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

Gastman B.R., Gerami P., Kurley S.J., Cook R.W., Leachman S., Vetto J.T.

A substantial number of patients who relapse and die from cutaneous melanoma (CM) are categorized as being at low risk by traditional staging factors. The 31-gene expression profile (31-GEP) test independently stratifies metastatic risk of patients with CM as low (Class 1, with 1A indicating lowest risk) or high (Class 2,with 2B indicating highest risk).To assess risk prediction by the 31-GEP test within 3 low-risk (according to the American Joint Committee on Cancer) populations of patients with CM: those who are sentinel lymph node (SLN) negative, those with stage I to IIA tumors, and those with thin (≤1 mm [T1]) tumors.A total of 3 previous validation studies provided a nonoverlapping cohort of 690 patients with 31-GEP results, staging information, and survival outcomes. Kaplan-Meier and Cox regression analysis were performed.The results included the identification of 70% of SLN-negative patients who experienced metastasis as Class 2, the discovery of reduced recurrence-free survival for patients with thin tumors and Class 2B biology compared with that of those with Class 1A biology (P < .0001); and determination of the 31-GEP test as an independent predictor of risk compared with traditional staging factors in patients with stage I to IIA tumors.Diagnoses spanned multiple versions of pathologic staging criteria.The 31-GEP test identifies high-risk patients who are likely to experience recurrence or die of melanoma within low-risk groups of subpopulations of patients with CM who have SLN-negative disease, stage I to IIA tumors, and thin tumors.

Andrés-Lencina J.J., Rachakonda S., García-Casado Z., Srinivas N., Skorokhod A., Requena C., Soriano V., Kumar R., Nagore E.

Mutations within the promoter of gene encoding telomerase reverse transcriptase subunit are frequent in many cancers including melanoma. Previously, the TERT promoter mutations were shown to associate with markers of poor outcome and reduced survival in patients with primary melanoma. In this study, we investigated the impact of the subtypes of TERT mutations on disease-free and melanoma-specific survival in 287 patients with stage I/II nonacral melanoma. Our results showed that of the three TERT promoter mutation subtypes, in multivariate models, the -138/-139 CC > TT tandem mutation associated with worst disease-free and melanoma-specific survival. In particular, in combination with BRAF/NRAS mutations, the -138/-139 CC > TT TERT promoter mutation associated with statistically significant poor disease-free and melanoma-specific survival with hazard ratios of 6.04 (95% CI 2.03-17.94, p = 0.001) and 12.59 (95% CI 2.18-72.70, p = 0.005), respectively. In contrast to the survival data, luciferase assays showed that the highest activity was observed in experiments with a promoter construct with -124 C > T mutation followed by the -138/-139 CC > TT and -146 C > T mutations, which showed similar activity. Based on previous reports, we speculate that the tandem mutation probably leads to greater genomic instability than the common TERT promoter mutations, hence the association with worst survival. However, the results from the study are only preliminary with limited patient data, therefore, require a cautious interpretation. The observations in this study, if confirmed, could have implications for melanoma patients treated with MAP-kinase inhibitors.

Rambow F., Rogiers A., Marin-Bejar O., Aibar S., Femel J., Dewaele M., Karras P., Brown D., Chang Y.H., Debiec-Rychter M., Adriaens C., Radaelli E., Wolter P., Bechter O., Dummer R., et. al.

Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance.

Yu S., Xu T., Dai J., Ma M., Tang H., Chi Z., Si L., Cui C., Sheng X., Kong Y., Guo J.

Asian populations are more likely to develop acral melanoma (AM) than Caucasians. The high-dose interferon (HD-IFN) α-2b regimen is the main adjuvant treatment for AM. TERT encodes the catalytic subunit of telomerase reverse transcriptase, which plays an important role in melanoma. Frequent TERT mutation and increased TERT gene expression have been described in AM. Our study aimed to investigate the status and the clinical significance of TERT copy number in a large cohort of patients with AM and to analyze the relationship between TERT copy number gain and the efficiency of HD-IFN.A total of 573 melanoma samples were retrospectively collected and analyzed for TERT copy number via Sanger sequencing. Clinical data of patients were also collected.TERT copy gain (copy number >2) was detected in 257 of the 573 patients with AM (44.9%). Of the 573 patients, 81 (14.1%) had a high copy gain (copy number >4). Patients with ulceration showed a significantly higher copy gain rate of TERT compared to the patients without ulceration (P=0.028). Patients with a tumor thicker than 4 mm also had a higher copy number rate of TERT than those with

Shain A.H., Joseph N.M., Yu R., Benhamida J., Liu S., Prow T., Ruben B., North J., Pincus L., Yeh I., Judson R., Bastian B.C.

We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent.

Park J.J., Diefenbach R.J., Joshua A.M., Kefford R.F., Carlino M.S., Rizos H.

Uveal melanoma is the most common primary cancer of the eye, and despite rapidly emerging insights into the molecular profile of this disease, prognosis of patients with metastatic uveal melanoma remains poor with mortality rates unchanged in over 35 years. Early genetic events activate G protein-coupled receptor signaling in nearly all uveal tumors via mutually exclusive mutations in the GNAQ, GNA11, CYSLTR2, or PLCB4 genes. A multitude of signaling cascades downstream of G protein activation, including protein kinase C and mitogen-activated protein kinase activity, are actionable, and many ongoing clinical trials are targeting these pathways. Additional cytogenetic and genetic changes, however, including chromosome 3 monosomy, mutations in the BAP1 tumor suppressor gene, alterations in the splicing factors SRSF2/SF3B1, and mutations in the translation initiation factor EIF1AX, modulate signaling output in uveal tumors and modify the risk of metastases. Here, we review the complex interactions between genetic, molecular signaling, and prognostic profiles in uveal melanoma; the clinical implications of these interactions; and the latest potential targets for rational therapy.

Studentova H., Kalabova H., Koranda P., Chytilova K., Kucerova L., Melichar B., Vrana D.

Mucosal melanoma is a rare form of melanoma presenting variably as sores or unexplained bleeding located mainly in the head and neck region, anorectal region or female genital tract. Mucosal melanoma is usually diagnosed at an advanced stage and is characterized by an aggressive behavior. Surgery represents the mainstay of treatment for early stage melanomas, but for advanced disease there have been until recently very limited treatment options. Ipilimumab, a human monoclonal antibody directed against the cytotoxic T lymphocyte antigen 4, was the first treatment modality to demonstrate survival benefit in advanced malignant melanoma.Description of a new case and review of the literature.We present here a patient with mucosal melanoma with aggressive biological behavior and documented late response to ipilimumab.Ipilimumab represents an effective treatment option in selected patients with mucosal melanoma.

Moon K.R., Choi Y.D., Kim J.M., Jin S., Shin M., Shim H., Lee J., Yun S.J.

Acral melanoma occurring on the palms, soles, and nails is the most common subtype of cutaneous melanoma in Asians. Genetic alterations in acral melanoma and acral melanocytic nevus are not well known. We performed next-generation sequencing and evaluated the correlations between genetic information and the clinicopathologic characteristics from 85 Korean patients with acral melanocytic neoplasms. Of the 64 patients with acral melanoma, most had lesions at the T2 stage or higher, and the heel was the most common anatomical site of melanoma (n = 34 [53.1%]). The five most common mutations were BRAF (22 [34.4%]), NRAS (14, [21.9%]), NF1 (11, [17.2%]), GNAQ (12, [17.2%]), and KIT (7, [10.9%]). In the 21 acral melanocytic nevi, those five gene mutations were also common. Copy number variations were also frequently detected in 75% of acral melanomas and 47.6% of acral melanocytic nevi, and amplification was more common than deletion in both lesions. BRAF mutation was associated with round epithelioid cells and NRAS and NF1 mutations with bizarre cells. NF1 and GNAQ mutations showed elongated and spindle cells with prominent dendrites in acral melanomas. KIT mutations were common in amelanotic acral melanoma. This study suggests that common mutated genes are associated with distinct cytomorphological features in acral melanocytic lesions.

Maio M., Lewis K., Demidov L., Mandalà M., Bondarenko I., Ascierto P.A., Herbert C., Mackiewicz A., Rutkowski P., Guminski A., Goodman G.R., Simmons B., Ye C., Yan Y., Schadendorf D., et. al.

Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma.BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419.The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug.The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population.F Hoffman-La Roche Ltd.

Zager J.S., Gastman B.R., Leachman S., Gonzalez R.C., Fleming M.D., Ferris L.K., Ho J., Miller A.R., Cook R.W., Covington K.R., Meldi-Plasseraud K., Middlebrook B., Kaminester L.H., Greisinger A., Estrada S.I., et. al.

The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP’s prognostic accuracy in an independent cohort of cutaneous melanoma patients. This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence-free (RFS) and distant metastasis-free (DMFS) survival. The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively (P < 0.001). The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each). GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate (RFS HR = 2.1, 1.2, and 2.5, respectively, P < 0.001 for each; and DMFS HR = 2.7, 1.3 and 3.0, respectively, P < 0.01 for each). The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual’s risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively.

Salgia R., Kulkarni P.

Drug resistance is a serious impediment to the treatment of cancer. However, the mechanisms involved remain poorly understood. While it is widely held that the phenomenon is genetic in nature, emerging evidence suggests that non-genetic mechanisms may also be important. Furthermore, at least in some cases, refractoriness to treatment can be reversed by epigenetic reprogramming, and combination and intermittent therapies, as opposed to sustained monotherapy, appear more effective in attenuating it. Here we iterate the confusion in understanding the phenomenon by which cancer cells evade drug response and underscore the need to recognize the genetic/non-genetic duality of drug resistance in cancer. We discuss how ecological and evolutionary principles may help to reconcile the duality and may even offer new treatment strategies.

Eroglu Z., Zaretsky J.M., Hu-Lieskovan S., Kim D.W., Algazi A., Johnson D.B., Liniker E., Ben Kong, Munhoz R., Rapisuwon S., Gherardini P.F., Chmielowski B., Wang X., Shintaku I.P., Wei C., et. al.

Immune checkpoint blockade with anti-PD-1 or anti-PD-L1 agents produces a high response rate in patients with desmoplastic melanoma. Desmoplastic melanoma (DM) is a rare subtype of skin cancer, characterized by dense stroma and a lack of targetable mutations, but a high mutational load related to UV exposure. The authors conduct a retrospective pathology review of 1,058 melanoma patients treated with immune checkpoint blockade therapy. They identify 60 cases of DM and find that around 70% of these respond to PD-1 or PD-L1 blockade. DM shows high infiltration of CD8 cells and high expression of PD-L1, with specific patterns associated with response to immunotherapy. The analysis suggests that DM has one of the highest rates of response to immunotherapy, and that this rate is not related to mutational load but correlates with immune cell infiltration. Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage1. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57–81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.

Yang J., Manson D.K., Marr B.P., Carvajal R.D.

Uveal melanoma, a rare subset of melanoma, is the most common primary intraocular malignancy in adults. Despite effective primary therapy, nearly 50% of patients will develop metastatic disease. Outcomes for those with metastatic disease remain dismal due to a lack of effective therapies. The unique biology and immunology of uveal melanoma necessitates the development of dedicated management and treatment approaches. Ongoing efforts seek to optimize the efficacy of targeted therapy and immunotherapy in both the adjuvant and metastatic setting. This review provides a comprehensive, updated overview of disease biology and risk stratification, the management of primary disease, options for adjuvant therapy, and the current status of treatment strategies for metastatic disease.

Lauss M., Donia M., Harbst K., Andersen R., Mitra S., Rosengren F., Salim M., Vallon-Christersson J., Törngren T., Kvist A., Ringnér M., Svane I.M., Jönsson G.

Adoptive T-cell therapy (ACT) is a highly intensive immunotherapy regime that has yielded remarkable response rates and many durable responses in clinical trials in melanoma; however, 50–60% of the patients have no clinical benefit. Here, we searched for predictive biomarkers to ACT in melanoma. Whole exome- and transcriptome sequencing and neoantigen prediction were applied to pre-treatment samples from 27 patients recruited to a clinical phase I/II trial of ACT in stage IV melanoma. All patients had previously progressed on other immunotherapies. We report that clinical benefit is associated with significantly higher predicted neoantigen load. High mutation and predicted neoantigen load are significantly associated with improved progression-free and overall survival. Further, clinical benefit is associated with the expression of immune activation signatures including a high MHC-I antigen processing and presentation score. These results improve our understanding of mechanisms behind clinical benefit of ACT in melanoma.Adoptive T cell therapy (ACT) has yielded high response rates in melanoma, however 50–60% of patients experience no clinical benefit. Here, the authors identify predictive biomarkers, high non-synonymous mutation and high expressed neoantigen load, that associate with clinical benefit in ACT melanoma patients.

Kong Y., Sheng X., Wu X., Yan J., Ma M., Yu J., Si L., Chi Z., Cui C., Dai J., Li Y., Yu H., Xu T., Tang H., Tang B., et. al.

AbstractPurpose: Effective therapies for the majority of metastatic acral melanoma patients have not been established. Thus, we investigated genetic aberrations of CDK4 pathway in acral melanoma and evaluated the efficacy of CDK4/6 inhibitors in targeted therapy of acral melanoma.Experimental Design: A total of 514 primary acral melanoma samples were examined for the copy number variations (CNV) of CDK4 pathway-related genes, including Cdk4, Ccnd1, and P16INK4a, by QuantiGenePlex DNA Assay. The sensitivity of established acral melanoma cell lines and patient-derived xenograft (PDX) containing typical CDK4 aberrations to CDK4/6 inhibitors was evaluated.Results: Among the 514 samples, 203 cases, 137 cases, and 310 cases, respectively, showed Cdk4 gain (39.5%), Ccnd1 gain (26.7%), and P16INK4a loss (60.3%). The overall frequency of acral melanomas that contain at least one aberration in Cdk4, Ccnd1, and P16INK4a was 82.7%. The median overall survival time for acral melanoma patients with concurrent Cdk4 gain with P16INK4a loss was significantly shorter than that for patients without such aberrations (P = 0.005). The pan-CDK inhibitor AT7519 and selective CDK4/6 inhibitor PD0332991 could inhibit the cell viability of acral melanoma cells and the tumor growth of PDX with Cdk4 gain plus Ccnd1 gain, Cdk4 gain plus P16INK4a loss, and Ccnd1 gain plus P16INK4a loss.Conclusions: Genetic aberration of CDK4 pathway is a frequent event in acral melanoma. Acral melanoma cell lines and PDX containing CDK4 pathway aberrations are sensitive to CDK4/6 inhibitors. Our study provides evidence for the testing of CDK4/6 inhibitors in acral melanoma patients. Clin Cancer Res; 23(22); 6946–57. ©2017 AACR.

Ványi G.S., Szigeti A., Pitter J.G., Battyáni Z., Repa I.

Deacon D.C., Stubben C., Marcacci E., Stone C.J., Birdsall M., Florell S.R., Boucher K., Grossman D., Judson-Torres R.L.

Wegman-Ostrosky T., Taja-Chayeb L., Zatarain-Barrón Z.L., Trejo-Becerril C., Shveid Gerson D., Espino-Gutiérrez I., Gutiérrez-Lara A., Bonilla Salcedo A.Y., Castellanos Mares M., García-Ortiz J.E., Robles-Espinoza C.D., Ruíz-Patiño A.

Variations in somatic genetic alterations can be observed across different cancer types and diverse populations. Understanding the frequency of oncogenic variants in specific populations helps elucidate carcinogenesis and risk factors, with somatic variants often serving as treatment markers. Data regarding the somatic landscape across the main tumor subtypes in patients from Latin America and the Caribbean (LAC) have increased recently, highlighting important differences from contrasting populations in North America, Europe, and Asia. Many of these differences have pressing implications regarding screening, risk factor management, targeted therapies, and health care policy. This review aims to synthesize the existing information on somatic oncogenic variants in patients' tumors from LAC. We included the frequency of somatic oncogenic variants of the most frequent tumors in LAC: prostate cancer, female breast cancer, colon cancer, gastric cancer, and lung cancer. Furthermore, we add information from tumors that are relevant in LAC because of their high incidence, specific subtypes, or aggressive phenotypes, namely gallbladder cancer, acral melanoma, and hematologic neoplasms, respectively. The data highlight distinct differences in the reported prevalences of various somatic variants across a spectrum of neoplasms. Moreover, it demonstrates that an extensive number of genetic and molecular studies have been carried out in the region, improving the level of characterization for this complex, admixed population. Nonetheless, data from many individual countries are still scarce or altogether missing, underscoring the need to establish collaborative groups to further advance progress in LAC. The need for further comprehensive research in the area should not be substituted with data from other regions as we seek to empower the choices to improve our health care outlook.

Moras B., Sissi C.

Melanoma is the deadliest form of skin cancer, and its treatment poses significant challenges due to its aggressive nature and resistance to conventional therapies. Long non-coding RNAs (lncRNAs) represent a new frontier in the search for suitable targets to control melanoma progression and invasiveness. Indeed, lncRNAs exploit a wide range of regulatory functions along chromatin remodeling, gene transcription, post-transcription, transduction, and post-transduction to ultimately tune multiple cellular processes. The understanding of this intricate and flexible regulatory network orchestrated by lncRNAs in pathological conditions can strategically support the rational identification of promising targets, ultimately speeding up the setup of new therapeutics to integrate the currently available approaches. Here, the most recent findings on lncRNAs involved in melanoma will be analyzed. In particular, the functional links between their mechanisms of action and some frequently underestimated features, like their different subcellular localizations, will be highlighted.

YANG L., LIU Y., GUO R., DU J., LIU L., LIU X., ZHAO J., SHI F., ZHANG X., SU J.

Nadelmann E.R., Singh A.K., Abbruzzese M., Adeuyan O.O., Kenchappa D.B., Kovrizhkin K., Lightman M., Samouha A., Tao K.L., Yun J., Zhu T.R., McLellan B.N., Saenger Y.M.

Acral melanoma (AM), also known as acral lentiginous melanoma (ALM), is a rare subtype of melanoma that predominantly occurs on the palms, soles, and nail beds (Figure 1) [...]

Bollon J., Tiberi S.

In this work, we study the problem of protein-isoform inference from mass spectrometry proteomics data. Inferring protein isoforms is complex because proteins are only indirectly measured via peptides. Here, we propose a Bayesian approach, based on a two-layer latent variable model to recover protein isoforms, starting from peptide-level data. Since isoform-level data is scarse, we further enhance information by embedding transcriptomics data (i.e., mRNA abundance), which are incorporated via informative priors. Our approach allows inferring the presence/absence and abundance of individual protein isoforms, and provides a measure of uncertainty of both estimates, via posterior probabilities and highest posterior density credible intervals. Notably, at present, existing proteomics tools do not allow inferring protein isoform abundances. Here, we present preliminary results, based on simulation studies, while more extensive benchmarks on real data are currently being performed. Our framework may be valuable for life scientists, and enable them to gain deeper insight into key biological mechanisms.

Kim S.H., Tsao H.

Acral melanoma is a distinct subtype of cutaneous malignant melanoma that uniquely occurs on ultraviolet (UV)-shielded, glabrous skin of the palms, soles, and nail beds. While acral melanoma only accounts for 2–3% of all melanomas, it represents the most common subtype among darker-skinned, non-Caucasian individuals. Unlike other cutaneous melanomas, acral melanoma does not arise from UV radiation exposure and is accordingly associated with a relatively low tumor mutational burden. Recent advances in genomic, transcriptomic, and epigenomic sequencing have revealed genetic alterations unique to acral melanoma, including novel driver genes, high copy number variations, and complex chromosomal rearrangements. This review synthesizes the current knowledge on the clinical features, epidemiology, and treatment approaches for acral melanoma, with a focus on the genetic pathogenesis that gives rise to its unique tumor landscape. These findings highlight a need to deepen our genetic and molecular understanding to better target this challenging subtype of melanoma.

Lumiala T., Koljonen V., Ojala K.

Smith E.A., Belote R.L., Cruz N.M., Moustafa T.E., Becker C.A., Jiang A., Alizada S., Prokofyeva A., Chan T.Y., Seasor T.A., Balatico M., Cortes-Sanchez E., Lum D.H., Hyngstrom J.R., Zeng H., et. al.

Abstract Background Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis. Methods An independent analysis of published sequencing data was performed to evaluate the frequency of receptor tyrosine kinase (RTK) ligands and adapter protein gene variants and expression. To target these genetic variants, a zebrafish acral melanoma model and preclinical patient-derived xenograft (PDX) mouse models were treated with a panel of RTK inhibitors. Residual PDX tumors were evaluated for changes in proliferation, vasculature, necrosis, and ferroptosis by histology and immunohistochemistry. Results RTK ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. Dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration in zebrafish, and the potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM PDX tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks. Conclusion Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.

Guo Q., Jian L., Hu Y., Wang S.

Fernandes M., Barcelos D., Carapeto F.C., Cardili L., Comodo A.N., Mazloum S.F., Marins M.M., Mendes A.R., Pesquero J.B., Landman G.

ABSTRACTIntroductionThe incidence of melanoma has been increasing in recent decades. BRAF mutations appear in 50%–70% of melanomas. The BRAF‐targeted therapy increased the disease‐free survival of patients with metastatic melanoma, but this response may be short, due to several resistance mechanisms, such as the presence of other subclones with mutations. Evaluation of mutations and heterogeneity in the coding region of the BRAF, MAP2K1, and MAP2K2 genes in primary and metastatic melanomas.Patients and MethodsTwenty‐seven samples of primary and metastatic superficial spreading melanoma (SSM) and acral lentiginous melanoma (ALM) were analyzed for BRAF, MAP2K1, and MAP2K2 mutations using the next‐generation sequencing technique.ResultsIn ALM, the mutation rate found was 50% in the BRAF and MAP2K1 genes and 28.6% in MAP2K2. In the SSM, BRAF was mutated in 76.9%, MAP2K1 in 30.8%, and MAP2K2 in 23.2% of the cases. All samples were formed by distinct tumor subclones in the same lesion. Intertumoral heterogeneity was present between primary and metastatic lesions of ALM in BRAF, MAP2K1, and MAP2K2; the cases of SSM were heterogeneous for BRAF and MAP2K1.ConclusionWe sought to evaluate the mutations in the BRAF, MAP2K1, and MAP2K2 genes, revealing a heterogeneous mutation profile in samples of ALM and SSM.

Arast Y., Esfandiari H., Kamranfar F., Mousavi Z., Ameri Shah Reza M., Pourahmad J.

Jawdekar R., Mishra V., Hatgoankar K., Tiwade Y.R., Bankar N.J.

ABSTRACT Recent developments in biotechnology have allowed us to identify unique and complicated biological traits associated with cancer. Genomic profiling through next-generation sequencing (NGS) has revolutionized cancer therapy by evaluating hundreds of genes and biomarkers in a single assay. Proteomics offers blood-based biomarkers for cancer detection, categorization, and therapy monitoring. Immune oncology and chimeric antigen receptor (CAR-T cell) therapy use the immune system to combat cancer. Personalized cancer treatment is on the rise. Although precision medicine holds great promise, its widespread application faces obstacles such as lack of agreement on nomenclature, the difficulty of classifying patients into distinct groups, the difficulties of multimorbidity, magnitude, and the need for prompt intervention. This review studies advances in the era of precision medicine for cancer treatment; the application of genomic profiling techniques, NGS, proteomics, and targeted therapy; and the challenge in the application of precision medicine and the beneficial future it holds in cancer treatment.

Mirek J., Bal W., Olbryt M.

AbstractIn the era of next-generation sequencing, the genetic background of cancer, including melanoma, appears to be thoroughly established. However, evaluating the oncogene BRAF mutation in codon V600 is still the only companion diagnostic genomic test commonly implemented in clinics for molecularly targeted treatment of advanced melanoma. Are we wasting the collected genomic data? Will we implement our current genomic knowledge of melanoma in clinics soon? This question is rather urgent because new therapeutic targets and biomarkers are needed to implement more personalized, patient-tailored therapy in clinics. Here, we provide an update on the molecular background of melanoma, including a description of four already established molecular subtypes: BRAF+, NRAS+, NF1+, and triple WT, as well as relatively new NGS-derived melanoma genes such as PREX2, ERBB4, PPP6C, FBXW7, PIK3CA, and IDH1. We also present a comparison of genomic profiles obtained in recent years with a focus on the most common melanoma genes. Finally, we propose our melanoma gene panel consisting of 22 genes that, in our opinion, are “must-have” genes in both melanoma-specific genomic tests and pan-cancer tests established to improve the treatment of melanoma further.