Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

Nicholas J Taylor; Nandita Mitra; Alisa M Goldstein; Margaret A Tucker; Marie-Françoise Avril; Esther Azizi; Wilma Bergman; D Timothy Bishop; Brigitte Bressac-de Paillerets; William Bruno; Donato Calista; Lisa A Cannon-Albright; Francisco Cuellar; Anne E Cust; Florence Demenais; David E Elder; Anne-Marie Gerdes; Paola Ghiorzo; Thais C Grazziotin; Johan Hansson; Mark Harland; Nicholas K Hayward; Marko Hocevar; Veronica Höiom; Christian Ingvar; Maria Teresa Landi; Gilles Landman; Alejandra Larre-Borges; Sancy A Leachman; Graham J Mann; Eduardo Nagore; Håkan Olsson; Jane M Palmer; Barbara Perić; Dace Pjanova; Antonia Pritchard; Susana Puig; Nienke van der Stoep; Karin A W Wadt; Linda Whitaker; Xiaohong R Yang; Julia A Newton Bishop; Nelleke A Gruis; Peter A Kanetsky; GenoMEL Study Group

doi:10.1016/j.jid.2017.07.829

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

Nicholas J Taylor, Nandita Mitra, Alisa M Goldstein, Margaret A Tucker, Marie-Françoise Avril, Esther Azizi, Wilma Bergman, D Timothy Bishop, Brigitte Bressac-de Paillerets, William Bruno, Donato Calista, Lisa A Cannon-Albright, Francisco Cuellar, Anne E Cust, Florence Demenais, David E Elder, Anne-Marie Gerdes, Paola Ghiorzo, Thais C Grazziotin, Johan HanssonMark Harland, Nicholas K Hayward, Marko Hocevar, Veronica Höiom, Christian Ingvar, Maria Teresa Landi, Gilles Landman, Alejandra Larre-Borges, Sancy A Leachman, Graham J Mann, Eduardo Nagore, Håkan Olsson, Jane M Palmer, Barbara Perić, Dace Pjanova, Antonia Pritchard, Susana Puig, Nienke van der Stoep, Karin A W Wadt, Linda Whitaker, Xiaohong R Yang, Julia A Newton Bishop, Nelleke A Gruis, Peter A Kanetsky, GenoMEL Study Group

Department of Clinical Medicine

9 Citations (Scopus)

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.

Original language	English
Journal	The Journal of Investigative Dermatology
Volume	137
Issue number	12
Pages (from-to)	2606-2612
Number of pages	7
ISSN	0022-202X
DOIs	https://doi.org/10.1016/j.jid.2017.07.829
Publication status	Published - Dec 2017

Keywords

Cyclin-Dependent Kinase Inhibitor p18/genetics
DNA Mutational Analysis
Family Health
Female
Genotype
Germ-Line Mutation
Humans
Male
Melanoma/genetics
Nevus/genetics
Nevus, Pigmented/genetics
Odds Ratio
Phenotype
Registries
Skin Neoplasms/genetics

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Taylor, N. J., Mitra, N., Goldstein, A. M., Tucker, M. A., Avril, M.-F., Azizi, E., Bergman, W., Bishop, D. T., Bressac-de Paillerets, B., Bruno, W., Calista, D., Cannon-Albright, L. A., Cuellar, F., Cust, A. E., Demenais, F., Elder, D. E., Gerdes, A.-M., Ghiorzo, P., Grazziotin, T. C., ... GenoMEL Study Group (2017). Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families. The Journal of Investigative Dermatology, 137(12), 2606-2612. https://doi.org/10.1016/j.jid.2017.07.829

Taylor, NJ, Mitra, N, Goldstein, AM, Tucker, MA, Avril, M-F, Azizi, E, Bergman, W, Bishop, DT, Bressac-de Paillerets, B, Bruno, W, Calista, D, Cannon-Albright, LA, Cuellar, F, Cust, AE, Demenais, F, Elder, DE, Gerdes, A-M, Ghiorzo, P, Grazziotin, TC, Hansson, J, Harland, M, Hayward, NK, Hocevar, M, Höiom, V, Ingvar, C, Landi, MT, Landman, G, Larre-Borges, A, Leachman, SA, Mann, GJ, Nagore, E, Olsson, H, Palmer, JM, Perić, B, Pjanova, D, Pritchard, A, Puig, S, van der Stoep, N, Wadt, KAW, Whitaker, L, Yang, XR, Newton Bishop, JA, Gruis, NA, Kanetsky, PA & GenoMEL Study Group 2017, 'Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families', The Journal of Investigative Dermatology, vol. 137, no. 12, pp. 2606-2612. https://doi.org/10.1016/j.jid.2017.07.829

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title = "Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families",

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.",

keywords = "Cyclin-Dependent Kinase Inhibitor p18/genetics, DNA Mutational Analysis, Family Health, Female, Genotype, Germ-Line Mutation, Humans, Male, Melanoma/genetics, Nevus/genetics, Nevus, Pigmented/genetics, Odds Ratio, Phenotype, Registries, Skin Neoplasms/genetics",

author = "Taylor, {Nicholas J} and Nandita Mitra and Goldstein, {Alisa M} and Tucker, {Margaret A} and Marie-Fran{\c c}oise Avril and Esther Azizi and Wilma Bergman and Bishop, {D Timothy} and {Bressac-de Paillerets}, Brigitte and William Bruno and Donato Calista and Cannon-Albright, {Lisa A} and Francisco Cuellar and Cust, {Anne E} and Florence Demenais and Elder, {David E} and Anne-Marie Gerdes and Paola Ghiorzo and Grazziotin, {Thais C} and Johan Hansson and Mark Harland and Hayward, {Nicholas K} and Marko Hocevar and Veronica H{\"o}iom and Christian Ingvar and Landi, {Maria Teresa} and Gilles Landman and Alejandra Larre-Borges and Leachman, {Sancy A} and Mann, {Graham J} and Eduardo Nagore and H{\aa}kan Olsson and Palmer, {Jane M} and Barbara Peri{\'c} and Dace Pjanova and Antonia Pritchard and Susana Puig and {van der Stoep}, Nienke and Wadt, {Karin A W} and Linda Whitaker and Yang, {Xiaohong R} and {Newton Bishop}, {Julia A} and Gruis, {Nelleke A} and Kanetsky, {Peter A} and {GenoMEL Study Group}",

year = "2017",

month = dec,

doi = "10.1016/j.jid.2017.07.829",

language = "English",

volume = "137",

pages = "2606--2612",

journal = "The Journal of Investigative Dermatology",

issn = "0022-202X",

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TY - JOUR

T1 - Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

AU - Taylor, Nicholas J

AU - Mitra, Nandita

AU - Goldstein, Alisa M

AU - Tucker, Margaret A

AU - Avril, Marie-Françoise

AU - Azizi, Esther

AU - Bergman, Wilma

AU - Bishop, D Timothy

AU - Bressac-de Paillerets, Brigitte

AU - Bruno, William

AU - Calista, Donato

AU - Cannon-Albright, Lisa A

AU - Cuellar, Francisco

AU - Cust, Anne E

AU - Demenais, Florence

AU - Elder, David E

AU - Gerdes, Anne-Marie

AU - Ghiorzo, Paola

AU - Grazziotin, Thais C

AU - Hansson, Johan

AU - Harland, Mark

AU - Hayward, Nicholas K

AU - Hocevar, Marko

AU - Höiom, Veronica

AU - Ingvar, Christian

AU - Landi, Maria Teresa

AU - Landman, Gilles

AU - Larre-Borges, Alejandra

AU - Leachman, Sancy A

AU - Mann, Graham J

AU - Nagore, Eduardo

AU - Olsson, Håkan

AU - Palmer, Jane M

AU - Perić, Barbara

AU - Pjanova, Dace

AU - Pritchard, Antonia

AU - Puig, Susana

AU - van der Stoep, Nienke

AU - Wadt, Karin A W

AU - Whitaker, Linda

AU - Yang, Xiaohong R

AU - Newton Bishop, Julia A

AU - Gruis, Nelleke A

AU - Kanetsky, Peter A

AU - GenoMEL Study Group

PY - 2017/12

Y1 - 2017/12

N2 - 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.

AB - 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.

KW - Cyclin-Dependent Kinase Inhibitor p18/genetics

KW - DNA Mutational Analysis

KW - Family Health

KW - Female

KW - Genotype

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - Melanoma/genetics

KW - Nevus/genetics

KW - Nevus, Pigmented/genetics

KW - Odds Ratio

KW - Phenotype

KW - Registries

KW - Skin Neoplasms/genetics

U2 - 10.1016/j.jid.2017.07.829

DO - 10.1016/j.jid.2017.07.829

M3 - Journal article

C2 - 28830827

SN - 0022-202X

VL - 137

SP - 2606

EP - 2612

JO - The Journal of Investigative Dermatology

JF - The Journal of Investigative Dermatology

IS - 12

ER -

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

Abstract

Keywords

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