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1.
Fam Cancer ; 21(3): 347-355, 2022 07.
Article in English | MEDLINE | ID: mdl-34215961

ABSTRACT

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.


Subject(s)
GTP Phosphohydrolases , Melanoma , Membrane Proteins , Skin Neoplasms , Cell Line, Tumor , GTP Phosphohydrolases/genetics , GTP Phosphohydrolases/metabolism , Germ-Line Mutation , Guanosine Triphosphate , Humans , Melanoma/genetics , Membrane Proteins/genetics , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-akt/genetics , Skin Neoplasms/genetics
2.
J Am Acad Dermatol ; 83(3): 860-869, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32283231

ABSTRACT

BACKGROUND: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes. OBJECTIVE: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1. METHODS: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and noncarriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family. RESULTS: Histologic slides were evaluated for 290 melanomas (139 from 132 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P < .0001 vs noncarriers). This finding was independently confirmed by 3 expert melanoma dermatopathologists in 9 of 15 invasive melanomas (60%). In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from noncarriers. LIMITATIONS: Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1). CONCLUSION: Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors.


Subject(s)
Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Melanoma/genetics , Skin Neoplasms/genetics , Skin/pathology , Telomere-Binding Proteins/genetics , Adult , Female , Genetic Predisposition to Disease , Germ-Line Mutation , Heterozygote , Humans , Italy , Male , Melanoma/pathology , Middle Aged , Neoplasm Invasiveness/genetics , Shelterin Complex , Skin Neoplasms/pathology , Spain , United States
3.
Nat Genet ; 52(5): 494-504, 2020 05.
Article in English | MEDLINE | ID: mdl-32341527

ABSTRACT

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10-8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.


Subject(s)
Genetic Predisposition to Disease/genetics , Melanoma/genetics , Skin Neoplasms/genetics , Female , Genetic Loci/genetics , Genome-Wide Association Study/methods , Genotype , Humans , Male , Phenotype , Pigmentation/genetics , Polymorphism, Single Nucleotide/genetics , Melanoma, Cutaneous Malignant
4.
PLoS Genet ; 15(11): e1008490, 2019 11.
Article in English | MEDLINE | ID: mdl-31730655

ABSTRACT

Despite genetics being accepted as the primary cause of familial aggregation for most diseases, it is still unclear whether afflicted families are likely to share a single highly penetrant rare variant, many minimally penetrant common variants, or a combination of the two types of variants. We therefore use recent estimates of SNP heritability and the liability threshold model to estimate the proportion of afflicted families likely to carry a rare, causal variant. We then show that Polygenic Risk Scores (PRS) may be useful for identifying families likely to carry such a rare variant and therefore for prioritizing families to include in sequencing studies with that aim. Specifically, we introduce a new statistic that estimates the proportion of individuals carrying causal rare variants based on the family structure, disease pattern, and PRS of genotyped individuals. Finally, we consider data from the MelaNostrum consortium and show that, despite an estimated PRS heritability of only 0.05 for melanoma, families carrying putative causal variants had a statistically significantly lower PRS, supporting the idea that PRS prioritization may be a useful future tool. However, it will be important to evaluate whether the presence of rare mendelian variants are generally associated with the proposed test statistic or lower PRS in future and larger studies.


Subject(s)
Genetic Diseases, Inborn/genetics , Genetic Predisposition to Disease , Melanoma/genetics , Sequence Analysis, DNA , Alleles , Genetic Variation/genetics , Genome-Wide Association Study , Genotype , Humans , Melanoma/epidemiology , Melanoma/pathology , Multifactorial Inheritance/genetics , Pedigree , Phenotype , Polymorphism, Single Nucleotide/genetics , Risk Factors
5.
J Am Acad Dermatol ; 81(2): 386-394, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30731170

ABSTRACT

BACKGROUND: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved. METHODS: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics. RESULTS: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance. CONCLUSION: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16/genetics , Genetic Predisposition to Disease , Logistic Models , Melanoma/genetics , Pancreatic Neoplasms , Skin Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Area Under Curve , Child , Genetic Testing , Germ-Line Mutation , Heterozygote , Humans , Internationality , Middle Aged , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/genetics , Phenotype , Predictive Value of Tests , Probability , ROC Curve , Risk Factors , Young Adult
6.
Genome Med ; 10(1): 99, 2018 12 24.
Article in English | MEDLINE | ID: mdl-30583724

ABSTRACT

BACKGROUND: Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982). METHODS: We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS). RESULTS: In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers. CONCLUSION: The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.


Subject(s)
Genes, Neoplasm/genetics , Genetic Predisposition to Disease , Mutation , Neoplasms/genetics , Polymorphism, Single Nucleotide , Aged , Cohort Studies , DNA Mutational Analysis , Ethnicity , Female , Humans , Male
7.
J Eur Acad Dermatol Venereol ; 32(12): 2134-2141, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30098061

ABSTRACT

BACKGROUND: Many melanoma observational studies have been carried out across different countries and geographic areas using heterogeneous assessments of epidemiologic risk factors and clinical variables. AIM: To develop a consensus questionnaire to standardize epidemiologic and clinical data collection for melanoma risk assessment. METHODS: We used a stepwise strategy that included: compilation of variables from case-control datasets collected at various centres of the MelaNostrum Consortium; integration of variables from published case-control studies; consensus discussion of the collected items by MelaNostrum members; revision by independent experts; addition of online tools and image-based charts; questionnaire testing across centres and generation of a final draft. RESULTS: We developed a core consensus questionnaire (MelanoQ) that includes four separate sections: A. general and demographic data; B. phenotypic and ultraviolet radiation exposure risk factors and lifestyle habits; C. clinical examination, medical and family history; and D. diagnostic data on melanoma (cases only). Accompanying online tools, informative tables, and image-based charts aid standardization. Different subsections of the questionnaire are designed for self-administration, patient interviews performed by a physician or study nurse, and data collection from medical records. CONCLUSIONS: The MelanoQ questionnaire is a useful tool for the collection and standardization of epidemiologic and clinical data across different studies, centres, cultures and languages. This will expedite ongoing efforts to compile high-quality data for pooled analyses or meta-analyses and offer a solid base for the design of clinical, epidemiologic and translational studies on melanoma.


Subject(s)
Melanoma/epidemiology , Skin Neoplasms/epidemiology , Surveys and Questionnaires , Consensus , Epidemiologic Methods , Humans , Life Style , Medical History Taking , Melanoma/diagnosis , Radiation Exposure , Risk Assessment/methods , Skin Neoplasms/diagnosis , Ultraviolet Rays
8.
Hum Mol Genet ; 27(23): 4145-4156, 2018 12 01.
Article in English | MEDLINE | ID: mdl-30060076

ABSTRACT

Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12 874 melanoma cases and 23 203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3102 cases and 2301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the receiver operator characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC = 64.4%; 95% confidence interval (CI) = 63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR = 1.35 (95% CI = 1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year-old Italian man ranged from 0.5 to 11.8% (relative risk  = 26.34), indicating good separation.


Subject(s)
Genetic Predisposition to Disease , Melanoma/genetics , Nevus/genetics , Skin Neoplasms/genetics , Adult , Aged , Female , Genome-Wide Association Study , Humans , Italy , Male , Melanoma/epidemiology , Melanoma/pathology , Middle Aged , Multifactorial Inheritance/genetics , Nevus/epidemiology , Nevus/pathology , Polymorphism, Single Nucleotide , Risk Assessment , Risk Factors , Skin Neoplasms/epidemiology , Skin Neoplasms/pathology , Melanoma, Cutaneous Malignant
9.
J Invest Dermatol ; 137(12): 2606-2612, 2017 12.
Article in English | MEDLINE | ID: mdl-28830827

ABSTRACT

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p18/genetics , Germ-Line Mutation , Melanoma/genetics , Nevus/genetics , Skin Neoplasms/genetics , Cyclin-Dependent Kinase Inhibitor p16 , DNA Mutational Analysis , Family Health , Female , Genotype , Humans , Male , Nevus, Pigmented/genetics , Odds Ratio , Phenotype , Registries , Melanoma, Cutaneous Malignant
10.
G Ital Dermatol Venereol ; 152(1): 18-23, 2017 02.
Article in English | MEDLINE | ID: mdl-27013147

ABSTRACT

BACKGROUND: To identify the prognostic factors and assess the outcome of a group of octogenarian patients who were diagnosed with cutaneous melanoma (CM) in the Department of Dermatology of the "M. Bufalini" Hospital, Cesena, Italy from 1996 to 2013. METHODS: From the 1136 consecutive patients in our database, we selected 82 patients (7.2%) diagnosed with CM at age 80 or older. Their major clinical and histopathologic parameters were extracted and matched with those of the residual 1054 younger patients. RESULTS: Comparing our 82 patients with the group of 1054 patients with CM diagnosed in the same period, but at a younger age, we found that: 1) there was no significant difference regarding the patient's gender; 2) CM diagnosed in octogenarians was more frequently located on the head and neck (24.4% vs. 12.8%), and lower extremities (24.4% vs. 14.4%) (P=0.0001); 3) early diagnosis of CM (T1) was less frequent in octogenarians (31.7% vs. 62.6%), intermedium thickness CM (T2) was nearly the same in the 2 groups (15.8% vs. 16.5%), while diagnosis in category T3/T4 (42.6% vs. 21.0%) were significantly greater in octogenarians (P=0.0001); 4) ulceration was detected more frequently in octogenarians (18.3% vs. 10.7%) but the difference was not statistically significant. After a follow-up period of a median 58 months, 52 octogenarians (63.4%) were still alive and free from disease. Thirty of them (36.6%) had died, 14 (17.1%) of which because of melanoma. On the contrary, among the younger patients, 840 (81.6%) were alive, 132 (12.5%) died for melanoma and 75 (7.1%) for other causes. CONCLUSIONS: In our octogenarians, death for CM was not related to the old age but to the delayed diagnosis of cancer. Our results suggest that continuing educational programs for early diagnosis of CM should specifically include this segment of population.


Subject(s)
Head and Neck Neoplasms/pathology , Melanoma/pathology , Skin Neoplasms/pathology , Age Factors , Aged, 80 and over , Delayed Diagnosis , Early Detection of Cancer , Female , Follow-Up Studies , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/epidemiology , Humans , Italy , Lower Extremity , Male , Melanoma/diagnosis , Prognosis , Retrospective Studies , Skin Neoplasms/diagnosis , Survival Rate
14.
J Invest Dermatol ; 136(5): 1066-1069, 2016 05.
Article in English | MEDLINE | ID: mdl-26827760
15.
Melanoma Res ; 24(5): 480-7, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25026000

ABSTRACT

Germline mutations determining increased cutaneous malignant melanoma (CMM) risk have been identified in familial and sporadic CMM cases, but they account only for a small proportion of CMM cases. Recent evidence suggests that germline epimutations (e.g. DNA methylation alterations), which can be inherited similarly to genomic mutations and can be detected in normal body cells (including blood), might increase susceptibility to cancer. The aim of the study was to identify germline epimutations of genes that were found to be mutated in familial CMM (p16, p14, CDK4, MC1R, hTERT), immune and inflammatory genes (ICAM-1, TNFα), DNA mismatch repair gene (MLH1), and repetitive elements (ALU, LINE-1, HERV-w). We measured DNA methylation using bisulfite pyrosequencing in peripheral blood mononuclear cells from 167 CMM cases and 164 sex-matched and age-matched controls. We used multivariable logistic regression models to evaluate the association between methylation levels and CMM status or presence of dysplastic nevi. We found an association between the risk of CMM and peripheral blood mononuclear cell methylation levels of TNFα [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03-1.18], CDK4 (OR=0.76, 95% CI=0.64-0.91), and MLH1 (OR=1.12, 95% CI=1.02-1.22). In control participants, the risk of developing dysplastic nevi was associated with methylation levels of TNFα (OR=0.81, 95% CI=0.69-0.95), hTERT (OR=0.90, 95% CI=0.82-0.99), and ALU (OR=1.56, 95% CI=1.02-2.39). Epimutations in CMM susceptibility genes and in genes involved in response to oxidative damage are associated with the risk of developing CMM or dysplastic nevi. Further studies measuring methylation levels of these genes in prospectively collected samples are warranted to further elucidate their role in the development and progression of CMM.


Subject(s)
DNA Methylation , Melanoma/blood , Melanoma/genetics , Nevus/genetics , Adaptor Proteins, Signal Transducing/genetics , Alu Elements , Case-Control Studies , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Female , Gene Products, env/genetics , Humans , Inflammation , Intercellular Adhesion Molecule-1/genetics , Leukocytes, Mononuclear/cytology , Long Interspersed Nucleotide Elements , Male , Multivariate Analysis , MutL Protein Homolog 1 , Mutation , Nevus/physiopathology , Nuclear Proteins/genetics , Pregnancy Proteins/genetics , Receptor, Melanocortin, Type 1/genetics , Risk Factors , Skin Neoplasms , Telomerase/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Suppressor Protein p14ARF/genetics , Melanoma, Cutaneous Malignant
16.
Nat Genet ; 46(5): 482-6, 2014 May.
Article in English | MEDLINE | ID: mdl-24686846

ABSTRACT

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.


Subject(s)
Genetic Predisposition to Disease/genetics , Melanoma/genetics , Models, Molecular , Mutation, Missense/genetics , Neoplasms, Connective Tissue/genetics , Telomere Homeostasis/genetics , Telomere-Binding Proteins/genetics , Amino Acid Sequence , Base Sequence , Computational Biology , Exome/genetics , France , Humans , In Situ Hybridization, Fluorescence , Italy , Molecular Sequence Data , Pedigree , Sequence Alignment , Sequence Analysis, DNA , Shelterin Complex , Skin Neoplasms , Telomere-Binding Proteins/chemistry , United States , Melanoma, Cutaneous Malignant
17.
J Invest Dermatol ; 134(2): 481-487, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23892592

ABSTRACT

Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each single-nucleotide polymorphism (SNP) separately, adjusted for age, sex, CMM, and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific P-values. Two genes, CDK6 (cyclin-dependent kinase 6) and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation-positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and -negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent data sets (random-effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.


Subject(s)
DNA-Binding Proteins/genetics , Dysplastic Nevus Syndrome/genetics , Melanoma/genetics , Skin Neoplasms/genetics , Adult , Cyclin-Dependent Kinase 6/genetics , Dysplastic Nevus Syndrome/epidemiology , Family Health , Female , Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/genetics , Genetic Variation , Humans , Male , Melanoma/epidemiology , Middle Aged , Risk Factors , Skin Neoplasms/epidemiology , X-ray Repair Cross Complementing Protein 1
18.
Nat Genet ; 45(4): 428-32, 432e1, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23455637

ABSTRACT

We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.


Subject(s)
Body Mass Index , Genetic Loci/genetics , Genetic Predisposition to Disease , Melanoma/etiology , Polymorphism, Single Nucleotide/genetics , Proteins/genetics , Alpha-Ketoglutarate-Dependent Dioxygenase FTO , Case-Control Studies , Cooperative Behavior , Female , Genome-Wide Association Study , Genotype , Humans , Meta-Analysis as Topic , Obesity , Risk Factors
19.
Pigment Cell Melanoma Res ; 25(2): 243-7, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22225770

ABSTRACT

Copy number variations (CNVs) have been shown to contribute substantially to disease susceptibility in several inherited diseases including cancer. We conducted a genome-wide search for CNVs in blood-derived DNA from 79 individuals (62 melanoma patients and 17 spouse controls) of 30 high-risk melanoma-prone families without known segregating mutations using genome-wide comparative genomic hybridization (CGH) tiling arrays. We identified a duplicated region on chromosome 4q13 in germline DNA of all melanoma patients in a melanoma-prone family with three affected siblings. We confirmed the duplication using quantitative PCR and a custom-made CGH array design spanning the 4q13 region. The duplicated region contains 10 genes, most of which encode CXC chemokines. Among them, CXCL1 (melanoma growth-stimulating activity α) and IL8 (interleukin 8) have been shown to stimulate melanoma growth in vitro and in vivo. Our data suggest that the alteration of CXC chemokine genes may confer susceptibility to melanoma.


Subject(s)
Chemokines, CXC/genetics , Chromosomes, Human, Pair 4/genetics , Gene Duplication/genetics , Genetic Predisposition to Disease , Melanoma/genetics , Skin Neoplasms/genetics , Adult , DNA, Neoplasm/genetics , Family , Female , Genome, Human/genetics , Humans , Male , Middle Aged , Pedigree , Polymerase Chain Reaction , Young Adult
20.
PLoS One ; 7(12): e52466, 2012.
Article in English | MEDLINE | ID: mdl-23300679

ABSTRACT

The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.


Subject(s)
Melanoma/complications , Melanoma/genetics , Nevus/complications , Skin Neoplasms/complications , Telomere/genetics , Adolescent , Adult , Aged , Case-Control Studies , Disease Progression , Dysplastic Nevus Syndrome/complications , Dysplastic Nevus Syndrome/pathology , Environmental Exposure/adverse effects , Environmental Exposure/statistics & numerical data , Female , Genetic Predisposition to Disease/genetics , Humans , Male , Melanoma/epidemiology , Melanoma/ethnology , Middle Aged , Nevus/pathology , Pigmentation , Polymorphism, Single Nucleotide , Risk Factors , Skin Neoplasms/pathology , Sunlight/adverse effects , Young Adult
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