toto 18janv2008
Post on 31-May-2018
227 Views
Preview:
TRANSCRIPT
-
8/14/2019 toto 18Janv2008
1/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
Protective effect of Glutathione S-Transferase T1 gene on melanoma risk in presence of
CDKN2A mutations,MC1R variants and host-related phenotypes.
V. CHAUDRU (1), MT. LO (1), F. LESUEUR (2,3), K. LAUD (4), H. MOHAMDI (1), C.
MARIAN (5), M. BARROIS (2), A. CHOMPRET (2), MF. AVRIL (6), F. DEMENAIS (1), B.
BRESSAC-DE PAILLERETS (2)
(1) INSERM U794, Universit dEvry, Evry, (2) Service de Gntique and FRE2939 CNRS,
Institut Gustave Roussy, Villejuif, (3) Genetic Susceptibility Group, IARC, Lyon, (4) Unit
830 INSERM, Institut Curie, (5) Biochemistry Department, University of Medecine and
Pharmacy, Romania, (6) AP-HP Hpital Cochin, Universit Ren Descartes Paris 5, Paris
-
8/14/2019 toto 18Janv2008
2/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
ABSTRACT
UV exposure is the major environmental risk factor of cutaneous melanoma mainly by
generating reactive oxygen species (ROS) causing molecular damages. Glutathione S-
transferases (GSTs) are enzymes playing an important role in detoxifying products of
oxidative stress, but only few case-control studies have investigated the effect of allelic
variants ofGSTgenes on melanoma risk and have led to controversial results. The effect of
these GST genes in melanoma-prone families segregating CDKN2A mutations has not yet
been studied. We examined the effect ofGSTP1, GSTM1 and GSTT1 genotypes on melanoma
risk in 25 melanoma-prone families with CDKN2A mutations, in presence of other risk factors
including MC1R gene variants, sun exposure, pigmentation characteristics and nevus
phenotypes. Logistic regression analyses were applied to 195 subjects genotyped for all three
genes investigated, using a generalized estimating equations (GEE) approach to take into
account correlations among family members. Different models were considered, which
-
8/14/2019 toto 18Janv2008
3/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
melanocytes. Ou The observed protective role ofGSTT1 deficiency on the development of
melanoma would need to be interpreted in the context of the other genes, CDKN2A, MC1R
and potentially those underlying dysplastic nevi, that influence melanoma risk and are
involved in multiple interacting pathways.
Key words: Glutathione S-Transferase, CDKN2A mutations, MC1R variants, Melanoma
-
8/14/2019 toto 18Janv2008
4/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
INTRODUCTION
Cutaneous malignant melanoma (CMM) is a complex disease resulting from genetic and
other risk factors. Epidemiological studies have shown that exposure to sunlight is the major
environmental risk factor associated with melanoma, while high numbers of melanocytic nevi
(clinically banal and/or atypical (dysplastic)), hair color, eye color, skin color, extent of
freckling and skin reactions to sun exposure are the major host factors [Tucker and Goldstein,
2003 for a review].
Approximately 10% of malignant melanomas are observed in a familial setting. Up-to now,
CDKN2A gene (9p21; MIM# 600160) is the major high-risk melanoma susceptibility gene.
Germline CDKN2A mutations have been observed in approximately 20 - 40 percent of
melanoma-prone families from around the world [Goldstein et al., 2007a]. Although
CDKN2A mutations confer a substantial risk for melanoma, there is a proportion of mutation
-
8/14/2019 toto 18Janv2008
5/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
risk factors by case-control studies [Kennedy et al., 2001; Matichard et al., 2004; Palmer et
al., 2000]. Joint analysis of host-related factors, sun exposure and MC1R in French families
with CDKN2A mutations have shown that CDKN2A penetrance is influenced significantly by
independent effects ofMC1R variants and dysplastic nevi [Chaudru et al., 2005].
Besides MC1R, other low-risk genes have been reported to be associated with melanoma
by a few case-control studies, but the results are most often controversial [Fargnoli et al.,
2006; Hayward, 2003]. These genes include the glutathione S-transferase genes (GSTP1
MIM# 134660, GSTM1 MIM# 138350, GSTT1 MIM# 600436) whose products detoxify
electrophilic xenobiotics and inactive endogenous metabolites generated during oxidative
stress, such as the reactive oxygen species (ROS) occurring after excessive ultraviolet (UV)
exposure [Hayes et al., 2005]. Human GSTgenes have been shown to be polymorphic. These
polymorphisms are either single nucleotide polymorphisms (SNPs) in the coding regions
(GSTP1), or gene deletions (GSTT1 and GSTM1). SNPs in exon 5 (p.I105V) and exon 6
-
8/14/2019 toto 18Janv2008
6/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
MATERIALS AND METHODS
Ascertainment of families and data collection
The 25 melanoma-prone families available for the present study have been recruited from
the Department of Dermatology at the Institut Gustave Roussy (IGR) and other French
hospitals forming the French Familial Melanoma Study Group. This sample includes five
additional families to our previous sample used to assess the effects of host factors and MC1R
on CDKN2A penetrance [Chaudru et al, 2005] and will be briefly described.
Eligible melanoma probands, from whom families were ascertained, were white
subjects living in France for more than ten years who had a newly diagnosed and
histologically confirmed melanoma. Family data were collected by interviewing the probands
on their first-degree, second-degree and third-degree relatives and included demographic
characteristics (gender, date of birth, and if deceased, age at death and cause of death) and the
-
8/14/2019 toto 18Janv2008
7/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
no), long stay (>1 year) in a sunny country, skin reactions to sunlight evaluated by the ability
to tan (low, medium, or high) and propensity to sunburn (low, medium or high). Information
on risk factors was obtained in all probands and at least 70% of all living relatives.
Written informed consent was obtained prior to participation under an Institutional
Review Board-approved protocol.
Genotyping
Genomic DNA from participants was extracted from peripheral blood lymphocytes, using the
QIAamp DNA Blood mini kit (QIAGEN, Hilden, Germany). A total of 18 different CDKN2A
mutations and 12 non-synonymous MC1R variants were detected in our 25 families (see
[Chaudru et al, 2004; 2005] for a list of CDKN2A mutations and MC1R variants).The gene
copy number variation for GSTT1 and GSTM1 were determined using an adapted protocol
from the Quantitative Multiplex PCR of Short fluorescent Fragments (QMPSF) method
[Casilli et al., 2002]. In brief, short exonic fragments ofGSTT1 (exon 5) and GSTM1 (exons 4
-
8/14/2019 toto 18Janv2008
8/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
Statistical analyses
Comparisons of GSTP1, GSTM1, and GSTT1 genotypes frequencies in affected and
unaffected members of the melanoma-prone families were first carried out by Fisher exact
test. Crude odds-ratios were computed to estimate the effects of these genotypes on melanoma
risk.
We then used logistic regression to assess the effects of each GSTgene on melanoma risk
by examining the following models: (1) GST in presence of CDKN2A mutation status; (2)
GSTin presence ofCDKN2A and number ofMC1R variants (or presence of RHC (Red Hair
Color) variants or NRHC (non-RHC) variants); (3) GST in presence of CDKN2A and by
entering MC1R, sun exposure, pigmentation and nevus phenotypes in the model using a
stepwise procedure. Age and sex were included in all regression models. We used a
generalized estimating equation (GEE) approach to take into account correlations among
-
8/14/2019 toto 18Janv2008
9/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
while the at-risk category included heterozygous mutation carriers (there was no homozygous
carriers in our sample). Since the risk of melanoma was found to increase with the number of
MC1R variants across populations [Goldstein et al., 2007b; Demenais, personal
communication], a MC1R variable was created by assigning subjects to one of the three
following categories: MC1R consensus homozygous subjects versus subjects with 1 MC1R
variant versus subjects with at least two MC1R variants. A RHC variable (pooling p.R151C,
p.R160W, p.D84E and p.D294H variants which are associated with red-hair color) and a
NRHC variable (pooling all non-RHC variants) were also considered: the baseline category
included MC1R consensus homozygous subjects while the at-risk category included subjects
with either at least one RHC variant (and no NRHC variant) or at least one NRHC variant
(and no RHC variant). Environmental and host-related covariates were dichotomized with the
baseline and at-risk categories being defined as follows: sun exposure (low or medium versus
high), hair color (dark or dark brown versus light brown, blond or red), skin color (dark
-
8/14/2019 toto 18Janv2008
10/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
subjects had melanoma while all other ones were unaffected. The mean age at diagnosis of
melanomapatients (38.56 11.70 years) and mean age at examination of unaffected subjects
(40.93 20.58 years) did not differ significantly (p=0.65). The risk of melanoma was
significantly higher in females than in males (p= 0.03; OR adjusted forCDKN2A = 2.17; 95%
CI, 1.09-4.31). Sex was thus included in all analyses.
The GSTP1, GSTM1, and GSTT1 genotypes as well as MC1R genotypes were determined
in all 195 individuals genotyped forCDKN2A. All GSTand MC1R variants were in Hardy-
Weinberg equilibrium (p> 0.05). Regarding MC1R, 85 subjects (43.6 %) carried one MC1R
variant and 69 had at last two variants (35.4 %), these proportions being 28.6% and 49.6% in
affected subjects and 58.9% and 25.9% in unaffecteds (p
-
8/14/2019 toto 18Janv2008
11/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
null allele nor by GSTP1 p.I105V or p.A114V variant (table 2). However, carrying at least
one GSTT1 null allele decreased melanoma risk significantly. This protective effect was
higher when MC1R was added to a model including CDKN2A as compared to a model with
CDKN2A alone: OR = 0.24 (95% CI, 0.15-0.58; p=0.001) with CDKN2A and MC1R vs OR =
0.41 (95% CI, 0.18-0.94; p=0.035) with CDKN2A alone. This decrease in melanoma risk
associated with GSTT1 null allele was similar in presence of RHC or NRHC variants,
although being more significant with NRHC variants (p = 0.008 with NRHC variants vs
p=0.046 with RHC variants). To investigate further the higher decrease in melanoma risk
when MC1R was incorporated in the regression model, we tested for interaction between
MC1R and GSTT1 variables but no significant interaction was evidenced. However, when
estimating odds-ratios by stratifying on number of MC1R variants, we observed a lower
melanoma risk associated with GSTT1 null allele in carriers of less than two MC1R variants as
compared to subjects having two or more variants (test of homogeneity between ORs being
-
8/14/2019 toto 18Janv2008
12/29
-
8/14/2019 toto 18Janv2008
13/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
puisquon ne peut rien comparer (diffrente mthode de gnotypage et diffrente population
tudie?) Ceci a t raccourci.
The decrease in odds-ratio associated with the effect ofGSTT1 was enhanced when MC1R
was added to the regression model including CDKN2A as compared to the model with
CDKN2A alone. No significant interaction between MC1R and GSTT1 on melanoma risk
could be detected. However, estimates of ORs associated with GSTT1, which were lower in
subjects with less than two MC1R variants than in those with two variants or more, suggest
such interaction which may become significant in larger samples. The protective effect of
GSTT1 was of the same order of magnitude when considering separately RHC and NRHC
variants. The higher significance level observed in presence of NRHC as compared to RHC
variants may be accounted for by differences in sample size (149 and 115 subjects examined
in presence of NRHC and RHC variants respectively). Moreover, the stepwise analysis
showed that dysplastic nevi increased significantly melanoma risk independently from the
-
8/14/2019 toto 18Janv2008
14/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
where a decrease in risk, although not significant, was found in subjects carrying at least one
GSTM1 null allele. As observed forGSTT1, the decrease in OR was higher when MC1R was
included in the model and was similar whether considering number ofMC1R variants, RHC
orNRHCvariants. Pooling the effects of both GSTM1 and GSTT1 gene (having at least one
GSTT1 or GSTM1 null allele) led also to a reduced melanoma risk which remained not
significant (results not shown).
To our knowledge, only one Slovenian case-control study has investigated the role of
GSTP1 gene on melanoma risk [Dolzan et al., 2006] and found that none ofGSTP1 genotypes
influenced significantly melanoma risk as in our study.
The finding of an association between the GSTT1 null allele and a decreased risk of
melanoma was somehow unexpected but has to be interpreted in the context of CDKN2A
mutations and MC1R variants. These three genes are involved in multiple pathways with
complex interactions between these pathways and it has been reported that key genetic factors
-
8/14/2019 toto 18Janv2008
15/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
can lead to proliferation, differentiation and stress adaptation but also apoptosis [Wittgen and
Kempen, 2007]. The -melanocyte-stimulating hormone (-MSH), acting through MC1R,
plays a major role in the pigmentation process which involves melanin synthesis that guards
against the photodamaging effects of UV and acts as a scavenger of ROS [Miyamura et al,
2007]. However, melanin can also turn into a prooxidant under oxidative stress as a result of
inflammation or higher metabolic processes [Wittgen and Kempen, 2007]. Besides its effects
on pigmentation, -MSH is involved in antiapoptotic and DNA repair pathways [Kadekaro et
al, 2005; Miyamura et al., 2007] and has also been shown to potentiate the expression of
CDKN2A gene product (p16) after UV exposure [Pavey and Gabrielli, 2002]. MC1R
expression is also regulated by oxidative products [Garcia-Borron et al., 2005]. The positive
and negative feedbacks among these various factors underlie the complexity of the
mechanisms involved.
O ibl l ti th t ld b t f d i th t th ti GSTT1 ti
-
8/14/2019 toto 18Janv2008
16/29
-
8/14/2019 toto 18Janv2008
17/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
_________________________________________________________________________
Previous version / biology
Biological hypotheses can be put forward in an attempt to explain the significant protective
effect ofGSTT1 null allele on melanoma risk as evidenced in the present genetic context of
CDKN2A mutations and MC1R variants. Increased UV exposure is regarded as the major
environmental factor contributing to melanoma. Pleiotropic effects of UV irradiation on skin
cells include direct DNA damage and formation of ROS. ROS can directly attack DNA or can
cause DNA damage following reaction with membrane lipids [Hayes et al., 2005].
Accordingly, genetic variations of enzymes involved in the detoxification of oxidative stress
products have been postulated to influence the risk of melanoma and other skin cancers
related to UV exposure [Afaq et al., 2001]. GSTs are a family of isoenzymes that catalyze the
detoxification of substrates of ROS and theconjugation of the tripeptide glutathione (GSH) to
minimize injurious events that results from toxic chemicals and normal oxidative products of
-
8/14/2019 toto 18Janv2008
18/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
shown that -MSH, acting through MC1R, potentiates the expression of CDKN2A gene
product (p16) after UV exposure (Pavey and Gabrielli, 2002). The -MSH protein, besides its
effect on pigmentation, plays a role in apoptotic/antiapoptotic and DNA repair pathways
(Kadekaro et al, 2005; Miyamura et al., 2006). Reactive oxygen species are involved in the
regulation of many signaling pathways which can lead to proliferation, differentiation and
stress adaptation but also apoptosis (Wittgen and Kempen, 2007).
A first hypothesis would be that the absence of GSTT1 protein induces an increase of cell
death when the number of deleterious genetic events (such as UV-induced DNA damages) in
melanocytes is accumulating, thus preventing the transformation to cancerous state. UV-
induced DNA damage could be BRAF oncogenic somatic mutations as it has been shown
recently that BRAF mutations are a characteristic feature of non-CSD melanoma in
individuals carriers of two variant MC1R alleles, such mutation could be the result of A>T
i d i d f ROS [L di l 2006] Th f h i
-
8/14/2019 toto 18Janv2008
19/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
that GSH depletion is involved in apoptosis, and that this process is independent of ROS
formation [Franco et al., 2007].
Because unrepaired DNA damages appear to play a central role in carcinogenesis, the
effect of GST genes had been widely studied in different types of cancer (such as breast,
colon, lung, and brain cancers). Although homozygous deletion forGSTM1 slightly increased
lung cancer risk and homozygous deletion forGSTM1 and GSTT1 slightly increased head and
neck cancer risk, controversial results were found for other cancers by epidemiological studies
[Hayes et al., 2005; Parl, 2005 for reviews]. Interestingly, one study [Roodi, 2004] has
suggested a protective effect of the GSTM1 deletion on breast cancer. Subjects carrying two
active GSTM1 alleles had increased risk of breast cancer, compared to subjects carrying the
GSTM1 null genotype: the relative risk adjusted for age was 2.83 (95% CI 1.45-5.59) in
Caucasian women while the increased risk was not significant in African-American women
(the relative risk adjusted for age was 1.66, 95% CI 0.66-4.20).
-
8/14/2019 toto 18Janv2008
20/29
-
8/14/2019 toto 18Janv2008
21/29
-
8/14/2019 toto 18Janv2008
22/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4
mutations. J Natl Cancer Inst 92:1006-10.
Goldstein AM, Landi MT, Tsang S, Fraser MC, Munroe DJ, Tucker MA. 2005. Association of
MC1R variants and risk of melanoma in melanoma-prone families with CDKN2A
mutations. Cancer Epidemiol Biomarkers Prev 14(9):2208-12.
Goldstein AM, Chan M, Harland M, Hayward NK, Demenais F, Bishop DT, Azizi E,
Bergman W, Bianchi-Scarra G, Bruno W Calista D, 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 SA, 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; Lund Melanoma Study Group; Melanoma Genetics
Consortium (GenoMEL). 2007a. Features associated with germline CDKN2A mutations: a
GenoMEL study of melanoma-prone families from three continents. J Med Genet
-
8/14/2019 toto 18Janv2008
23/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
Heagerty AH, Fitzgerald D, Smith A, Bowers B, Jones P, Fryer AA, Zhao L, Alldersea J,
Strange RC. 1994. Glutathione S-transferase GSTM1 phenotypes and protection against
cutaneous tumours. Lancet 343(8892):266-8.
Kadekaro AL, Kavanagh R, Kanto H, Terzieva S, Hauser J, Kobayashi N, Schwemberger S,
Cornelius J, Babcock G, Shertzer HG, Scott G, Abdel-Malek ZA. 2005. alpha-
Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in
human melanocytes. Cancer Res 65(10):4292-9.
Kanetsky PA, Holmes R, Walker A, Najarian D, Swoyer J, Guerry D, Halpern A, Rebbeck
TR. 2001. Interaction of glutathione S-transferase M1 and T1 genotypes and malignant
melanoma. Cancer Epidemiol Biomarkers Prev 10(5):509-13.
Kennedy C, ter Huurne J, Berkhout M, Gruis N, Bastiaens M, Bergman W, Willemze R, JN B.
2001. Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk
for cutaneous melanoma which is largely independent of skin type and hair color. J Invest
-
8/14/2019 toto 18Janv2008
24/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
Miyamura Y, Coelho SG, Wolber R, Miller SA, Wakamatsu K, Zmudzka BZ, Ito S, Smuda C,
Passeron T, Choi W, Batzer J, Yamaguchi Y, Beer JZ, Hearing VJ. 2007. Regulation of
human skin pigmentation and responses to ultraviolet radiation. Pigment Cell Res
20(1):2-13. Review.
Mossner R, Anders N, Konig IR, Kruger U, Schmidt D, Berking C, Ziegler A, Brockmoller J,
Kaiser R, Volkenandt M, Westphal GA, Reich K. 2007. Variations of the melanocortin-1
receptor and the glutathione-S transferase T1 and M1 genes in cutaneous malignant
melanoma. Arch Dermatol Res 298(8):371-9.
Palmer JS, Duffy DL, Box NF, Aitken JF, O'Gorman LE, Green AC, Hayward NK, Martin
NG, RA S. 2000. Melanocortin-1 receptor polymorphisms and risk of melanoma: is the
association explained solely by pigmentation phenotype? Am J Hum Genet 66:176-86.
Parl FF. 2005. "Glutathione S-transferase genotypes and cancer risk." Cancer Lett 221(2):
123-9.
-
8/14/2019 toto 18Janv2008
25/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
carcinoma syndrome or sporadic melanoma. Carcinogenesis 16(8):2003-4.
Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D,
Benard J, Bressac-de Paillerets B. 1998. Prevalence of p16 and CDK4 germline mutations
in 48 melanoma-prone families in France. The French Familial Melanoma Study Group.
Hum Mol Genet 7:209-16.
Sturm RA, Teasdale RD, NF B. 2001. Human pigmentation genes: identification, structure
and consequences of polymorphisms variations. Gene 277:49-62.
Tucker MA and Goldstein AM. 2003. " Melanoma etiology: where are we?" Oncogene 22:
3042-52.
van der Velden PA, Sandkuijl LA, Bergman W, Pavel S, van Mourik L, Frants RR, NA G.
2001. Melanocortin-1 receptor variant Arg151Cys modifies melanoma risk in Dutch
families with melanoma. Am J Hum Genet 69:774-9.
-
8/14/2019 toto 18Janv2008
26/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
Table 1
Distribution of GST genotyped by melanoma affection status and crude odds-ratio associated to the GSTgenes in the total sample and in
the subset ofCDKN2A mutation carriers
Carriers and non carriers ofCDKN2A mutations
(N=195)
carriers ofCDKN2A mutations
(N=96)
No. of
GST genotypes genotyped
subject (%)
Cases/Controls Odds-Ratio 95% CI
No. of
genotyped
subject (%)
Cases/Controls Odds-Ratio 95% CI
GSTM1b
+/+
+/-
-/-
24 (12.9)
93 (47.3)
78 (39.8)
9/15
28/65
19/59
1.00
0.72
0.54
-
0.28-
1.83
0.20-
1.42
15 (15.6)
47 (48.9)
34 (35.4)
8/7
27/20
18/16
1.00
1.18
0.98
-
0.37-
3.80
0.29-
3.33pa =0.43 pa =0.96
GSTT1b
+/+
+/-
-/-
54 (27.7)
105 (53.8)
36 (18.5)
21/33
27/78
8/28
1.00
0.54
0.45
-
0.27-
1.10
0.17-
1.17
29 (30.2)
49 (51.0)
18 (18.7)
20/9
25/24
8/10
1.00
0.47
0.36
-
0.18-
1.23
0.11-1.22
pa=0.14 pa =0.18
GSTP1
p.I105V (A>G): A/A
A/G
G/G
91 (46.7)
92 (47.2)
12 (6.1)
24/67
27/65
5/7
1.00
1.16
1.99
-
0.61-
2.22
0.58-
6.88
44 (45.8)
43 (44.8)
9 (9.4)
23/21
25/18
5/4
1.00
1.27
1.14
-
0.54-
2.96
0.27-
4.83
pa =0.49 pa =0.91
- 26 -
-
8/14/2019 toto 18Janv2008
27/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
p.A114V (C>T): C/C
C/T
T/T
170 (87.2)
25 (12.8)
0 (0)
50/120
6/19
-
1.00
0.76
-
-
0.29-
2.01
-
86 (89.6)
10 (10.4)
0 (0)
47/39
6/4
-
1.00
1.25
-
-
0.33-
4.73
-
pa =0.64 pa =1.00a
: p = p-value associated to the Fisher exact test in order to compare GST allele frequencies in affected and non affected members of melanoma-prone familiesb: + = active allele, - = null allele
- 27 -
-
8/14/2019 toto 18Janv2008
28/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
Table 2
Effect of GST genes on melanoma risk by taking into account successively age, sex, CDKN2A, andMC1R in the total sample of carriers
and non carriers ofCDKN2A mutations.
Adjustment model
Age, sex, CDKN2A Age, sex, CDKN2A,
MC1RaAge, sex, CDKN2A,
RHC
Age, sex, CDKN2A,
NRHC
Gene testedOR (95% CI)
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
N=195 N=195 N=115b N=149b
GSTT1 c
+/- or -/-0.41 [0.18-0.94]
0.035
0.24 [0.15-0.58]0.001
0.29 [0.09-0.98]0.046
0.33 [0.14-0.75]0.008
GSTM1 c
+/- or -/-0.84 [0.35-2.01]
0.699
0.42 [0.15-1.11]0.081
0.46 [0.09-2.25]0.338
0.45 [0.12-1.67]0.230
GSTP1p. I105VC/T or T/T
1.22 [0.63-2.35]0.550
1.28 [0.57-2.89]0.545
1.36 [0.42-4.46]0.607
1.55 [0.72-3.32]0.264
GSTP1 p.A114VA/G or G/G
0.99 [0.42-2.33]0.987
1.29 [0.41-4.09]0.661
4.02 [0.49-33.20]0.196
0.82 [0.21-3.20]0.771
a: the MC1R variable includes two dummy variables : a variable were the baseline category included MC1R consensus compared to subject with
1 MC1R variant and a second variable were the baseline category included MC1R consensus compared to subject with at least 2 MC1R variants.
b: When the RHC and NRHC variables were considered, some subjects were excluded from the analyse since the baseline category included
MC1R consensus homozygous subjects while the at-risk category included subjects with either at least one RHC variant (and no NRHC variant)
or at least one NRHC variant (and no RHC variant) .
c: + = active allele, - = null allele
- 28 -
-
8/14/2019 toto 18Janv2008
29/29
Version modif Fab_Oct 2007_corrVC_FD_BB_FL_16Janv2008
Table 3
Outcomes of the unconditional logistic regression analyses selecting the effects ofMC1R gene, GSTT1 gene, and host factors (nevi
phenotypes) by a stepwise procedure in the total sample of carriers and non carriers ofCDKN2A mutations.
Effect of the following variable on melanoma risk
1 MC1R variant 2 MC1R variants GSTT1 b
+/- or -/-
Presence of
Dysplastic nevi
(DN)
High number
of nevi
(HNN)
Model ORa (95% CI)
p-value
ORa (95% CI)
p-value
ORa (95% CI)
p-value
ORa (95% CI)
p-value
ORa (95% CI)
p-value
1. MC1R 1.42 [0.46-4.42]0.546
6.24 [1.68-23.21]0.006
- - -
2. GSTT1 added to model 1 1.33 [0.42-4.21]0.627
7.68 [2.16-27.33]0.002
0.24 [0.10-0.58]0.001
- -
3. DN added to model 2 1.34 [0.42-4.23]0.623
10.17 [2.88-35.91]
top related