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author:("Puig, susanae")
1.  The Effect on Melanoma Risk of Genes Previously Associated With Telomere Length 
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10-9, two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.
doi:10.1093/jnci/dju267
PMCID: PMC4196080  PMID: 25231748
2.  Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer 
Oncotarget  2013;5(6):1439-1451.
Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer.
We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach.
As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson’s, Alzheimer and Huntington.
Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development.
PMCID: PMC4039222  PMID: 24742402
Familial Melanoma; CDKN2A; MC1R; gene expression; p16; mutations
3.  Genetic alterations in RAS regulated pathway in Acral Lentiginous Melanoma 
Experimental dermatology  2013;22(2):148-150.
Studies integrating clinicopathological and genetic features have revealed distinct patterns of genomic aberrations in Melanoma. Distributions of BRAF or NRAS mutations and gains of several oncogenes differ among melanoma subgroups while 9p21 deletions are found in all melanoma subtypes.
In the study, status of genes involved in cell cycle progression and apoptosis were evaluated in a panel of 17 frozen primary acral melanomas.
NRAS
mutations were found in 17% of the tumours. In contrast, BRAF mutations were not found. Gains of AURKA gene (20q13.3) were detected in 37.5% of samples, gains of CCND1 gene (11q13) or TERT gene (5p15.33) in 31.2% and gains of NRAS gene (1p13.2) in 25%. Alterations in 9p21 were identified in 69% of tumours. Gains of 11q13 and 20q13 were mutually exclusive; and 1p13.2 gain was associated with 5p15.33.
Our findings showed that alterations in RAS related pathways are present in 87.5% of acral lentiginous melanomas.
doi:10.1111/exd.12080
PMCID: PMC3563247  PMID: 23362874
Acral lentiginous melanoma; melanoma; MLPA; NRAS; AURKA
4.  DERMA: A Melanoma Diagnosis Platform Based on Collaborative Multilabel Analog Reasoning 
The Scientific World Journal  2014;2014:351518.
The number of melanoma cancer-related death has increased over the last few years due to the new solar habits. Early diagnosis has become the best prevention method. This work presents a melanoma diagnosis architecture based on the collaboration of several multilabel case-based reasoning subsystems called DERMA. The system has to face up several challenges that include data characterization, pattern matching, reliable diagnosis, and self-explanation capabilities. Experiments using subsystems specialized in confocal and dermoscopy images have provided promising results for helping experts to assess melanoma diagnosis.
doi:10.1155/2014/351518
PMCID: PMC3918694  PMID: 24578629
5.  A variant in FTO shows association with melanoma risk not due to BMI 
Iles, Mark M | Law, Matthew H | Stacey, Simon N | Han, Jiali | Fang, Shenying | Pfeiffer, Ruth | Harland, Mark | MacGregor, Stuart | Taylor, John C | Aben, Katja K | Akslen, Lars A | Avril, Marie-Françoise | Azizi, Esther | Bakker, Bert | Benediktsdottir, Kristrun R | Bergman, Wilma | Scarrà, Giovanna Bianchi | Brown, Kevin M | Calista, Donato | Chaudru, Valerié | Fargnoli, Maria Concetta | Cust, Anne E | Demenais, Florence | de Waal, Anne C | Dębniak, Tadeusz | Elder, David E | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Gillanders, Elizabeth M | Goldstein, Alisa M | Gruis, Nelleke A | Hansson, Johan | Helsing, Per | Hočevar, Marko | Höiom, Veronica | Hopper, John L | Ingvar, Christian | Janssen, Marjolein | Jenkins, Mark A | Kanetsky, Peter A | Kiemeney, Lambertus A | Lang, Julie | Lathrop, G Mark | Leachman, Sancy | Lee, Jeffrey E | Lubiński, Jan | Mackie, Rona M | Mann, Graham J | Mayordomo, Jose I | Molven, Anders | Mulder, Suzanne | Nagore, Eduardo | Novaković, Srdjan | Okamoto, Ichiro | Olafsson, Jon H | Olsson, Håkan | Pehamberger, Hubert | Peris, Ketty | Grasa, Maria Pilar | Planelles, Dolores | Puig, Susana | Puig-Butille, Joan Anton | Randerson-Moor, Juliette | Requena, Celia | Rivoltini, Licia | Rodolfo, Monica | Santinami, Mario | Sigurgeirsson, Bardur | Snowden, Helen | Song, Fengju | Sulem, Patrick | Thorisdottir, Kristin | Tuominen, Rainer | Van Belle, Patricia | van der Stoep, Nienke | van Rossum, Michelle M | Wei, Qingyi | Wendt, Judith | Zelenika, Diana | Zhang, Mingfeng | Landi, Maria Teresa | Thorleifsson, Gudmar | Bishop, D Timothy | Amos, Christopher I | Hayward, Nicholas K | Stefansson, Kari | Bishop, Julia A Newton | Barrett, Jennifer H
Nature genetics  2013;45(4):428-432.
We report the results of an association study of melanoma 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 a novel association between several single nucleotide polymorphisms (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 OR for A=1.16). As well as identifying a novel melanoma susceptibility locus, this is 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 show 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.
doi:10.1038/ng.2571
PMCID: PMC3640814  PMID: 23455637
6.  GENETIC COUNSELLING IN MELANOMA 
Dermatologic therapy  2012;25(5):397-402.
Summary
Genetic counselling may be offered to families with melanoma and to individuals with multiple melanomas to better understand the genetic susceptibility of the disease, the influence of environmental factors, the inheritance of the risk and behaviour that decreases the risk of dying from melanoma including specific dermatological follow-up such as total body photography and digital dermoscopy. Genetic testing may be offered to those individuals with more than a 10% chance of being a carrier of a mutation. This risk varies according to the incidence of melanoma in the country and sun behaviour. In countries with a low-medium incidence of melanoma, genetic testing should be offered to families with two cases of melanoma or an individual with two primary melanomas. In countries with a high incidence, families with three cases of melanoma, with two melanomas and one pancreatic adenocarcinoma, or patients with three primary melanomas may benefit from genetic testing.
doi:10.1111/j.1529-8019.2012.01499.x
PMCID: PMC3470473  PMID: 23046018
melanoma; predisposition; gene; genetic counselling; mutation
7.  BENEFITS OF TOTAL BODY PHOTOGRAPHY AND DIGITAL DERMOSCOPY (“TWO-STEP METHOD OF DIGITAL FOLLOW-UP”) IN THE EARLY DIAGNOSIS OF MELANOMA IN HIGH-RISK PATIENTS 
Background
Early detection of melanoma is the best way to improve prognosis. Digital follow up (DFU) programs of high-risk populations could be an efficient strategy for detecting early melanomas with low morbidity.
Objective
to report the added value of the use of the “two-step method” (digital total-body photography and digital dermoscopy)
Methods
Analysis of the surveillance of 618 high-risk melanoma patients included in our DFU-program from 1999 to 2008.
Results
A total of 11396 lesions were monitored (mean 18.44 per patient) during a median follow-up of 96 months (median 10 visits per patient). 1152 lesions, 1.86 per patient, were excised. Almost 70% (798) were lesions previously registered at least twice, while 356 (30%) were detected and removed in the same visit. During follow-up, 98 melanomas (8.5% of excised lesions) were diagnosed in 78 patients (12.6%). 53 melanomas were in situ (53.3%), while invasive (45) showed a Breslow index of less than 1 mm (median 0.5 mm) and none was ulcerated.
Limitations
Since there are no control groups we cannot convey if the combined use of total-body photography and digital dermoscopy is more beneficial than these techniques used separately.
Conclusion
DFU with Total-Body Photography and Dermoscopy in a selected high-risk population demonstrated the early detection of melanomas with a low rate of excisions. Long-term follow-up is required to allow the detection of slow growing melanomas. Based on our 10-year experience, melanomas can be diagnosed at any time, suggesting that in high-risk population, DFU should be maintained with time.
doi:10.1016/j.jaad.2011.04.008
PMCID: PMC3215791  PMID: 21683472
malignant melanoma; dermoscopy; follow-up; imaging techniques; atypical mole syndrome; outcome
8.  Predictors of Sun Protection Behaviours and Severe Sunburn inan International on-line study 
Background
The incidence of melanoma continues to increase in many countries, and primary prevention of melanoma includes avoidance of sunburn as well as adequate sun protection behaviour. The aim of this study was to examine the prevalence of self-reported sun protection behaviours and sunburn in users of the Internet, and to identify the demographic, clinical and attitudinal/motivational correlates of sun protection behaviours.
Methods
Self-report data were gathered on behalf of GenoMEL (www.genomel.org) using an online survey available in 10 different languages, and 8,178 individuals successfully completed at least 80% of survey items, with 73% of respondents from Europe, 12% from Australia, 7% from the USA, 2% from Israel, and 6% from other countries.
Results
Half of all respondents and 27% of those with a previous melanoma reported at least one severe sunburn during the previous 12 months. The strongest factors associated with sun protection behaviour were perceived barriers to protection (β=−0.44/β=−0.37), and respondents who reported a positive attitude towards suntans were less likely to protect (β=−0.16/β=−0.14). Reported use of protective clothing and shade, as well as avoidance of midday sun exposure, were more strongly related to reduced risk of sunburn than sunscreen use.
Conclusions
Despite widespread dissemination of public health messages about the importance of sun protection, a substantial proportion of this international sample, including respondents with a previous melanoma, reported inadequate sun protection behaviours resulting in severe sunburn.
Impact
Future strategies to decrease sunburn should target the practical, social and psychological barriers associated with non-uptake of sun protection.
doi:10.1158/1055-9965.EPI-10-0196
PMCID: PMC3672402  PMID: 20643826
Sun exposure; Sunburn; Sun protection; Melanoma
9.  Melanoma Risk Factors, Perceived threat and Intentional Tanning: An Online Survey 
Background
Cutaneous melanoma continues to increase in incidence in many countries, and intentional tanning is a risk factor for melanoma. The aim of this study was to understand how melanoma risk factors, perceived threat, and preferences for a suntan relate to intentional tanning.
Methods
Self-report data were collected on behalf of GenoMEL (www.genomel.org) from members of the general population using an online survey. A total of 8,178 individuals successfully completed at least 80% of the survey, with 72.8% of respondents from Europe, 12.1% from Australia, 7.1% from the USA, 2.5% from Israel, and 5.5% from other countries.
Results
Seven percent of respondents had previously been diagnosed with melanoma and 8% had at least one first-degree relative with a previous melanoma. Overall, 70% of the respondents reported some degree of intentional tanning during the past year, and 38% of respondents previously diagnosed with melanoma had intentionally tanned. Total number of objective risk factors was positively correlated with perceived risk of melanoma (correlation coefficient (ρ)=0.27), and negatively correlated with intentional tanning (ρ=−0.16). Preference for a dark suntan was the strongest predictor of intentional tanning (regression coefficient (β)=0.35, p<0.001), even in those with a previous melanoma (β=0.33, p<0.01).
Conclusions
A substantial proportion of participants reported having phenotypic and behavioural risk factors for melanoma. The preference regarding suntans seemed more important in the participants’ decision to intentionally tan than their perceived risk of developing melanoma, and this finding was consistent among respondents from different countries. The drive to sunbathe in order to tan appears to be a key psychological factor to be moderated if melanoma incidence is to be reduced.
doi:10.1097/CEJ.0b013e3283354847
PMCID: PMC3672405  PMID: 20093934
Intentional tanning; Sunbathing, Suntan; Perceived threat; Melanoma; Risk factors; Familial risk
10.  Duplication of CXC chemokine genes on chromosome 4q13 in a melanoma-prone family 
Pigment cell & melanoma research  2012;25(2):243-247.
Summary
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 suggests that the alteration of CXC chemokine genes may confer susceptibility to melanoma.
doi:10.1111/j.1755-148X.2012.00969.x
PMCID: PMC3288577  PMID: 22225770
Familial melanoma; Germline copy number variations; disease susceptibility; CXC chemokines; chromosome 4q13
11.  Serum 25-hydroxyvitamin D3 levels and vitamin D receptor variants in melanoma patients from the Mediterranean area of Barcelona 
BMC Medical Genetics  2013;14:26.
Background
Serum 25-hydroxyvitamin D3 (Vitamin D) insufficiency and single-nucleotide polymorphisms (SNPs) on its receptor, Vitamin D receptor (VDR), have been reported to be involved in melanoma susceptibility in populations mostly from northern countries.
Objective
To investigate 25-hydroxyvitamin D3 levels and VDR SNPs in melanoma patients from sunny area of Barcelona, two studies were carried out. The first study evaluated the levels of Vitamin D at time of melanoma diagnosis and the second one analyzed the association between VDR genetic variants and risk of having a high nevus number, the strongest phenotypic risk factor for melanoma.
Methods
The levels of 25-hydroxyvitamin D3 in 81 melanoma patients at diagnosis were measured. In a second group of melanoma patients, including 150 with low and 113 with high nevus number, 11 VDR SNPs were analyzed for their association with nevus number.
Results
In the first study, 68% of patients had insufficient levels of 25-hydroxyvitamin D3 (<25 ng/ml). Autumn-winter months and fair phototype were associated with 25-hydroxyvitamin D3 insufficiency; after multivariate analysis, season of sampling remained the only independent predictor of 25-hydroxyvitamin D3 levels. In the second study, VDR variant rs2189480 (P = 0.006) was associated with risk of high nevus number whereas rs2239179 (P = 0.044) and rs7975128 (P = 0.0005) were protective against high nevus number. After Bonferroni adjustment only rs7975128 remained significant. In stratified analysis, SNP rs7975128 was found protective against multiple melanomas (P = 0.021).
Conclusion
This study showed that even in Barcelona, a sunny Mediterranean area, 25-hydroxyvitamin D3 levels were sub-optimal in the majority of melanoma patients at diagnosis. The involvement of VDR in nevi and, in turn, in melanoma susceptibility has also been suggested. Larger studies are needed to confirm our findings.
doi:10.1186/1471-2350-14-26
PMCID: PMC3648347  PMID: 23413917
Vitamin D; VDR; SNP; Melanoma
13.  Genome-wide association study identifies three new melanoma susceptibility loci 
Barrett, Jennifer H | Iles, Mark M | Harland, Mark | Taylor, John C | Aitken, Joanne F | Andresen, Per Arne | Akslen, Lars A | Armstrong, Bruce K | Avril, Marie-Francoise | Azizi, Esther | Bakker, Bert | Bergman, Wilma | Bianchi-Scarrà, Giovanna | Paillerets, Brigitte Bressac-de | Calista, Donato | Cannon-Albright, Lisa A | Corda, Eve | Cust, Anne E | Dębniak, Tadeusz | Duffy, David | Dunning, Alison | Easton, Douglas F | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Giles, Graham G | Hansson, Johan | Hocevar, Marko | Höiom, Veronica | Hopper, John L | Ingvar, Christian | Janssen, Bart | Jenkins, Mark A | Jönsson, Göran | Kefford, Richard F | Landi, Giorgio | Landi, Maria Teresa | Lang, Julie | Lubiński, Jan | Mackie, Rona | Malvehy, Josep | Martin, Nicholas G | Molven, Anders | Montgomery, Grant W | van Nieuwpoort, Frans A | Novakovic, Srdjan | Olsson, Håkan | Pastorino, Lorenza | Puig, Susana | Puig-Butille, Joan Anton | Randerson-Moor, Juliette | Snowden, Helen | Tuominen, Rainer | Van Belle, Patricia | van der Stoep, Nienke | Whiteman, David C | Zelenika, Diana | Han, Jiali | Fang, Shenying | Lee, Jeffrey E | Wei, Qingyi | Lathrop, G Mark | Gillanders, Elizabeth M | Brown, Kevin M | Goldstein, Alisa M | Kanetsky, Peter A | Mann, Graham J | MacGregor, Stuart | Elder, David E | Amos, Christopher I | Hayward, Nicholas K | Gruis, Nelleke A | Demenais, Florence | Newton Bishop, Julia A | Bishop, D Timothy
Nature Genetics  2011;43(11):1108-1113.
We report a genome-wide association study of melanoma, conducted by GenoMEL, of 2,981 cases, of European ancestry, and 1,982 study-specific controls, plus a further 6,426 French and UK population controls, all genotyped for 317,000 or 610,000 SNPs. The analysis confirmed previously known melanoma susceptibility loci. The 7 novel regions with at least one SNP with p<10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Houston, Texas). Additional replication came from UK and Dutch case-control series. Three of the 7 regions replicated at p<10−3: an ATM missense polymorphism (rs1801516, overall p=3.4×10−9); a polymorphism within MX2 (rs45430, p=2.9×10−9) and a SNP adjacent to CASP8 (rs13016963, p=8.6×10−10). A fourth region near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication. Unlike the previously known regions, the novel loci showed no association with nevus or pigmentation phenotypes in a large UK case-control series.
doi:10.1038/ng.959
PMCID: PMC3251256  PMID: 21983787
14.  Selection criteria for genetic assessment of patients with familial melanoma 
Approximately 5% to 10% of melanoma may be hereditary in nature, and about 2% of melanoma can be specifically attributed to pathogenic germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A). To appropriately identify the small proportion of patients who benefit most from referral to a genetics specialist for consideration of genetic testing for CDKN2A, we have reviewed available published studies of CDKN2A mutation analysis in cohorts with invasive, cutaneous melanoma and found variability in the rate of CDKN2A mutations based on geography, ethnicity, and the type of study and eligibility criteria used. Except in regions of high melanoma incidence, such as Australia, we found higher rates of CDKN2A positivity in individuals with 3 or more primary invasive melanomas and/or families with at least one invasive melanoma and two or more other diagnoses of invasive melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family. The work summarized in this review should help identify individuals who are appropriate candidates for referral for genetic consultation and possible testing.
doi:10.1016/j.jaad.2009.03.016
PMCID: PMC3307795  PMID: 19751883
CDKN2A; familial; genetic counseling; genetic testing; hereditary; melanoma; p16
15.  A Novel Flexible Multiplex Bead-based Assay for Detecting Germline CDKN2A and CDK4 Variants in Melanoma-Prone Kindreds 
Background
The presence of recurrent high-risk mutations in CDKN2A and CDK4 among melanoma-prone kindreds suggests that a high-throughput, multiplex assay could serve as an effective initial screening tool. Moreover, with the emergence of new melanoma risk single nucleotide polymorphisms (SNPs) through genome-wide association studies, a flexible platform that can easily accommodate these new risk alleles is needed for more accurate genetic risk profiling. To this end, we have developed a novel melanoma-associated mutation detection method using a multiplex bead-based assay. This assay is suitable for high-throughput CDKN2A and CDK4 genotyping and can be eventually adapted to multiple loci across various constituent populations.
Methods
Genomic DNA from a 1603 subjects (1005 in training set, 598 in validation set) were amplified by multiplex PCR using five primer sets followed by multiplex allele-specific primer extension for 39 different known germline variants. The products were then sorted on an xMAP™ (formerly Tag-It™) array and detected by use of the Luminex xMAP™ system. Genotypes were compared to previously-determined sequence data.
Results
In the Toronto training cohort, variants were detected in 145 samples, giving complete concordance between the bead assay and direct sequencing results. Analysis of the 598 samples from the GenoMEL validation set led to identification of 150/155 expected variants (96.77% concordance). Overall, the bead assay correctly genotyped 1540/1603 (96.07%) of all individuals in the study and 1540/1545 (99.68%) of individuals whose mutations were represented in the probe set. Out of a total of 62,512 SNP calls, 62,517 (99.99%) were correctly assigned.
Conclusions
In this initial evaluation, the multiplex bead-based assay for familial melanoma appears to be a highly accurate method for genotyping CDKN2A and CDK4 variants.
doi:10.1038/jid.2010.331
PMCID: PMC3045700  PMID: 21085193
Melanoma; CDKN2A; CDK4; p14ARF; familial; high-throughput
16.  Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma‐prone families from three continents 
Journal of Medical Genetics  2006;44(2):99-106.
Background
The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer.
Methods
These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents.
Results
Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk.
Conclusions
The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.
doi:10.1136/jmg.2006.043802
PMCID: PMC2598064  PMID: 16905682
melanoma;  CDKN2A ; multiple primary melanomas; pancreatic cancer
17.  Genome-wide association study identifies three loci associated with melanoma risk 
Nature genetics  2009;41(8):920-925.
We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317k tagging SNPs for 1650 genetically-enriched cases (from Europe and Australia) and 4336 controls and subsequent replication in 1149 genetically-enriched cases and 964 controls and a population-based case-control study of 1163 cases and 903 controls. The genome-wide screen identified five regions with genotyped or imputed SNPs reaching p < 5×10−7; three regions were replicated: 16q24 encompassing MC1R (overall p=2.54×10−27 for rs258322), 11q14-q21 encompassing TYR (p=2.41×10−14 for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (p=4.03×10−7 for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognised melanoma risk factors, while the 9p21 locus is novel for common variants associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and contribute independently to melanoma risk.
doi:10.1038/ng.411
PMCID: PMC2741419  PMID: 19578364
18.  Common sequence variants on 20q11.22 confer melanoma susceptibility 
Nature genetics  2008;40(7):838-840.
We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totalling 2019 cases and 2105 controls. Using pooling we identified a novel melanoma risk locus on chromosome 20 (rs910873, rs1885120), with replication in two further samples (combined P <1 × 10-15). The odds ratio is 1.75 (1.53, 2.01), with evidence for stronger association in early onset cases.
doi:10.1038/ng.163
PMCID: PMC2755512  PMID: 18488026
19.  A comparison of CDKN2A mutation detection within the Melanoma Genetics Consortium (GenoMEL) 
CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by “blind” exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing. Three samples with mutations identified at local centres were not detected by the DHPLC screen. No additional mutations were detected by DHPLC. Mutation detection across groups within GenoMEL is carried out to a consistently high standard. The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes.
doi:10.1016/j.ejca.2008.03.005
PMCID: PMC2494985  PMID: 18394881
CDKN2A; melanoma; mutation detection; sequencing; polymorphism; audit; DHPLC; False negative
20.  Inherited variants in the MC1R gene and survival from cutaneous melanoma: a BioGenoMEL study 
Pigment Cell & Melanoma Research  2012;25(3):384-394.
Summary
Inherited MC1R variants modulate MITF transcription factor signaling, which in turn affects tumor cell proliferation, apoptosis, and DNA repair. The aim of this BioGenoMEL collaborative study in 10 melanoma cohorts was to test the hypothesis that inherited variants thereby moderate survival expectation. A survival analysis in the largest cohort (Leeds) was carried out adjusting for factors known to impact on survival. The results were then compared with data from nine smaller cohorts. The absence of any consensus MC1R alleles was associated with a significantly lower risk of death in the Leeds set (HR, 0.64; 95% CI, 0.46–0.89) and overall in the 10 data sets (HR, 0.78; 95% CI, 0.65–0.94) with some support from the nine smaller data sets considered together (HR, 0.83; 95% CI, 0.67–1.04). The data are suggestive of a survival benefit for inherited MC1R variants in melanoma patients.
doi:10.1111/j.1755-148X.2012.00982.x
PMCID: PMC3490389  PMID: 22325793
MC1R; survival analysis; MITF; melanoma; forest plot
21.  Role of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters 
Experimental Dermatology  2013;22(7):494-496.
Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P = 0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P = 0.012) and IL-1B (P = 0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions.
doi:10.1111/exd.12177
PMCID: PMC3748792  PMID: 23800065
actinic keratoses; CPI-17; cutaneous field of cancerization; expression array; PPP1R14A
22.  An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study 
Pigment Cell & Melanoma Research  2013;27(2):234-243.
An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma-specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization.
doi:10.1111/pcmr.12193
PMCID: PMC4065372  PMID: 24219834
vitamin D; melanoma; survival analysis; mendelian randomization; GC
23.  Inherited variation in the PARP1 gene and survival from melanoma 
We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04–1.28, p = 0.005, eleven cohorts) and MSS (HR = 1.20 per allele, 95% CI 1.01–1.39, p = 0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS.
What's New?
Although staging systems predict outcome fairly well for melanoma, survival still varies among individual patients. In this meta-analysis, the authors found that inheritance of a rare genetic variant of PARP1 was associated with improved survival of melanoma patients. Increased expression of PARP1 has been associated with poorer outcome, and depletion of PARP1 may reduce both melanoma growth and angiogenesis. The identification of this and other germline variants that affect survival may help to identify key biological pathways active in host/tumor interactions, which may lead to the discovery of new therapeutic targets for treating advanced melanoma.
doi:10.1002/ijc.28796
PMCID: PMC4106984  PMID: 24535833
melanoma; survival; PARP1; genetic determinants of survival; random effects meta-analysis; bioinformatics

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