A novel germline mutation in <i><scp>CDK4</scp></i> codon 24 associated to familial melanoma

Bottillo, Irene; Starza, Roberta La; Radio, Francesca Clementina; Molica, Carmen; Pedace, Lucia; Pierini, Tiziana; Bernardo, Carmelilia De; Stingeni, Luca; Bargiacchi, Simone; Paiardini, Alessandro; Janson, Giacomo; Mecucci, Cristina; Grammatico, Paola

doi:10.1111/cge.13129

Cited by 5 publications

(3 citation statements)

References 4 publications

(3 reference statements)

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“…Germline pathogenic variants in CDKN2A/ARF have been found in 20-45% of familial CM cases [1] and in 11-19% of multiple primary melanomas (MPM) [2] from the Italian population, characterized by a high prevalence of CDKN2A pathogenetic variants [3] often associated with pancreatic cancer (PC) and other cancers [4,5]. Conversely, a small number of families carrying pathogenic variants in CDK4 have been described worldwide, including some Italian families [6,7].…”

Section: Introductionmentioning

confidence: 99%

“…1 Gene reference: ATM LRG_135 (NM_000051.3) 2. ACMG: American College of Medical Genetics and Genomics; 3 dbSNP: single nucleotide polymorphism database; 4 gnomAD: genome aggregation database; 5 CADD: combined annotation-dependent depletion; 6 SIFT: sorting intolerant from tolerant;7 PolyPhen: polymorphism phenotyping;8 LRT: likelihood ratio test;9 Clin Var (ClinVar aggregates information about genomic variation and its relationship to human health); 10 co-segregation analysis of variant with melanoma phenotype in the family (Y: the observed variant co-segregates in at least two affected members; ND: not done). Abbreviations; ATM: ataxia-telangiectasia mutated; BC: breast cancer; BCC: basal cell carcinoma; BLC: bladder cancer; CC: colon cancer; CM: cutaneous melanoma; D: deleterious; GC: gastric cancer; HL: Hodgkin lymphoma; LX: larinx cancer; LP: likely pathogenic; MES: malignant mesothelioma; MPM: multiple primary melanoma; ON: pncocytoma; P: pathogenic; PC: pancreatic cancer; PR: prostate cancer; T: tolerant; UC: uterine cancer; UM: uveal melanoma; UNC: uncertain; VUS: variant of unknown significance.…”

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confidence: 99%

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Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Pastorino

Andreotti

Dalmasso

et al. 2020

Cancers

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The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 CDKN2A/ARF and CDK4-negative probands through a custom-designed targeted gene panel that included CDKN2A/ARF, CDK4, ACD, BAP1, MITF, POT1, TERF2IP, ATM, and PALB2. Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes (BAP1, POT1, ACD, MITF, and TERF2IP), including two novel variants in BAP1 and 4 in POT1. We also found four deleterious and five likely deleterious variants in ATM (3.3%). Thus, including potentially deleterious variants in ATM increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative ATM deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Pastorino

Andreotti

Dalmasso

et al. 2020

Cancers

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“…The phenotype of CDK4-mutated families is indistinguishable from CDKN2A-mutated ones [11]. Only 20 families have been identified with GPVs in the CDK4 gene to date [12,13].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Potential Melanoma Predisposition Genes in High-Risk Brazilian Patients

Soares de Sá,

Moredo,

Torrezan

et al. 2023

IJMS

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Increased genetic risk for melanoma can occur in the context of germline pathogenic variants in high-penetrance genes, such as CDKN2A and CDK4, risk variants in low- to moderate-penetrance genes (MC1R and MITF), and possibly due to variants in emerging genes, such as ACD, TERF2IP, and TERT. We aimed to identify germline variants in high- and low- to moderate-penetrance melanoma risk genes in Brazilian patients with clinical criteria for familial melanoma syndrome. We selected patients with three or more melanomas or melanoma patients from families with three tumors (melanoma and pancreatic cancer) in first- or second-degree relatives. Genetic testing was performed with a nine-gene panel (ACD, BAP1, CDK4, CDKN2A, POT1, TERT, TERF2IP, MC1R, and MITF). In 36 patients, we identified 2 (5.6%) with germline pathogenic variants in CDKN2A and BAP1 and 4 (11.1%) with variants of uncertain significance in the high-penetrance genes. MC1R variants were found in 86.5%, and both red hair color variants and unknown risk variants were enriched in patients compared to a control group. The low frequency of germline pathogenic variants in the high-penetrance genes and the high prevalence of MC1R variants found in our cohort show the importance of the MC1R genotype in determining the risk of melanoma in the Brazilian melanoma-prone families.

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A comprehensive review on novel targeted therapy methods and nanotechnology-based gene delivery systems in melanoma

Rahimi,

Esmaeili,

Dana

et al. 2023

European Journal of Pharmaceutical Sciences

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A novel germline mutation in CDK4 codon 24 associated to familial melanoma

Cited by 5 publications

References 4 publications

Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, ATM, BAP1, and POT1

Characterization of Potential Melanoma Predisposition Genes in High-Risk Brazilian Patients

A comprehensive review on novel targeted therapy methods and nanotechnology-based gene delivery systems in melanoma

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