Molecular landscape of Hereditary Melanoma

Arnaut, Joyce Ribeiro Moura Brasil; Guimarães, Isabella dos Santos; Santos, Anna Cláudia Evangelista dos; Silva, Flora de Moraes Lino da; Machado, Jorge Ricardo; Melo, Andréia Cristina de

doi:10.1016/j.critrevonc.2021.103425

Cited by 22 publications

(29 citation statements)

References 105 publications

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“…TP53, also known as the "guardian of the genome", encodes a tumor suppressor protein that plays a vital role in cellular stress (Scatena et al, 2021). Mutations in the TP53 gene occur at a lower frequently in skin cancer compared with all human cancers (Ribeiro Moura Brasil Arnaut et al, 2021;Scatena et al, 2021), indicating the potiential role of TP53 in the induction of ferroptosis. TP53 mutation is one of the most common mutations in UVR-induced DNA damage and leads to tumor initiation and progression (Strashilov and Yordanov, 2021;Torrens-Mas et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Construction and Validation of a Ferroptosis-Related Prognostic Signature for Melanoma Based on Single-Cell RNA Sequencing

Liu

Shou

Zhu

et al. 2022

Front. Cell Dev. Biol.

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Melanoma, the deadliest type of skin cancer, is on the rise globally. The generally poor prognosis makes melanoma still an enormous public health problem. Ferroptosis is a newly emerging form of iron-dependent regulated cell death, which has been implicated in the development and treatment of several tumors. However, whether there is a connection between ferroptosis-related genes and the prognosis of melanoma patients remains an enigma. In the present study, we identified a ferroptosis-related genes signature to predict the prognosis of melanoma patients by analyzing single-cell RNA-sequencing data from the Gene Expression Omnibus (GEO). Single-cell trajectory analysis was performed to explore malignant differentiation. CellChat was used to investigate intercellular communications in melanoma. Collectively, a novel four-gene signature (CP, MAP1LC3A, transferrin, and TP53) was constructed for prognosis prediction. COX proportional hazards regression analysis showed that the established ferroptosis-associated risk model was an independent prognostic predictor for melanoma patients (HR = 2.3293; 95%CI 1.1528–4.706) (p < 0.018). Patients with low-risk scores had significantly better overall survival (OS) than those with high-risk scores in The Cancer Genome Atlas, GSE59455, and GSE22153 dataset (p = 0.0015, p = 0.031, p = 0.077). Furthermore, the gene expression level of the four genes were verified in multistrain melanoma cell lines and normal human epidermal melanocytes (NHEM). The protein expression level of the four genes in clinical samples were further verified in the Human Protein Atlas (HPA) databases. Taken together, our study identified the prognostic significance of the ferroptosis-related genes in melanoma and developed a novel four-gene prognostic signature, which may shed light on the prognostic assessment and clinical decision making for melanoma patients.

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Section: Discussionmentioning

confidence: 99%

Construction and Validation of a Ferroptosis-Related Prognostic Signature for Melanoma Based on Single-Cell RNA Sequencing

Liu

Shou

Zhu

et al. 2022

Front. Cell Dev. Biol.

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“…12,15,[16][17][18][19][20][21][22][23] Pathogenic variants in other established high-risk genes contribute to less than 10% of heritability. 5,6,24 CDK4 variants, occurring in exon 2, have been associated with early diagnosis. 25 Variants in telomere-linked genes (TERT, POT1, ACD, TERF2IP) have been described in families with a high density of additional cancers.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Approximately 5%-12% of melanomas are diagnosed in familial contexts. 5,6 Individuals with one first-degree relative with melanoma have approximately twofold (range 1.7-13.6) higher risk of developing the disease than the general population and the risk increases with the number of affected relatives. 7 Within the family, melanoma patients often have an early diagnosis, multiple primary melanomas (MPM), and may develop other malignancies.…”

Section: Introductionmentioning

confidence: 99%

High‐ and intermediate‐risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium

Pellegrini,

Cardelli,

Ghiorzo

et al. 2023

Acad Dermatol Venereol

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BackgroundMost of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark‐skinned individuals, are underrepresented.ObjectivesWe report a comprehensive pooled analysis of established high‐ and intermediate‐penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium.MethodsPooled epidemiological, cinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analyzed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country.ResultsWe included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1;95%CI 3.3‐19.7), >3 affected members (OR 2.6; 95%CI 1.3‐5.2) and occurrence of pancreatic cancer (OR 4.8; 95%CI 2.4‐9.4) in the family (AUC 0.76, 95%CI 0.71‐0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4;95%CI 1.0‐2.0 and OR 4.3;95%CI 1.2‐14.6, respectively).ConclusionsVariants in known high‐penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk‐assessment.

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“…[4][5][6][7][8][9][10][11][12][13][14] The main predisposing genes, indications for genetic testing, and recommendations for cancer surveillance were recently reviewed by our research group elsewhere. 15 CDKN2A is the main predisposition gene and the first highrisk gene described. 4,6,16,17 It is located on chromosome 9p21 and consists of four exons (1a, 1b, 2, and 3) that encode two unrelated tumor suppressor proteins (p16INK4a and p14ARF).…”

Section: Introductionmentioning

confidence: 99%

CDKN2A/CDK4 status in Brazilian patients meeting clinical criteria for hereditary melanoma: a cross‐sectional descriptive trial

et al. 2023

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Background Melanoma is the most lethal skin cancer, and its incidence has increased worldwide. About 10% of cases are classified as hereditary melanoma (HM). CDKN2A and CDK4 are the major high‐risk genes. Families are also more prone to develop pancreatic cancer, and different forms of oncological surveillance are recommended. Objectives Describe the prevalence of CDKN2A/CDK4 germline mutations in melanoma‐prone patients and their phenotypic and histopathological features. Methods A total of 69 patients meeting the clinical criteria for HM were included in this cross‐sectional descriptive study. Amplification by PCR and genomic sequencing were used. The variants were classified according to American College of Medical Genetics (ACMG) criteria. Results The mean age at first diagnosis of melanoma was 44.8 years (SD ± 17.83). Most patients had phototype II (44.9%), more than 50 melanocytic nevi (76.8%), atypical nevus syndrome (72.5%), history of sunburn (76.8%), and multiple primary melanomas without a family history of this tumor (74.3%). Two hundred melanomas were observed. Most tumors had a Breslow index ≤1.0 mm (84.5%), location in the trunk (60.5%), and superficial spreading histological subtype (22.5%). Four variants were found in CDKN2A exons in seven patients (c.305C>A, c.26T>A, c.361G>A e c.442G>A), two variants in the 5′UTR region in five patients (c.‐25C>T and c.‐33G>C), and two variants in the 3′UTR region in 21 patients (c.*29C>G and c.*69C>T). One likely pathogenic variant (c.305C>A) was identified in one patient (1.4%). No variant was found in CDK4. Conclusion The prevalence of CDKN2A mutations was 1.4% in Brazilian patients meeting clinical criteria for HM.

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Molecular landscape of Hereditary Melanoma

Cited by 22 publications

References 105 publications

Construction and Validation of a Ferroptosis-Related Prognostic Signature for Melanoma Based on Single-Cell RNA Sequencing

Construction and Validation of a Ferroptosis-Related Prognostic Signature for Melanoma Based on Single-Cell RNA Sequencing

High‐ and intermediate‐risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium

CDKN2A/CDK4 status in Brazilian patients meeting clinical criteria for hereditary melanoma: a cross‐sectional descriptive trial

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