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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.
Fam Cancer 2009; 8(4):371-7FC

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 >or=1 null GSTT1 allele was shown: OR(adjusted for age,sex,CDKN2A) = 0.41 (0.18-0.94) and OR(adjusted 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.

Authors+Show Affiliations

INSERM, U946, Fondation Jean Dausset/CEPH, 75010 Paris, France. valerie.chaudru@inserm.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19484507

Citation

Chaudru, Valérie, 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, vol. 8, no. 4, 2009, pp. 371-7.
Chaudru V, Lo MT, 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. Fam Cancer. 2009;8(4):371-7.
Chaudru, V., Lo, M. T., Lesueur, F., Marian, C., Mohamdi, H., Laud, K., ... Bressac-de Paillerets, B. (2009). 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(4), pp. 371-7. doi:10.1007/s10689-009-9249-5.
Chaudru V, 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. Fam Cancer. 2009;8(4):371-7. PubMed PMID: 19484507.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Chaudru,Valérie, AU - Lo,M T, AU - Lesueur,F, AU - Marian,C, AU - Mohamdi,H, AU - Laud,K, AU - Barrois,M, AU - Chompret,A, AU - Avril,M F, AU - Demenais,F, AU - Bressac-de Paillerets,B, Y1 - 2009/05/31/ PY - 2008/11/26/received PY - 2009/05/14/accepted PY - 2009/6/2/entrez PY - 2009/6/2/pubmed PY - 2010/1/9/medline SP - 371 EP - 7 JF - Familial cancer JO - Fam. Cancer VL - 8 IS - 4 N2 - 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 >or=1 null GSTT1 allele was shown: OR(adjusted for age,sex,CDKN2A) = 0.41 (0.18-0.94) and OR(adjusted 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. SN - 1573-7292 UR - https://www.unboundmedicine.com/medline/citation/19484507/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_ L2 - https://doi.org/10.1007/s10689-009-9249-5 DB - PRIME DP - Unbound Medicine ER -