25% [3,51,54] GNAQ ∼1.5-2.1% [3,55] rarely seen [13,43] ∼0-17% [3,47] ∼43-57% [48,49]…”

Section: Gene Expression Profiles and Their Prognostic Implicationmentioning

confidence: 99%

“…∼0-3% [3,44] rarely seen, methylated in ∼50% [59] rarely seen [3,50,51,54] CDKN2A (loss) rarely seen [3] rarely seen [13] rarely seen [3] ∼70-83% (but the great majority of metastatic UM) [48,49] rarely seen [3,50,51,54] PI3K/AKT PTEN (mut or loss)…”

Section: Gene Expression Profiles and Their Prognostic Implicationmentioning

confidence: 99%

“…AM is a rarer histological variant arising on the palms, soles and nail beds and accounts for a greater proportion of melanomas in patients of African, Asian and Latin American descent [96][97][98][99]. When compared to CM tumours, AMs have a much lower single nucleotide mutational burden yet display a higher number of somatic structural aberrations [3,44]. The few AM samples sequenced to date demonstrate a lower contribution of the UV signature [3,44].…”

Section: Am: Numerous Copy Number Changes and Low Point Mutation Burdenmentioning

confidence: 99%

“…When compared to CM tumours, AMs have a much lower single nucleotide mutational burden yet display a higher number of somatic structural aberrations [3,44]. The few AM samples sequenced to date demonstrate a lower contribution of the UV signature [3,44]. A handful of cases from subungual sites, however, do demonstrate a significant proportion of UV-associated mutations, which might suggest that skin in these locations might not be completely protected from sun-induced UV-radiation [100].…”

Section: Am: Numerous Copy Number Changes and Low Point Mutation Burdenmentioning

confidence: 99%

“…A large proportion of AMs fall into the TWT subtype, with only 42-55% of tumours having mutations in BRAF, NRAS or NF1 [3,44] (Table 1). KIT mutation and amplifications are also AM drivers, with between 3 and 36% of tumours bearing these alterations [44,52].…”

Section: Am: Numerous Copy Number Changes and Low Point Mutation Burdenmentioning

confidence: 99%

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Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities

Rabbie

Ferguson

Molina‐Aguilar

et al. 2019

The Journal of Pathology

162

205

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Melanoma is characterised by its ability to metastasise at early stages of tumour development. Current clinico‐pathologic staging based on the American Joint Committee on Cancer criteria is used to guide surveillance and management in early‐stage disease, but its ability to predict clinical outcome has limitations. Herein we review the genomics of melanoma subtypes including cutaneous, acral, uveal and mucosal, with a focus on the prognostic and predictive significance of key molecular aberrations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Gene Expression Profiles and Their Prognostic Implicationmentioning

confidence: 99%

Section: Gene Expression Profiles and Their Prognostic Implicationmentioning

confidence: 99%

Section: Am: Numerous Copy Number Changes and Low Point Mutation Burdenmentioning

confidence: 99%

Section: Am: Numerous Copy Number Changes and Low Point Mutation Burdenmentioning

confidence: 99%

Section: Am: Numerous Copy Number Changes and Low Point Mutation Burdenmentioning

confidence: 99%

See 3 more Smart Citations

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities

Rabbie

Ferguson

Molina‐Aguilar

et al. 2019

The Journal of Pathology

162

205

View full text Add to dashboard Cite

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Role of ultraviolet mutational signature versus tumor mutation burden in predicting response to immunotherapy

Pham¹,

Boichard²,

Goodman

et al. 2020

Molecular Oncology

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Hydrophobic neoantigens are more immunogenic because they are better presented by the major histocompatibility complex and better recognized by T cells. Tumor cells can evade the immune response by expressing checkpoints such as programmed death ligand 1. Checkpoint blockade reactivates immune recognition and can be effective in diseases such as melanoma, which harbors a high tumor mutational burden (TMB). Cancers presenting low or intermediate TMB can also respond to checkpoint blockade, albeit less frequently, suggesting the need for biological markers predicting response. We calculated the hydrophobicity of neopeptides produced by probabilistic in silico simulation of the genomic UV exposure mutational signature. We also computed the hydrophobicity of potential neopeptides and extent of UV exposure based on the UV mutational signature enrichment (UVMSE) score in The Cancer Genome Atlas (TCGA; N = 3543 tumors), and in our cohort of 151 immunotherapy‐treated patients. In silico simulation showed that UV exposure significantly increased hydrophobicity of neopeptides, especially over multiple mutagenic cycles. There was also a strong correlation ( R 2 = 0.953) between weighted UVMSE and hydrophobicity of neopeptides in TCGA melanoma patients. Importantly, UVMSE was able to predict better response ( P = 0.0026), progression‐free survival ( P = 0.036), and overall survival ( P = 0.052) after immunotherapy in patients with low/intermediate TMB, but not in patients with high TMB. We show that higher UVMSE scores could be a useful predictor of better immunotherapy outcome, especially in patients with low/intermediate TMB, likely due to increased hydrophobicity (and hence immunogenicity) of neopeptides.

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Gender and melanoma subtype‐based prognostic implications of MUC16 and TTN co‐occurrent mutations in melanoma: A retrospective multi‐study analysis

Kodali,

Alomary,

Bhattaru

et al. 2024

Cancer Medicine

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BackgroundMost primary cutaneous melanomas have pathogenesis driven by ultraviolet exposure and genetic mutations, whereas acral lentiginous melanoma (ALM) and metastatic melanoma are much less, if at all, linked with the former. Thus, we evaluated both ultraviolet related and non‐ultraviolet related melanomas. Mutations in the MUC16 and TTN genes commonly occur concurrently in these melanoma patients, but their combined prognostic significance stratified by gender and cancer subtype remains unclear.MethodsThe cBioPortal database was queried for melanoma studies and returned 16 independent studies. Data from 2447 melanoma patients were utilized including those with ALM, cutaneous melanoma (CM), and melanoma of unknown primary (MUP). Patients were grouped based on the presence or absence of MUC16 and TTN mutations. Univariate Cox regression and Student's t‐tests were used to analyze hazard ratios and total mutation count comparisons, respectively.ResultsTTN mutations, either alone or concurrently with MUC16 mutations, significantly correlated with worse prognosis overall, in both genders, and in CM patients. ALM patients with both mutations had better prognoses than CM patients, while ALM patients with neither mutation had worse prognosis than CM patients. For MUP patients, only MUC16 mutations correlated with worse prognosis. ALM patients with neither MUC16 nor TTN mutations had significantly more total mutations than MUP patients, followed by CM patients.ConclusionTTN mutations are a potential marker of poor prognosis in melanoma, which is amplified in the presence of concurrent MUC16 mutations. ALM patients with neither gene mutations had worse prognosis, suggesting a protective effect of having both MUC16 and TTN mutations. Only MUC16 mutations conferred a worse prognosis for MUP patients. Comprehensive genetic profiling in melanoma patients may facilitate personalized treatment strategies to optimize patient outcomes.

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Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma

Cited by 117 publications

References 47 publications

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities

Role of ultraviolet mutational signature versus tumor mutation burden in predicting response to immunotherapy

Gender and melanoma subtype‐based prognostic implications of MUC16 and TTN co‐occurrent mutations in melanoma: A retrospective multi‐study analysis

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