MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.

BACKGROUND: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. METHODS: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. FINDINGS: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. INTERPRETATION: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies. FUNDING: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831

Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial.

The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P < 0.001) and exon skipping (28.9-fold; P < 0.001). At 3 years, 6MWT change from baseline was -99.0 m for golodirsen-treated patients versus -181.4 m for external controls (P = 0.067), and loss of ambulation occurred in 9% versus 26% (P = 0.21). FVC%p declined 8.4% over 3 years in golodirsen-treated patients, comparing favorably with literature-reported rates. This study provides evidence for golodirsen biologic activity and long-term safety in a declining DMD population and suggests functional benefit versus external controls. Clinical Trial Registration number: NCT02310906

Melanocortin-1receptor, skincancer and phenotypic characteristics (MSKIP) project: study design and methods for pooling results of genetic epidemiological studies.

Raimondi, Sara Gandini, Sara Fargnoli, Maria Concetta Bagnardi, Vincenzo Maisonneuve, Patrick Specchia, Claudia Kumar, Rajiv Nagore, Eduardo Han, Jiali Hansson, Johan Kanetsky, Peter A Ghiorzo, Paola Gruis, Nelleke A Dwyer, Terry Blizzard, Leigh Fernandez-de-Misa, Ricardo Branicki, Wojciech Debniak, Tadeusz Morling, Niels Landi, Maria Teresa Palmieri, Giuseppe Ribas, Gloria Stratigos, Alexander Cornelius, Lynn Motokawa, Tomonori Anno, Sumiko Helsing, Per Wong, Terence H Autier, Philippe Garcia-Borron, Jose C Little, Julian Newton-Bishop, Julia Sera, Francesco Liu, Fan Kayser, Manfred Nijsten, Tamar eng CA112243-05 S1/CA/NCI NIH HHS/ R01 CA112243/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2012/08/07 06:00 BMC Med Res Methodol. 2012 Aug 3;12:116. doi: 10.1186/1471-2288-12-116.International audienceBACKGROUND: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. DESIGN AND METHODS: Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling. DISCUSSION: Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort

Background Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. Methods In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. Findings We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02–2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06–3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05–2·44; p=0·04) and Asp294His (2·15, 1·05–4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. Interpretation Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies.</p

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.

BACKGROUND: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls. METHODS: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger. FINDINGS: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1\ub754, 95% CI 1\ub702-2\ub733), including when analysis was restricted to patients aged 18 years or younger (1\ub780, 1\ub706-3\ub707). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1\ub760, 95% CI 1\ub705-2\ub744; p=0\ub704) and Asp294His (2\ub715, 1\ub705-4\ub740; p=0\ub704). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants. INTERPRETATION: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies

MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project

BACKGROUND: The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics. METHODS: Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses. RESULTS: Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair. CONCLUSIONS: Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype

MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: A pooled-analysis from the M-SKIP project

The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a summary odds ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random-effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17-1.84) for V60L to 2.74 (1.53-4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared with wildtype subjects (SOR; 95%CI: 1.66; 1.41-1.96) and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R-associated melanoma risk increased only for darker-pigmented Caucasians: SOR (95%CI) was 3.14 (2.06-4.80) for subjects with no freckles, no red hair and skin Type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker-pigmented Caucasians with MC1R variants as well as to lightly pigmented, fairskinned subjects. © 2014 UICC

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort

149nonenonePellegrini C.; Botta F.; Massi D.; Martorelli C.; Facchetti F.; Gandini S.; Maisonneuve P.; Avril M.-F.; Demenais F.; Bressac-de Paillerets B.; Hoiom V.; Cust A.E.; Anton-Culver H.; Gruber S.B.; Gallagher R.P.; Marrett L.; Zanetti R.; Dwyer T.; Thomas N.E.; Begg C.B.; Berwick M.; Puig S.; Potrony M.; Nagore E.; Ghiorzo P.; Menin C.; Manganoni A.M.; Rodolfo M.; Brugnara S.; Passoni E.; Sekulovic L.K.; Baldini F.; Guida G.; Stratigos A.; Ozdemir F.; Ayala F.; Fernandez-de-Misa R.; Quaglino P.; Ribas G.; Romanini A.; Migliano E.; Stanganelli I.; Kanetsky P.A.; Pizzichetta M.A.; Garcia-Borron J.C.; Nan H.; Landi M.T.; Little J.; Newton-Bishop J.; Sera F.; Fargnoli M.C.; Raimondi S.; Alaibac M.; Ferrari A.; Valeri B.; Sicher M.; Mangiola D.; Nazzaro G.; Tosti G.; Mazzarol G.; Giudice G.; Ribero S.; Astrua C.; Mazzoni L.; Orlow I.; Mujumdar U.; Hummer A.; Busam K.; Roy P.; Canchola R.; Clas B.; Cotignola J.; Monroe Y.; Armstrong B.; Kricker A.; Litchfield M.; Tucker P.; Stephens N.; Switzer T.; Theis B.; From L.; Chowdhury N.; Vanasse L.; Purdue M.; Northrup D.; Rosso S.; Sacerdote C.; Leighton N.; Gildea M.; Bonner J.; Jeter J.; Klotz J.; Wilcox H.; Weiss H.; Millikan R.; Mattingly D.; Player J.; Tse C.-K.; Rebbeck T.; Walker A.; Panossian S.; Setlow R.; Mohrenweiser H.; Autier P.; Han J.; Caini S.; Hofman A.; Kayser M.; Liu F.; Nijsten T.; Uitterlinden A.G.; Kumar R.; Bishop T.; Elliott F.; Lazovich D.; Polsky D.; Hansson J.; Pastorino L.; Gruis N.A.; Bouwes Bavinck J.N.; Aguilera P.; Badenas C.; Carrera C.; Gimenez-Xavier P.; Malvehy J.; Puig-Butille J.A.; Tell-Marti G.; Blizzard L.; Cochrane J.; Branicki W.; Debniak T.; Morling N.; Johansen P.; Mayne S.; Bale A.; Cartmel B.; Ferrucci L.; Pfeiffer R.; Palmieri G.; Kypreou K.; Bowcock A.; Cornelius L.; Council M.L.; Motokawa T.; Anno S.; Helsing P.; Andresen P.A.; Guida S.; Wong T.H.Pellegrini, C.; Botta, F.; Massi, D.; Martorelli, C.; Facchetti, F.; Gandini, S.; Maisonneuve, P.; Avril, M. -F.; Demenais, F.; Bressac-de Paillerets, B.; Hoiom, V.; Cust, A. E.; Anton-Culver, H.; Gruber, S. B.; Gallagher, R. P.; Marrett, L.; Zanetti, R.; Dwyer, T.; Thomas, N. E.; Begg, C. B.; Berwick, M.; Puig, S.; Potrony, M.; Nagore, E.; Ghiorzo, P.; Menin, C.; Manganoni, A. M.; Rodolfo, M.; Brugnara, S.; Passoni, E.; Sekulovic, L. K.; Baldini, F.; Guida, G.; Stratigos, A.; Ozdemir, F.; Ayala, F.; Fernandez-de-Misa, R.; Quaglino, P.; Ribas, G.; Romanini, A.; Migliano, E.; Stanganelli, I.; Kanetsky, P. A.; Pizzichetta, M. A.; Garcia-Borron, J. C.; Nan, H.; Landi, M. T.; Little, J.; Newton-Bishop, J.; Sera, F.; Fargnoli, M. C.; Raimondi, S.; Alaibac, M.; Ferrari, A.; Valeri, B.; Sicher, M.; Mangiola, D.; Nazzaro, G.; Tosti, G.; Mazzarol, G.; Giudice, G.; Ribero, S.; Astrua, C.; Mazzoni, L.; Orlow, I.; Mujumdar, U.; Hummer, A.; Busam, K.; Roy, P.; Canchola, R.; Clas, B.; Cotignola, J.; Monroe, Y.; Armstrong, B.; Kricker, A.; Litchfield, M.; Tucker, P.; Stephens, N.; Switzer, T.; Theis, B.; From, L.; Chowdhury, N.; Vanasse, L.; Purdue, M.; Northrup, D.; Rosso, S.; Sacerdote, C.; Leighton, N.; Gildea, M.; Bonner, J.; Jeter, J.; Klotz, J.; Wilcox, H.; Weiss, H.; Millikan, R.; Mattingly, D.; Player, J.; Tse, C. -K.; Rebbeck, T.; Walker, A.; Panossian, S.; Setlow, R.; Mohrenweiser, H.; Autier, P.; Han, J.; Caini, S.; Hofman, A.; Kayser, M.; Liu, F.; Nijsten, T.; Uitterlinden, A. G.; Kumar, R.; Bishop, T.; Elliott, F.; Lazovich, D.; Polsky, D.; Hansson, J.; Pastorino, L.; Gruis, N. A.; Bouwes Bavinck, J. N.; Aguilera, P.; Badenas, C.; Carrera, C.; Gimenez-Xavier, P.; Malvehy, J.; Puig-Butille, J. A.; Tell-Marti, G.; Blizzard, L.; Cochrane, J.; Branicki, W.; Debniak, T.; Morling, N.; Johansen, P.; Mayne, S.; Bale, A.; Cartmel, B.; Ferrucci, L.; Pfeiffer, R.; Palmieri, G.; Kypreou, K.; Bowcock, A.; Cornelius, L.; Council, M. L.; Motokawa, T.; Anno, S.; Helsing, P.; Andresen, P. A.; Guida, S.; Wong, T. H