Features associated with germline CDKN2A mutations

A GenoMEL study of melanoma-prone families from three continents

Alisa M. Goldstein, May Chan, Mark Harland, Nicholas K. Hayward, Florence Demenais, D. Timothy Bishop, Esther Azizi, Wilma Bergman, Giovanna Bianchi-Scarra, William Bruno, Donato Calista, Lisa A. Cannon Albright, Valerie Chaudru, Agnes Chompret, Francisco Cuellar, David E. Elder, Paola Ghiorzo, Elizabeth M. Gillanders, Nelleke A. Gruis, Johan Hansson & 69 others David Hogg, Elizabeth A. Holland, Peter A. Kanetsky, Richard F. Kefford, Maria Teresa Landi, Julie Lang, Sancy Leachman, Rona M. MacKie, Veronica Magnusson, Graham J. Mann, Julia Newton Bishop, Jane M. Palmer, Susana Puig, Joan A. Puig-Butille, Mitchell Stark, Hensin Tsao, Margaret A. Tucker, Linda Whitaker, Emanuel Yakobson, Christian Ingvar, Ake Borg, Johan Westerdahl, Anna Masback, Hakan Olsson, Josep Malvehy, Celia Badenas, Remedios Cervera, Rosa Martí, Joan Brunet-Vidal, Guang Yang, Nicholas Martin, David Whiteman, Adele Green, Joanne Aitken, Paola Minghetti, Michela Mantelli, Lorenza Pastorino, Sabina Nasti, Sara Gargiulo, Sara Gliori, Sushila Mistry, Juliette Randerson-Moor, Femke A. De Snoo, Jeanet A C Ter Huurne, Jasper Van Der Rhee, Leny Van Mourik, Frans Van Nieuwpoort, Clasine Van Der Drift, Brigitte Bressac-De Paillerets, Marie Francoise Avril, F. Grange, B. Sassolas, F. Boitier, J. Chevrant-Breton, C. Lasset, C. Dugast, P. Vabres, Arupa Ganguly, Michael Ming, Patricia Van Belle, Anton Platz, Suzanne Egyhazi, Rainer Tuominen, Diana Linden, Helen Schmid, Alon Scope, Felix Pavlotsky, Eitan Friedman, Mark Eliason

Research output: Contribution to journalArticle

232 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)99-106
Number of pages8
JournalJournal of Medical Genetics
Volume44
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

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Germ-Line Mutation
Melanoma
Mutation
Pancreatic Neoplasms
North America
Mutation Rate

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Goldstein, A. M., Chan, M., Harland, M., Hayward, N. K., Demenais, F., Bishop, D. T., ... Eliason, M. (2007). Features associated with germline CDKN2A mutations: A GenoMEL study of melanoma-prone families from three continents. Journal of Medical Genetics, 44(2), 99-106. https://doi.org/10.1136/jmg.2006.043802

Features associated with germline CDKN2A mutations : A GenoMEL study of melanoma-prone families from three continents. / Goldstein, Alisa M.; Chan, May; Harland, Mark; Hayward, Nicholas K.; Demenais, Florence; Bishop, D. Timothy; Azizi, Esther; Bergman, Wilma; Bianchi-Scarra, Giovanna; Bruno, William; Calista, Donato; Cannon Albright, Lisa A.; Chaudru, Valerie; Chompret, Agnes; Cuellar, Francisco; Elder, David E.; Ghiorzo, Paola; Gillanders, Elizabeth M.; Gruis, Nelleke A.; Hansson, Johan; Hogg, David; Holland, Elizabeth A.; Kanetsky, Peter A.; Kefford, Richard F.; Landi, Maria Teresa; Lang, Julie; Leachman, Sancy; MacKie, Rona M.; Magnusson, Veronica; Mann, Graham J.; Bishop, Julia Newton; Palmer, Jane M.; Puig, Susana; Puig-Butille, Joan A.; Stark, Mitchell; Tsao, Hensin; Tucker, Margaret A.; Whitaker, Linda; Yakobson, Emanuel; Ingvar, Christian; Borg, Ake; Westerdahl, Johan; Masback, Anna; Olsson, Hakan; Malvehy, Josep; Badenas, Celia; Cervera, Remedios; Martí, Rosa; Brunet-Vidal, Joan; Yang, Guang; Martin, Nicholas; Whiteman, David; Green, Adele; Aitken, Joanne; Minghetti, Paola; Mantelli, Michela; Pastorino, Lorenza; Nasti, Sabina; Gargiulo, Sara; Gliori, Sara; Mistry, Sushila; Randerson-Moor, Juliette; De Snoo, Femke A.; Ter Huurne, Jeanet A C; Van Der Rhee, Jasper; Van Mourik, Leny; Van Nieuwpoort, Frans; Van Der Drift, Clasine; Bressac-De Paillerets, Brigitte; Avril, Marie Francoise; Grange, F.; Sassolas, B.; Boitier, F.; Chevrant-Breton, J.; Lasset, C.; Dugast, C.; Vabres, P.; Ganguly, Arupa; Ming, Michael; Van Belle, Patricia; Platz, Anton; Egyhazi, Suzanne; Tuominen, Rainer; Linden, Diana; Schmid, Helen; Scope, Alon; Pavlotsky, Felix; Friedman, Eitan; Eliason, Mark.

In: Journal of Medical Genetics, Vol. 44, No. 2, 02.2007, p. 99-106.

Research output: Contribution to journalArticle

Goldstein, AM, Chan, M, Harland, M, Hayward, NK, Demenais, F, Bishop, DT, Azizi, E, Bergman, W, Bianchi-Scarra, G, Bruno, W, Calista, D, Cannon Albright, LA, Chaudru, V, Chompret, A, Cuellar, F, Elder, DE, Ghiorzo, P, Gillanders, EM, Gruis, NA, Hansson, J, Hogg, D, Holland, EA, Kanetsky, PA, Kefford, RF, Landi, MT, Lang, J, Leachman, S, MacKie, RM, Magnusson, V, Mann, GJ, Bishop, JN, Palmer, JM, Puig, S, Puig-Butille, JA, Stark, M, Tsao, H, Tucker, MA, Whitaker, L, Yakobson, E, Ingvar, C, Borg, A, Westerdahl, J, Masback, A, Olsson, H, Malvehy, J, Badenas, C, Cervera, R, Martí, R, Brunet-Vidal, J, Yang, G, Martin, N, Whiteman, D, Green, A, Aitken, J, Minghetti, P, Mantelli, M, Pastorino, L, Nasti, S, Gargiulo, S, Gliori, S, Mistry, S, Randerson-Moor, J, De Snoo, FA, Ter Huurne, JAC, Van Der Rhee, J, Van Mourik, L, Van Nieuwpoort, F, Van Der Drift, C, Bressac-De Paillerets, B, Avril, MF, Grange, F, Sassolas, B, Boitier, F, Chevrant-Breton, J, Lasset, C, Dugast, C, Vabres, P, Ganguly, A, Ming, M, Van Belle, P, Platz, A, Egyhazi, S, Tuominen, R, Linden, D, Schmid, H, Scope, A, Pavlotsky, F, Friedman, E & Eliason, M 2007, 'Features associated with germline CDKN2A mutations: A GenoMEL study of melanoma-prone families from three continents', Journal of Medical Genetics, vol. 44, no. 2, pp. 99-106. https://doi.org/10.1136/jmg.2006.043802
Goldstein, Alisa M. ; Chan, May ; Harland, Mark ; Hayward, Nicholas K. ; Demenais, Florence ; Bishop, D. Timothy ; Azizi, Esther ; Bergman, Wilma ; Bianchi-Scarra, Giovanna ; Bruno, William ; Calista, Donato ; Cannon Albright, Lisa A. ; Chaudru, Valerie ; Chompret, Agnes ; Cuellar, Francisco ; Elder, David E. ; Ghiorzo, Paola ; Gillanders, Elizabeth M. ; Gruis, Nelleke A. ; Hansson, Johan ; Hogg, David ; Holland, Elizabeth A. ; Kanetsky, Peter A. ; Kefford, Richard F. ; Landi, Maria Teresa ; Lang, Julie ; Leachman, Sancy ; MacKie, Rona M. ; Magnusson, Veronica ; Mann, Graham J. ; Bishop, Julia Newton ; Palmer, Jane M. ; Puig, Susana ; Puig-Butille, Joan A. ; Stark, Mitchell ; Tsao, Hensin ; Tucker, Margaret A. ; Whitaker, Linda ; Yakobson, Emanuel ; Ingvar, Christian ; Borg, Ake ; Westerdahl, Johan ; Masback, Anna ; Olsson, Hakan ; Malvehy, Josep ; Badenas, Celia ; Cervera, Remedios ; Martí, Rosa ; Brunet-Vidal, Joan ; Yang, Guang ; Martin, Nicholas ; Whiteman, David ; Green, Adele ; Aitken, Joanne ; Minghetti, Paola ; Mantelli, Michela ; Pastorino, Lorenza ; Nasti, Sabina ; Gargiulo, Sara ; Gliori, Sara ; Mistry, Sushila ; Randerson-Moor, Juliette ; De Snoo, Femke A. ; Ter Huurne, Jeanet A C ; Van Der Rhee, Jasper ; Van Mourik, Leny ; Van Nieuwpoort, Frans ; Van Der Drift, Clasine ; Bressac-De Paillerets, Brigitte ; Avril, Marie Francoise ; Grange, F. ; Sassolas, B. ; Boitier, F. ; Chevrant-Breton, J. ; Lasset, C. ; Dugast, C. ; Vabres, P. ; Ganguly, Arupa ; Ming, Michael ; Van Belle, Patricia ; Platz, Anton ; Egyhazi, Suzanne ; Tuominen, Rainer ; Linden, Diana ; Schmid, Helen ; Scope, Alon ; Pavlotsky, Felix ; Friedman, Eitan ; Eliason, Mark. / Features associated with germline CDKN2A mutations : A GenoMEL study of melanoma-prone families from three continents. In: Journal of Medical Genetics. 2007 ; Vol. 44, No. 2. pp. 99-106.
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abstract = "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.",
author = "Goldstein, {Alisa M.} and May Chan and Mark Harland and Hayward, {Nicholas K.} and Florence Demenais and Bishop, {D. Timothy} and Esther Azizi and Wilma Bergman and Giovanna Bianchi-Scarra and William Bruno and Donato Calista and {Cannon Albright}, {Lisa A.} and Valerie Chaudru and Agnes Chompret and Francisco Cuellar and Elder, {David E.} and Paola Ghiorzo and Gillanders, {Elizabeth M.} and Gruis, {Nelleke A.} and Johan Hansson and David Hogg and Holland, {Elizabeth A.} and Kanetsky, {Peter A.} and Kefford, {Richard F.} and Landi, {Maria Teresa} and Julie Lang and Sancy Leachman and MacKie, {Rona M.} and Veronica Magnusson and Mann, {Graham J.} and Bishop, {Julia Newton} and Palmer, {Jane M.} and Susana Puig and Puig-Butille, {Joan A.} and Mitchell Stark and Hensin Tsao and Tucker, {Margaret A.} and Linda Whitaker and Emanuel Yakobson and Christian Ingvar and Ake Borg and Johan Westerdahl and Anna Masback and Hakan Olsson and Josep Malvehy and Celia Badenas and Remedios Cervera and Rosa Mart{\'i} and Joan Brunet-Vidal and Guang Yang and Nicholas Martin and David Whiteman and Adele Green and Joanne Aitken and Paola Minghetti and Michela Mantelli and Lorenza Pastorino and Sabina Nasti and Sara Gargiulo and Sara Gliori and Sushila Mistry and Juliette Randerson-Moor and {De Snoo}, {Femke A.} and {Ter Huurne}, {Jeanet A C} and {Van Der Rhee}, Jasper and {Van Mourik}, Leny and {Van Nieuwpoort}, Frans and {Van Der Drift}, Clasine and {Bressac-De Paillerets}, Brigitte and Avril, {Marie Francoise} and F. Grange and B. Sassolas and F. Boitier and J. Chevrant-Breton and C. Lasset and C. Dugast and P. Vabres and Arupa Ganguly and Michael Ming and {Van Belle}, Patricia and Anton Platz and Suzanne Egyhazi and Rainer Tuominen and Diana Linden and Helen Schmid and Alon Scope and Felix Pavlotsky and Eitan Friedman and Mark Eliason",
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month = "2",
doi = "10.1136/jmg.2006.043802",
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issn = "0022-2593",
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TY - JOUR

T1 - Features associated with germline CDKN2A mutations

T2 - A GenoMEL study of melanoma-prone families from three continents

AU - Goldstein, Alisa M.

AU - Chan, May

AU - Harland, Mark

AU - Hayward, Nicholas K.

AU - Demenais, Florence

AU - Bishop, D. Timothy

AU - Azizi, Esther

AU - Bergman, Wilma

AU - Bianchi-Scarra, Giovanna

AU - Bruno, William

AU - Calista, Donato

AU - Cannon Albright, Lisa A.

AU - Chaudru, Valerie

AU - Chompret, Agnes

AU - Cuellar, Francisco

AU - Elder, David E.

AU - Ghiorzo, Paola

AU - Gillanders, Elizabeth M.

AU - Gruis, Nelleke A.

AU - Hansson, Johan

AU - Hogg, David

AU - Holland, Elizabeth A.

AU - Kanetsky, Peter A.

AU - Kefford, Richard F.

AU - Landi, Maria Teresa

AU - Lang, Julie

AU - Leachman, Sancy

AU - MacKie, Rona M.

AU - Magnusson, Veronica

AU - Mann, Graham J.

AU - Bishop, Julia Newton

AU - Palmer, Jane M.

AU - Puig, Susana

AU - Puig-Butille, Joan A.

AU - Stark, Mitchell

AU - Tsao, Hensin

AU - Tucker, Margaret A.

AU - Whitaker, Linda

AU - Yakobson, Emanuel

AU - Ingvar, Christian

AU - Borg, Ake

AU - Westerdahl, Johan

AU - Masback, Anna

AU - Olsson, Hakan

AU - Malvehy, Josep

AU - Badenas, Celia

AU - Cervera, Remedios

AU - Martí, Rosa

AU - Brunet-Vidal, Joan

AU - Yang, Guang

AU - Martin, Nicholas

AU - Whiteman, David

AU - Green, Adele

AU - Aitken, Joanne

AU - Minghetti, Paola

AU - Mantelli, Michela

AU - Pastorino, Lorenza

AU - Nasti, Sabina

AU - Gargiulo, Sara

AU - Gliori, Sara

AU - Mistry, Sushila

AU - Randerson-Moor, Juliette

AU - De Snoo, Femke A.

AU - Ter Huurne, Jeanet A C

AU - Van Der Rhee, Jasper

AU - Van Mourik, Leny

AU - Van Nieuwpoort, Frans

AU - Van Der Drift, Clasine

AU - Bressac-De Paillerets, Brigitte

AU - Avril, Marie Francoise

AU - Grange, F.

AU - Sassolas, B.

AU - Boitier, F.

AU - Chevrant-Breton, J.

AU - Lasset, C.

AU - Dugast, C.

AU - Vabres, P.

AU - Ganguly, Arupa

AU - Ming, Michael

AU - Van Belle, Patricia

AU - Platz, Anton

AU - Egyhazi, Suzanne

AU - Tuominen, Rainer

AU - Linden, Diana

AU - Schmid, Helen

AU - Scope, Alon

AU - Pavlotsky, Felix

AU - Friedman, Eitan

AU - Eliason, Mark

PY - 2007/2

Y1 - 2007/2

N2 - 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.

AB - 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.

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U2 - 10.1136/jmg.2006.043802

DO - 10.1136/jmg.2006.043802

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VL - 44

SP - 99

EP - 106

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

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