|Grant Number:||5R01CA083115-10 Interpret this number|
|Primary Investigator:||Elder, David|
|Organization:||University Of Pennsylvania|
|Project Title:||Genetic Epidemiology of Melanoma|
DESCRIPTION (provided by applicant): During the present funding cycle (09/01/01 to 08/31/06) we, GenoMEL, characterized the major effects of the known high penetrance melanoma susceptibility genes (cyclin dependent kinase [CDK] inhibitor 2A [CDKN2A] and CDK4) and increased understanding of interactions with lower penetrance genes, in particular MC1R. We also collected extensive data relating to geographic, environmental and phenotypic interactions. GenoMEL (www.genomel.org) was created in 1997; it brought together on an informal basis for exchange and promotion of melanoma science numerous international research groups interested in understanding the genetics of familial melanoma. In September 2001, funding was obtained from the NCI (this R01 CA83115) that served to underpin the fledgling, cooperative group. A successful application to the European Union for a Network of Excellence (NoE) "Framework 6" grant has ensured the viability of a considerably enlarged consortium by funding its administration and core data collection; as a result we have grown in effectiveness and size, with the recruitment of new participant groups in Utah, Toronto, Tel Aviv, Latvia, Poland, Slovenia and Queensland. This application for competitive renewal of the R01 will utilize the support of the members of GenoMEL and the European-based infrastructure established by the NoE funds to efficiently extend our exploration of the biological basis of susceptibility to melanoma and its application to risk assessment. This application will also support a large scale screening for identification of new high penetrance melanoma susceptibility genes. This application has two overarching objectives: Aim 1 is to determine the precise contribution of the CDKN2A locus to familial aggregation of melanoma and other cancers, and to develop tools which will enable clinicians to translate this information for use in counseling the population. We hypothesize that the prevalence and penetrance of CDKN2A mutations will vary strongly by region, by population, by population incidence, by the number and type of cancers in close relatives, and by covariates such as ethnicity, skin type, nevus phenotypes and sun exposure. Further, we hypothesize that specific classes of CDKN2A mutations differentially affect risk of melanoma, pancreatic and other cancers, as well as important intermediate phenotypes such as nevus count. We also hypothesize that current estimates of these parameters require validation because of concerns with respect to the effect of ascertainment; Aim 2 is to identify novel high-penetrance melanoma susceptibility genes. We hypothesize that other high penetrance melanoma susceptibility genes exist and that these encode members of the p16/CDK4/pRb and p14/MDM2/p53 pathways that have been previously implicated in melanoma susceptibility. Identification of additional high penetrance genes is important because our research to date has shown that 50% of families with 3+ cases of melanoma do not have mutations in CDKN2A and CDK4.
Histologic features of melanoma associated with CDKN2A genotype.
Authors: Sargen MR, Kanetsky PA, Newton-Bishop J, Hayward NK, Mann GJ, Gruis NA, Tucker MA, Goldstein AM, Bianchi-Scarra G, Puig S, Elder DE
Source: J Am Acad Dermatol, 2015 Mar;72(3), p. 496-507.e7.
EPub date: 2015 Jan 13.
The effect on melanoma risk of genes previously associated with telomere length.
Authors: Iles MM, Bishop DT, Taylor JC, Hayward NK, Brossard M, Cust AE, Dunning AM, Lee JE, Moses EK, Akslen LA, AMFS Investigators, Andresen PA, Avril MF, Azizi E, Scarrà GB, Brown KM, D?bniak T, Elder DE, Friedman E, Ghiorzo P, Gillanders EM, Goldstein AM, Gruis NA, Hansson J, Harland M, Helsing P, Ho?evar M, Höiom V, IBD investigators, Ingvar C, Kanetsky PA, Landi MT, Lang J, Lathrop GM, Lubi?ski J, Mackie RM, Martin NG, Molven A, Montgomery GW, Novakovi? S, Olsson H, Puig S, Puig-Butille JA, QMEGA and QTWIN Investigators, Radford-Smith GL, Randerson-Moor J, SDH Study Group, van der Stoep N, van Doorn R, Whiteman DC, MacGregor S, Pooley KA, Ward SV, Mann GJ, Amos CI, Pharoah PD, Demenais F, Law MH, Newton Bishop JA, Barrett JH, GenoMEL Consortium
Source: J Natl Cancer Inst, 2014 Oct;106(10), p. null.
EPub date: 2014 Sep 17.
The clinicopathological and gene expression patterns associated with ulceration of primary melanoma.
Authors: Jewell R, Elliott F, Laye J, Nsengimana J, Davies J, Walker C, Conway C, Mitra A, Harland M, Cook MG, Boon A, Storr S, Safuan S, Martin SG, Jirström K, Olsson H, Ingvar C, Lauss M, Bishop T, Jönsson G, Newton-Bishop J
Source: Pigment Cell Melanoma Res, 2015 Jan;28(1), p. 94-104.
EPub date: 2014 Oct 1.
TERT gene amplification is associated with poor outcome in acral lentiginous melanoma.
Authors: Diaz A, Puig-Butillé JA, Muñoz C, Costa D, Díez A, Garcia-Herrera A, Carrera C, Badenas C, Solé F, Malvehy J, Puig S, Alos L
Source: J Am Acad Dermatol, 2014 Oct;71(4), p. 839-41.
TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma.
Authors: Griewank KG, Murali R, Puig-Butille JA, Schilling B, Livingstone E, Potrony M, Carrera C, Schimming T, Möller I, Schwamborn M, Sucker A, Hillen U, Badenas C, Malvehy J, Zimmer L, Scherag A, Puig S, Schadendorf D
Source: J Natl Cancer Inst, 2014 Sep;106(9), p. null.
EPub date: 2014 Sep 13.
Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions.
Authors: Barrett JH, Taylor JC, Bright C, Harland M, Dunning AM, Akslen LA, Andresen PA, Avril MF, Azizi E, Bianchi Scarrà G, Brossard M, Brown KM, D?bniak T, Elder DE, Friedman E, Ghiorzo P, Gillanders EM, Gruis NA, Hansson J, Helsing P, Ho?evar M, Höiom V, Ingvar C, Landi MT, Lang J, Lathrop GM, Lubi?ski J, Mackie RM, Molven A, Novakovi? S, Olsson H, Puig S, Puig-Butille JA, van der Stoep N, van Doorn R, van Workum W, Goldstein AM, Kanetsky PA, Pharoah PD, Demenais F, Hayward NK, Newton Bishop JA, Bishop DT, Iles MM, GenoMEL Consortium
Source: Int J Cancer, 2015 Mar 15;136(6), p. 1351-60.
EPub date: 2014 Aug 14.
Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling.
Authors: Potrony M, Puig-Butillé JA, Aguilera P, Badenas C, Carrera C, Malvehy J, Puig S
Source: J Am Acad Dermatol, 2014 Nov;71(5), p. 888-95.
EPub date: 2014 Jul 24.
Targeting human apurinic/apyrimidinic endonuclease 1 (APE1) in phosphatase and tensin homolog (PTEN) deficient melanoma cells for personalized therapy.
Authors: Abbotts R, Jewell R, Nsengimana J, Maloney DJ, Simeonov A, Seedhouse C, Elliott F, Laye J, Walker C, Jadhav A, Grabowska A, Ball G, Patel PM, Newton-Bishop J, Wilson DM 3rd, Madhusudan S
Source: Oncotarget, 2014 May 30;5(10), p. 3273-86.
Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer.
Authors: Puig-Butille JA, Escámez MJ, Garcia-Garcia F, Tell-Marti G, Fabra À, Martínez-Santamaría L, Badenas C, Aguilera P, Pevida M, Dopazo J, del Río M, Puig S
Source: Oncotarget, 2014 Mar 30;5(6), p. 1439-51.
In vivo reflectance confocal microscopy to monitor the response of lentigo maligna to imiquimod.
Authors: Alarcon I, Carrera C, Alos L, Palou J, Malvehy J, Puig S
Source: J Am Acad Dermatol, 2014 Jul;71(1), p. 49-55.
EPub date: 2014 Apr 13.
Inherited variation in the PARP1 gene and survival from melanoma.
Authors: Davies JR, Jewell R, Affleck P, Anic GM, Randerson-Moor J, Ozola A, Egan KM, Elliott F, García-Casado Z, Hansson J, Harland M, Höiom V, Jian G, Jönsson G, Kumar R, Nagore E, Wendt J, Olsson H, Park JY, Patel P, Pjanova D, Puig S, Schadendorf D, Sivaramakrishna Rachakonda P, Snowden H, Stratigos AJ, Bafaloukos D, Ogbah Z, Sucker A, Van den Oord JJ, Van Doorn R, Walker C, Okamoto I, Wolter P, Barrett JH, Timothy Bishop D, Newton-Bishop J
Source: Int J Cancer, 2014 Oct 1;135(7), p. 1625-33.
EPub date: 2014 Mar 6.
An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study.
Authors: Davies JR, Field S, Randerson-Moor J, Harland M, Kumar R, Anic GM, Nagore E, Hansson J, Höiom V, Jönsson G, Gruis NA, Park JY, Guan J, Sivaramakrishna Rachakonda P, Wendt J, Pjanova D, Puig S, Schadendorf D, Okamoto I, Olsson H, Affleck P, García-Casado Z, Puig-Butille JA, Stratigos AJ, Kodela E, Donina S, Sucker A, Hosen I, Egan KM, Barrett JH, van Doorn R, Bishop DT, Newton-Bishop J
Source: Pigment Cell Melanoma Res, 2014 Mar;27(2), p. 234-43.
EPub date: 2013 Dec 11.
Impact of in vivo reflectance confocal microscopy on the number needed to treat melanoma in doubtful lesions.
Authors: Alarcon I, Carrera C, Palou J, Alos L, Malvehy J, Puig S
Source: Br J Dermatol, 2014 Apr;170(4), p. 802-8.
Surveillance of second-degree relatives from melanoma families with a CDKN2A germline mutation.
Authors: van der Rhee JI, Boonk SE, Putter H, Cannegieter SC, Flinterman LE, Hes FJ, de Snoo FA, Mooi WJ, Gruis NA, Vasen HF, Kukutsch NA, Bergman W
Source: Cancer Epidemiol Biomarkers Prev, 2013 Oct;22(10), p. 1771-7.
EPub date: 2013 Jul 29.
Green colour as a novel dermoscopic finding in the diagnosis of haemosiderotic dermatofibroma.
Authors: Roldán-Marín R, Barreiro-Capurro A, García-Herrera A, Puig S, Alarcón-Salazar I, Carrera C, Malvehy J
Source: Australas J Dermatol, 2014 Aug;55(3), p. 196-7.
EPub date: 2013 Jul 19.
Distribution of MC1R variants among melanoma subtypes: p.R163Q is associated with lentigo maligna melanoma in a Mediterranean population.
Authors: Puig-Butillé JA, Carrera C, Kumar R, Garcia-Casado Z, Badenas C, Aguilera P, Malvehy J, Nagore E, Puig S
Source: Br J Dermatol, 2013 Oct;169(4), p. 804-11.
Dermoscopic patterns of melanoma metastases: interobserver consistency and accuracy for metastasis recognition.
Authors: Costa J, Ortiz-Ibañez K, Salerni G, Borges V, Carrera C, Puig S, Malvehy J
Source: Br J Dermatol, 2013 Jul;169(1), p. 91-9.
A variant in FTO shows association with melanoma risk not due to BMI.
Authors: Iles MM, Law MH, Stacey SN, Han J, Fang S, Pfeiffer R, Harland M, Macgregor S, Taylor JC, Aben KK, Akslen LA, Avril MF, Azizi E, Bakker B, Benediktsdottir KR, Bergman W, Scarrà GB, Brown KM, Calista D, Chaudru V, Fargnoli MC, Cust AE, Demenais F, de Waal AC, D?bniak T, Elder DE, Friedman E, Galan P, Ghiorzo P, Gillanders EM, Goldstein AM, Gruis NA, Hansson J, Helsing P, Ho?evar M, Höiom V, Hopper JL, Ingvar C, Janssen M, Jenkins MA, Kanetsky PA, Kiemeney LA, Lang J, Lathrop GM, Leachman S, Lee JE, Lubi?ski J, Mackie RM, Mann GJ, Martin NG, Mayordomo JI, Molven A, Mulder S, Nagore E, Novakovi? S, Okamoto I, Olafsson JH, Olsson H, Pehamberger H, Peris K, Grasa MP, Planelles D, Puig S, Puig-Butille JA, Randerson-Moor J, Requena C, Rivoltini L, Rodolfo M, Santinami M, Sigurgeirsson B, Snowden H, Song F, Sulem P, Thorisdottir K, Tuominen R, Van Belle P, van der Stoep N, van Rossum MM, Wei Q, Wendt J, Zelenika D, Zhang M, Landi MT, Thorleifsson G, Bishop DT, Amos CI, Hayward NK, Stefansson K, Bishop JA, Barrett JH, GenoMEL Consortium, Q-MEGA and AMFS Investigators
Source: Nat Genet, 2013 Apr;45(4), p. 428-32, 432e1.
EPub date: 2013 Mar 3.
Serum 25-hydroxyvitamin D3 levels and vitamin D receptor variants in melanoma patients from the Mediterranean area of Barcelona.
Authors: Ogbah Z, Visa L, Badenas C, Ríos J, Puig-Butille JA, Bonifaci N, Guino E, Augé JM, Kolm I, Carrera C, Pujana MÁ, Malvehy J, Puig S
Source: BMC Med Genet, 2013 Feb 16;14, p. 26.
EPub date: 2013 Feb 16.
Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants.
Authors: Puntervoll HE, Yang XR, Vetti HH, Bachmann IM, Avril MF, Benfodda M, Catricalà C, Dalle S, Duval-Modeste AB, Ghiorzo P, Grammatico P, Harland M, Hayward NK, Hu HH, Jouary T, Martin-Denavit T, Ozola A, Palmer JM, Pastorino L, Pjanova D, Soufir N, Steine SJ, Stratigos AJ, Thomas L, Tinat J, Tsao H, Veinalde R, Tucker MA, Bressac-de Paillerets B, Newton-Bishop JA, Goldstein AM, Akslen LA, Molven A
Source: J Med Genet, 2013 Apr;50(4), p. 264-70.
EPub date: 2013 Feb 5.
Genetic alterations in RAS-regulated pathway in acral lentiginous melanoma.
Authors: Puig-Butillé JA, Badenas C, Ogbah Z, Carrera C, Aguilera P, Malvehy J, Puig S
Source: Exp Dermatol, 2013 Feb;22(2), p. 148-50.