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Protective effect of copy number polymorphism of glutathione S-transferase T1 gene on melanoma risk in presence of CDKN2A mutations, MC1R variants and host-related phenotypes

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Abstract

The effect of CDKN2A, the major high-risk melanoma susceptibility gene, has been shown to be modified by host-related phenotypes and variants of MC1R gene. The glutathione S-transferase (GSTs) genes, implicated in detoxification of metabolites after UV exposure, are candidates for modulating CDKN2A penetrance. Few case-control studies have investigated the effect of GSTs on melanoma risk, and have led to controversial results while these genes have not yet been studied in CDKN2A melanoma-prone families. We examined the effect of GSTP1, GSTM1 and GSTT1 genotypes on melanoma risk in 25 multi-generational melanoma-prone families with CDKN2A mutations, in presence of MC1R gene variants, sun exposure, and host-related phenotypes. These data included 195 genotyped subjects for all studied genes. We applied the GEE (Generalized Estimating Equations) approach to test for the effect of GSTs while adjusting for age, sex and CDKN2A mutation status and including successively MC1R, sun exposure and host factors in the model. No significant effect of null GSTM1 allele and GSTP1 variants (p.I105V, p.A114V) on melanoma risk was found. However, a significant protective effect of carrying ≥1 null GSTT1 allele was shown: ORadjusted for age,sex,CDKN2A  = 0.41 (0.18–0.94) and ORadjusted for age,sex,CDKN2A,MC1R  = 0.24 (0.15–0.58). Altogether, the factors modifying significantly the melanoma risk associated with CDKN2A mutations (stepwise procedure) were: MC1R and dysplastic nevi (increasing the risk) and GSTT1 (decreasing the risk). This study shows that even when a high-risk gene (CDKN2A) has been identified, multiple genetic modifiers influence melanoma risk.

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Acknowledgments

We are thankful to the participating families, whose cooperation has made this study possible. We acknowledge B. Bachollet, P. Berthet, F. Boitier, J-P. Cesarini, J. Chevrant-Breton, O. Dereure, P. Duvillard, F. Grange, B. Guillot, R. Guimbaud, P. Joly, C. Lasset, J-L. Michel, J-C. Ortoli, B. Sassolas, R. Triller, F. Truchetet, L. Vernes, as part of the French familial melanoma study group who contributing to the recruitment of families.

This work was funded by Ligue Contre le Cancer (Ligue Nationale PRE2005.LNCC/FD1 and Comité du Val de Marne 2003–2004), ARC (grant No. 3222, 2003), INCA—Cancéropole Ile de France (melanoma network RS#13), National Cancer Institute grant R01 CA 083115, European Commission under the 6th Framework Programme (Contract no. LSHC-CT-2006-018702 / GenoMEL consortium). F. Lesueur was recipient of a postdoctoral fellowship from the Fondation pour la Recherche Médicale (UFP20051105597).

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Authors and Affiliations

  1. INSERM, U946, Fondation Jean Dausset/CEPH, 27 Rue Juliette Dodu, 75010, Paris, France

    Valérie Chaudru, M. T. Lo, H. Mohamdi & F. Demenais

  2. Université d’Evry, Evry, France

    Valérie Chaudru

  3. Université Paris Diderot, Paris 7, Paris, France

    M. T. Lo, H. Mohamdi & F. Demenais

  4. Service de Génétique and FRE2939 CNRS, Institut Gustave Roussy, Villejuif, France

    F. Lesueur, M. Barrois & B. Bressac-de Paillerets

  5. Genetic Susceptibility Group, IARC, Lyon, France

    F. Lesueur

  6. Cancer Genetics and Epidemiology Division, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    C. Marian

  7. INSERM, U830, Institut Curie, Paris, France

    K. Laud

  8. Département de Médecine, Institut Gustave Roussy, Villejuif, France

    A. Chompret

  9. AP-HP Hôpital Cochin, Université René Descartes Paris 5, Paris, France

    M. F. Avril

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  1. Valérie Chaudru
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  4. C. Marian
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  6. K. Laud
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  7. M. Barrois
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  8. A. Chompret
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  10. F. Demenais
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  11. B. Bressac-de Paillerets
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Corresponding author

Correspondence to Valérie Chaudru.

Additional information

This work is dedicated to our late colleague Agnès Chompret.

B. Bressac-de Paillerets and F. Demenais contributed equally to this work.

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Chaudru, V., Lo, M.T., Lesueur, F. et al. Protective effect of copy number polymorphism of glutathione S-transferase T1 gene on melanoma risk in presence of CDKN2A mutations, MC1R variants and host-related phenotypes. Familial Cancer 8, 371–377 (2009). https://doi.org/10.1007/s10689-009-9249-5

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