ORIGINAL PAPER

Assessment of the XPC (A2920C), XPF (T30028C),TP53 (Arg72Pro) and GSTP1 (Ile105Val) polymorphismsin the risk of cutaneous melanoma

Cristiane Oliveira • Jose Augusto Rinck-Junior •

Gustavo Jacob Lourenco • Aparecida Machado Moraes •

Carmen Silvia Passos Lima

Received: 7 February 2013 / Accepted: 25 March 2013 / Published online: 9 April 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract

Purpose We examined the influence of XPC A2920C,

XPF T30028C, TP53 Arg72Pro and GSTP1 Ile105Val

polymorphisms in the risk of cutaneous melanoma (CM).

Methods DNA from 146 CM patients and 146 controls

was analysed by polymerase chain reaction (PCR)—

restriction fragment length polymorphism (RFLP).

Results The frequencies of XPC CC (15.1 vs. 6.9 %,

P = 0.02), TP53 ArgArg (59.6 vs. 45.9 %, P = 0.02),

XPC CC plus TP53 ArgArg (19.7 vs. 5.2 %, P = 0.01) and

TP53 ArgArg plus GSTP1 IleIle (50.7 vs. 35.6 %,

P = 0.03) genotypes were higher in patients than in con-

trols. Carriers of the respective genotypes were under a

2.51 (95 % CI: 1.13–5.55), 1.76 (95 % CI: 1.09–2.83), 4.52

(95 % CI: 1.35–15.16), and 2.01 (95 % CI: 1.04–3.90)-fold

increased risks for CM than others, respectively. An excess

of TP53 ArgArg genotype was seen in patients with

excessive sun exposure compared to patients with standard

sun exposure (69.2 vs. 44.1 %, P = 0.02) and also com-

pared to controls (69.2 vs. 45.9 %, P = 0.002). Individuals

with TP53 ArgArg genotype and highly exposed to sun-

light had 2.65 (95 % CI: 1.42–4.92)-fold increased risk for

CM than others. XPC CC (27.8 vs. 10.4 %, P = 0.02) and

the GSTP1 IleIle (58.3 vs. 36.8 %, P = 0.04) genotypes

were more common in patients with advanced tumours

than in patients with localized tumours and were also more

common in these patients than in controls (27.8 vs. 6.9 %,

P = 0.001; 58.3 vs. 37.0 %, P = 0.02, respectively).

Individuals with the respective genotypes had 5.23 (95 %

CI: 1.97–13.82)-fold and 2.38 (95 % CI: 1.13–5.01)-

fold increased risks for advanced tumour than others,

respectively.

Conclusion Our data suggest that inherited abnormalities

of XPC, XPF, TP53 and GSTP1 pathways of the DNA

repair, apoptosis and metabolism of reactive oxygen spe-

cies are important determinants of CM in individuals from

south-eastern Brazil.

Keywords Cutaneous melanoma � Risk � Polymorphisms �DNA repair � Apoptosis

Introduction

Cutaneous melanoma (CM) incidence has been increasing

worldwide among white population (MacKie et al. 2009).

This trend is also observed in south-east Brazil (Bakos

et al. 2009). The ultraviolet (UV) radiation of the sunlight,

including the UVA and UVB components, is recognized as

the most important environmental risk factor for CM

development (Gandini et al. 2011). While UVA and UVB

radiation induces DNA damage in the form of cyclobutane

pyrimidine dimmers and pyrimidine (6–4) pyrimidone

photoproducts, the UVA radiation also induces single-

strand breaks and produces reactive oxygen species (ROS)

that cause oxidative damage (Svobodova et al. 2011;

Mouret et al. 2012). UVA and UVB damage repair in the

DNA of epithelial cells is required to maintain the genome

C. Oliveira � J. A. Rinck-Junior � G. J. Lourenco �C. S. P. Lima (&)

Clinical Oncology Service, Department of Internal Medicine,

Faculty of Medical Sciences, State University of Campinas,

Rua Alexander Fleming, 181, Cidade Universitaria

‘‘Zeferino Vaz’’, Distrito de Barao Geraldo, Campinas,

SP CEP 13083–970, Brazil

e-mail: carmenl@fcm.unicamp.br

A. M. Moraes

Dermatology Service, Department of Internal Medicine,

Faculty of Medical Sciences, State University of Campinas,

Campinas, SP, Brazil

123

J Cancer Res Clin Oncol (2013) 139:1199–1206

DOI 10.1007/s00432-013-1430-4

integrity and upon repair failure may initiate the photo-

carcinogenic process and originate CM (Sarasin and Ka-

uffmann 2008).

The nucleotide excision repair (NER) pathway elimi-

nates damages caused by UVA and UVB radiation (Kra-

emer et al. 1994; Yeh et al. 2012). The proteins encoded by

the seven xeroderma pigmentosum genes (XPA until XPG)

operate in the NER pathway; XPC is involved in DNA

damage recognition during the early steps of the NER

process, and XPF is directly related to the demarcation and

excision of the lesion (Friedberg 2001; Ford 2005). The

repair of the single-strand breaks and oxidative DNA

damage produced by the UVA radiation also involves other

proteins: P53 protein modulates transcription of target

genes that govern cell cycle arrest, DNA repair, apoptosis

(Whibley et al. 2009) and the detoxifying by glutathione S-

transferase GSTP1 also act on the process (Henderson et al.

1998; Dusinska et al. 2012).

It is already well established that abilities to DNA

damage repair or induction of apoptosis are variable in

humans and may affect susceptibility to CM (Goode et al.

2002; Shen et al. 2003; Povey et al. 2007; Stefanaki et al.

2007; Li et al. 2008; Gu et al. 2009; Ibarrola-Villava et al.

2011; Jiang et al. 2011; Dusinska et al. 2012). The XPC

polymorphism with an A ? C substitution at nucleotide

2920 (Lys939Gln) has been related to decreased activity of

the encoded enzyme (Zhu et al. 2008). The XPF poly-

morphism with a T ? C substitution at nucleotide 30028

(Ser835Ser) is not related to the change in the protein

encoded by different alleles, but could influence mRNA

stability or structure and effect levels of protein expression

(Winsey et al. 2000). A common TP53 polymorphism is

located at the 72nd amino acid residue, with an arginine

(Arg) to proline (Pro) change because of a G ? C trans-

version (Matlashewski et al. 1987). The proteins encoded

by Arg and Pro alleles have been reported to differ in the

functional activity (Dumont et al. 2003). The protein

encoded by the Pro variant allele is more efficient than the

Arg wild protein in inducing the expression of genes

involved in nuclear DNA repair (Siddique and Sabapathy

2006; Altilia et al. 2012).

Glutathione S-transferases (GSTs) are multifunctional

enzymes involved in the detoxification of a wide range of

ROS produced during the synthesis of melanin, drugs and

potential carcinogens and are important players in cellular

defence systems. The GSTP1 is the major GST isoenzyme

expressed in melanocytes of the normal skin basal layers,

as well as in CM (Moral et al. 1997; Dusinska et al. 2012).

A common GSTP1 polymorphism is located at the 105th

amino acid residue, with an isoleucine (Ile) to valine (Val)

change because of an A ? G transversion (Zimniak et al.

1994). The protein encoded by the G allele has a defective

enzymatic activity as the residue lies in substrate-binding

site and the substitution influences substrate-specific

affinity and activity (Henderson et al. 1998). Furthermore,

it is known that the GSTs, especially GSTP1 protein, also

act against apoptosis through direct interaction with c-Jun

N-terminal kinase (JNK) (Laborde 2010; Dusinska et al.

2012).

The roles of the XPC A2920C (Khan et al. 2000;

Blankenburg et al. 2005; Li et al. 2006; Millikan et al.

2006; Mocellin et al. 2009; Figl et al. 2010; Goncalves

et al. 2011), XPF T30028C (Winsey et al. 2000; Goode

et al. 2002; Povey et al. 2007), TP53 Arg72Pro (Shen et al.

2003; Han et al. 2006; Povey et al. 2007; Stefanaki et al.

2007; Li et al. 2008; Capasso et al. 2010; Jiang et al. 2011)

and GSTP1 Ile105Val (Bu et al. 2007; Ibarrola-Villava

et al. 2011) polymorphisms in CM risk are still contro-

versial. These polymorphisms have been analysed pre-

dominantly in Caucasians from Europe and North America,

where solar radiation intensity is lower due to the high

latitude.

The Brazilian population is heterogeneous, mixed and

composed of Amerindians and immigrants from Europe,

Asia and Africa (Pena et al. 2011). Brazilians have been

highly exposed to UV rays, and the incidence of CM is

rising rapidly in the country (Mendes et al. 2010). Since

analyses of various distinct populations are necessary to

define the roles of genetic polymorphisms in the origin of a

certain disease, the identification of XPC A2920C, XPF

T30028C, TP53 Arg72Pro and GSTP1 Ile105Val poly-

morphisms in mixed individuals highly exposed to UV rays

was considered necessary to test their influences in CM risk.

Materials and methods

Study population

The case group was comprised of 146 consecutive CM

patients at diagnosis (median age 55.1 years, range 20–89;

74 men, 72 women) seen at the Clinical Oncology Service

of the University Hospital (State University of Campinas,

Sao Paulo, Brazil) from June 2007 to May 2011. The

control group comprised 146 healthy blood donors (median

age 52.8 years, range 23–60; 74 men, 72 women) seen at

the same University Hospital during the same period of

time in order to provide a representative group of the

general population that seeks medical assistance in our

hospital. Selection criteria for patients and controls were no

evidence of personal or family history of CM, and those

who did not agree to participate in the study were excluded

from the analyses. The control group was matched with

CM patients by age and gender. All procedures were car-

ried out according to the Helsinki Declaration and subjects

provided a written informed consent.

1200 J Cancer Res Clin Oncol (2013) 139:1199–1206

123

Information obtained from a standardized questionnaire

included self-reported host characteristics. Sunburn was

defined as an event of sun exposure resulting in redness and

heat skin for at least 2 days. Individuals exposed to the sun

for more than 2 h per day and for more than 10 years were

considered positive for sun exposure, in accord with the

report of Rigel et al. (1983). On the basis of smoking habit

and physical characteristics, patients were classified as

smokers or non-smokers as previously described (Huang

et al. 2003), and according to light or non-light skin colour,

light (blue/green) or non-light (black/brown) eyes colour,

and light (red/blond) or non-light (brown/black) natural

hair colour. Nevus and freckles were classified as presence

or absence. The tumour site was classified into axial (head,

neck and trunk) and peripheral (limbs), and the diagnosis of

CM was histologically confirmed by a dermatopathologist

with expertise in CM. The depth of invasion and stage of

the tumour were identified using the Breslow and Clark

(Marghoob et al. 2000) and the American Joint Committee

on Cancer ‘‘Melanoma Staging System’’ criteria (Balch

et al. 2009).

Polymorphisms analysis

Genomic DNA was obtained from peripheral blood sam-

ples of subjects using the proteinase K technique (Wood-

head et al. 1986). The genotypes were identified using the

polymerase chain reaction followed by the enzymatic

digestion with specific enzymes, as previously reported for

the XPC A2920C (rs2228001) (Hu et al. 2005), XPF

T30028C (rs1799801) (Povey et al. 2007), TP53 Arg72Pro

(rs1042522) (Honma et al. 2008) and GSTP1 Ile105Val

(rs947894) (Hohaus et al. 2005) polymorphisms.

Statistical analysis

The Hardy–Weinberg (HW) equilibrium was tested with

chi-square (v2) statistics for the goodness-to-fit test. The

differences between groups were analysed by v2 or Fisher

test. Multivariate analysis was performed using the logistic

regression model and served to obtain age-adjusted crude

odds ratios (ORs) and assess the associations between

genotypes and CM. Power of analysis (PA) was used to

calculate the minimum effect size that is likely to be

detected in a study using a given sample size. PA was

calculated according to Pocock (1983) and Hulley et al.

(1988), in analyses involving patients and controls, and

using the tool DSS Research Statistical Power Calculators

(http://www.dssresearch.com/KnowledgeCenter/toolkitcal

culators/statisticalpowercalculators.aspx), in analyses of

group of patients stratified by clinical aspects and

by tumour characteristics. Statistical significance was

established at a P \ 0.05, and all testes were done using

the SPSS 15.0 software (SPSS Incorporation, Chicago,

USA).

Results

Patients’ and controls’ samples were in HW equilibrium

at the XPC A2920C (v2 = 0.34, P = 0.95; v2 = 2.96,

P = 0.08), XPF T30028C (v2 = 0.28, P = 0.56;

v2 = 0.001, P = 0.97), TP53 Arg72Pro (v2 = 1.40, P =

0.59; v2 = 0.09, P = 0.76) and GSTP1 Ile105Val (v2 =

0.43, P = 0.51; v2 = 0.11, P = 0.74) loci, respectively.

Association between genotypes and melanoma risk

We observed that the XPC CC (15.1 vs. 6.9 %, P = 0.02;

PA: 66 %), TP53 ArgArg (59.6 vs. 45.9 %, P = 0.02; PA:

67 %), XPC CC plus TP53 ArgArg (19.7 vs. 5.2 %,

P = 0.01; PA: 73 %) and TP53 ArgArg plus GSTP1 IleIle

(50.7 vs. 35.6 %, P = 0.03; PA: 57 %) genotypes were

more common in patients than in controls. Carriers of

the respective genotypes were under a 2.51 (95 % CI:

1.13–5.55), 1.76 (95 % CI: 1.09–2.83), 4.52 (95 % CI:

1.35–15.16) and 2.01 (95 % CI: 1.04–3.90)-fold increased

risks for CM than others, respectively (Table 1).

Similar frequencies of the XPC plus XPF, XPC plus

GSTP1, XPF plus TP53 and XPF plus GSTP1 were seen in

patients and controls (data not shown). Individuals with the

combined genotypes of the genes above-mentioned were

under similar risks for CM.

Association between genotypes and clinical and tumour

characteristics

The frequencies of genotypes of the analysed polymor-

phisms in patients stratified by sun exposure, skin colour

and tumour stage are presented in Table 2.

The TP53 ArgArg genotype was more common in

patients with excessive sun exposure than in patients with

standard sun exposure (69.2 vs. 44.1 %, P = 0.02; PA:

91 %). The frequency of the genotype was also higher in

this group of patients than in controls (69.2 vs. 45.9 %,

P = 0.002; PA: 89 %). Individuals with TP53 ArgArg

genotype and highly exposed to sunlight had 2.65 (95 %

CI: 1.42–4.92)-fold increased risk for CM than others.

Excesses of the TP53 ArgArg ? ArgPro (94.0 vs. 72.7 %,

P = 0.01; PA: 65 %), XPC AC ? CC plus TP53 ArgArg ?

ArgPro (98.7 vs. 66.7 %, P = 0.003; PA: 87 %) and XPF

TC ? CC plus TP53 ArgArg ? ArgPro (92.9 vs. 50.0 %,

P = 0.02; PA: 71 %) genotypes were seen in patients with

light skin compared to patients with non-light skin.

The XPC CC (27.8 vs. 10.4 %, P = 0.02; PA: 69 %)

and the GSTP1 IleIle (58.3 vs. 36.8 %, P = 0.04; PA:

J Cancer Res Clin Oncol (2013) 139:1199–1206 1201

123

62 %) genotypes were more common in patients with

advanced tumours than in patients with localized tumours.

Moreover, the frequencies of the XPC CC (27.8 vs. 6.9 %,

P = 0.001; PA: 89 %) and GSTP1 IleIle (58.3 vs. 37.0 %,

P = 0.02; PA: 69 %) genotypes in these patients were also

higher than those found in controls. Individuals with the

respective genotypes had 5.23 (95 % CI: 1.97–13.82)-fold

and 2.38 (95 % CI: 1.13–5.01)-fold increased risks for

advanced tumour than others, respectively.

No consistent differences were found in patients strati-

fied by genotypes and other clinical and tumour charac-

teristics (data not shown).

Discussion

We investigated herein whether the XPC A2920C, XPF

T30028C, TP53 Arg72Pro and the GSTP1 Ile105Val

Table 1 Frequencies of the XPC A2920C, XPF T30028C, TP53 Arg72Pro and GSTP1 Ile105Val genotypes in 146 cutaneous melanomas and

146 controls

Genotypes Patients (%) Controls (%) P value OR* (95 % CI) PA (%)

XPC A2920C

AA 59 (40.4) 64 (43.8) Reference

AC 65 (44.5) 72 (49.3) 0.81 0.94 (0.57–1.54) 5

CC 22 (15.1) 10 (6.9) 0.03 2.43 (1.05–5.59) 62

AA ? AC 124 (84.9) 136 (93.1) Reference

CC 22 (15.1) 10 (6.9) 0.02 2.51 (1.13–5.55) 66

XPF T30028C

TT 74 (50.7) 74 (50.7) Reference

TC 58 (39.7) 60 (41.1) 0.87 0.96 (0.59–1.56) 4

CC 14 (9.6) 12 (8.2) 0.77 1.13 (0.48–2.63) 5

TT ? TC 132 (90.4) 134 (91.8) Reference

CC 14 (9.6) 12 (8.2) 0.75 1.14 (0.50–2.57) 5

TP53 Arg72Pro

ArgArg 87 (59.6) 67 (45.9) 0.23 1.75 (0.70–4.37) 66

ArgPro 48 (32.9) 65 (44.5) 0.02 1.81 (1.10–2.98) 71

ProPro 11 (7.5) 14 (9.6) Reference

ArgPro ? ProPro 59 (40.4) 79 (54.1) Reference

ArgArg 87 (59.6) 67 (45.9) 0.02 1.76 (1.09–2.83) 67

GSTP1 Ile105Val

IleIle 60 (41.1) 54 (37.0) 0.14 1.74 (0.83–3.65) 65

IleVal 70 (47.9) 68 (46.6) 0.27 1.50 (0.73–3.08) 41

ValVal 16 (11.0) 24 (16.4) Reference

IleIle ? IleVal 130 (89.0) 122 (83.6) 0.41 1.22 (0.75–1.96) 9

ValVal 16 (11.0) 24 (16.4) Reference

XPC ? TP53

AA ? AC ? ArgPro ? ProPro 49 (80.3) 73 (94.8) Reference

CC ? ArgArg 12 (19.7) 4 (5.2) 0.01 4.52 (1.35–15.16) 73

CC ? AC ? ArgArg ? ArgPro 80 (95.2) 73 (93.6) 0.46 1.77 (0.38–8.28) 12

AA ? ProPro 4 (4.8) 5 (6.4) Reference

TP53 ? GSTP1

ArgPro ? ProPro ? IleVal ? ValVal 35 (49.3) 56 (64.4) Reference

ArgArg ? IleIle 36 (50.7) 31 (35.6) 0.03 2.01 (1.04–3.90) 57

ArgArg ? ArgPro ? IleIle ? IleVal 119 (100.0) 109 (99.1) – – –

ProPro ? ValVal 0 (0.0) 1 (0.9) Reference

A, T, Arg and Ile are wild-type alleles, and C, C, Pro and Val are variant alleles of the XPC A2920C, XPF T30028C, TP53 Arg72Pro and GSTP1Ile105Val polymorphisms, respectively

OR* odds ratio adjusted by age by the multivariate analysis, CI confidence interval, PA power of analysis

–: values were not calculated

1202 J Cancer Res Clin Oncol (2013) 139:1199–1206

123

polymorphisms alter the risk, demographic characteristics

and biological features of tumour in Brazilian CM patients.

We initially observed that the XPC CC variant genotype

was associated with increased risk for CM, as previously

seen in Germany by Blankenburg et al. (2005) and in

Brazil by Goncalves et al. (2011). In contrast, no associa-

tion of the polymorphism with CM risk was seen in indi-

viduals from North America (Li et al. 2006) and Europe

(Figl et al. 2010). The discrepancies of results found among

studies might be attributed to the ethnic variation of the

analysed populations, since the frequency of the XPC CC

variant genotype was lower in our controls than in North-

American (6.9 vs. 16.1 %; P = 0.03) and European

(6.9 vs. 15.7 %; P = 0.03) controls. In fact, the XPC

gene encodes a protein that plays a pivotal role in the

recognition of distorted DNA structure caused by sunlight

and contributes to recruiting of other proteins of the NER

complex (Friedberg 2001). The reduced capacity of the

protein encoded by the C variant allele of the XPC A2920C

polymorphism for repairing DNA damage (Zhu et al. 2008)

may explain the increased risk for CM in carriers of the

XPC CC genotype seen in ours and in Blankenburg’s and

Goncalvez’s studies.

We found no association with the XPF T30028C poly-

morphism and risk for CM in our study, as previously

reported in Caucasians from England (Winsey et al. 2000).

Only Povey et al. (2007) found an excess of the variant

genotype in CM cases in Scotland. The discrepancies seen

among studies might not be attributed to the ethnic origin

of the populations, since similar frequencies of the XPF CC

Table 2 Frequencies of XPC A2920C, XPF T30028C, TP53 Arg72Pro and GSTP1 Ile105Val genotypes in cutaneous melanoma patients

stratified by clinical and tumour characteristics

Genotype Sun exposure Skin colour Tumour stage

Yes No PA (%) Light Others PA (%) 0 ? I ? II III ? IV PA (%)

XPC A2920C

AA 26 (40.0) 16 (47.0) 10 53 (39.5) 5 (45.4) 7 42 (39.6) 16 (44.4) 8

AC ? CC 39 (60.0) 18 (53.0) 81 (60.5) 6 (54.6) 64 (60.4) 20 (55.6)

P value 0.52 0.54 0.92

AA ? AC 53 (81.5) 28 (82.3) 5 115 (85.8) 8 (72.7) 26 95 (89.6) 26 (72.2) 69

CC 12 (18.5) 6 (17.7) 19 (14.2) 3 (27.3) 11 (10.4) 10 (27.8)

P value 0.92 0.23 0.02

TP53 Arg72Pro

ArgArg ? ArgPro 62 (95.4) 29 (85.3) 68 126 (94.0) 8 (72.7) 65 99 (93.4) 32 (88.8) 17

ProPro 3 (4.6) 5 (14.7) 8 (6.0) 3 (27.3) 7 (6.6) 4 (11.2)

P value 0.08 0.01 0.85

ArgArg 45 (69.2) 15 (44.1) 91 82 (61.2) 4 (36.4) 36 66 (62.2) 19 (52.7) 17

ArgPro ? ProPro 20 (30.8) 19 (55.9) 52 (38.8) 7 (63.6) 40 (37.8) 17 (47.3)

P value 0.02 0.14 0.34

GSTP1 Ile105Val

IleIle 22 (33.8) 17 (50.0) 35 55 (41.0) 5 (45.4) 6 39 (36.8) 21 (58.3) 62

IleVal ? ValVal 43 (66.2) 17 (50.0) 79 (59.0) 6 (54.6) 67 (63.2) 15 (41.7)

P value 0.12 0.66 0.04

XPC ? TP53

AA ? ProPro 1 (2.6) 1 (6.7) 16 1 (1.3) 3 (33.3) 87 2 (3.4) 2 (10.0) 27

AC ? CC ? ArgArg ? ArgPro 37 (97.4) 14 (93.3) 74 (98.7) 6 (66.7) 59 (96.6) 18 (90.0)

P value 0.99 0.003 0.70

XPF ? TP53

TT ? ProPro 2 (5.5) 3 (17.6) 32 5 (7.1) 2 (50.0) 71 4 (7.4) 3 (15.0) 20

TC ? CC ? ArgArg ? ArgPro 34 (94.5) 14 (82.4) 65 (92.9) 2 (50.0) 50 (92.6) 17 (85.0)

P value 0.15 0.02 0.54

A, T, Arg and Ile are wild alleles, and C, C, Pro and Val are variant alleles of the XPC A2920C, XPF T30028C, TP53 Arg72Pro and GSTP1Ile105Val polymorphisms, respectively; P values are presented herein after adjustment by the multivariate analysis. The numbers of patients

stratified by sun exposure, skin colour and tumour stage were not the same included in study (n = 146) because no consistent information could

be obtained from some patients

PA power of analysis

J Cancer Res Clin Oncol (2013) 139:1199–1206 1203

123

variant genotype were seen in ours and in Povey’s (90.0 vs.

91.8 %, P = 0.62) controls. Differences in sun exposure

may explain the discordant results found in our study and

in Povey’s study.

The TP53 ArgArg wild genotype was associated with an

increased risk for CM in our cases, in accordance with two

studies conducted in United States (Shen et al. 2003; Li

et al. 2008). The TP53 Arg72Pro polymorphism did not

alter the risk for CM in the studies conducted in United

States by Han et al. (2006), in Scotland by Povey et al.

(2007) and in Italy by Capasso et al. (2010). In contrast, the

TP53 ProPro variant genotype was associated with an

increased risk for CM in Greeks with dark skin in the

Stefanaki’s study (Stefanaki et al. 2007). The discrepancies

seen among studies might not be attributed to the ethnic

origin of the populations, since similar frequencies of the

TP53 ArgArg wild genotype were seen in ours and in

Han’s (45.9 vs. 48.9 %; P = 1.00), Povey’s (45.9 vs.

53.7 %, P = 0.12), Capasso’s (45.9 vs. 58 %; P = 0.14)

and Stefanaki’s (45.9 vs. 50.4 %; P = 0.48) controls. In

fact, the TP53 gene has an important role in the protection

of cells from DNA damage due to UV exposure, and

sequence variation in the gene might alter CM suscepti-

bility. The protein encoded by the Pro allele is more effi-

cient than Arg in inducing the expression of genes involved

in nuclear DNA repair (Siddique and Sabapathy 2006;

Altilia et al. 2012), and therefore, carriers of the TP53

ArgArg wild genotype might be under increased risk for

CM, as seen in our study. However, different patterns of

sun exposure might modify the influence of known risk

factors of the disease and may explain the association with

the TP53 ProPro genotype and increased risk for CM in

Greeks with dark skin (Stefanaki et al. 2007), since this

group is considered to have a low risk for this tumour

(Lasithiotakis et al. 2004; Whibley et al. 2009).

The GSTP1 Ile105Val polymorphism did not alter the

risk for CM in our study, in accordance with the study

conducted by Bu et al. (2007) in Sweden. In contrast, the

GSTP1 ValVal variant genotype was associated with an

increased risk for CM in Spanish in the Ibarrola-Villava’s

study (Ibarrola-Villava et al. 2011). The discrepancies of

results found among studies might be attributed to the

ethnic variation of the analysed populations, since the

frequency of the GSTP1 ValVal variant genotype was

higher in our controls than in Spanish (16.4 vs. 8.0 %;

P = 0.02) controls (Ibarrola-Villava et al. 2011). In fact,

the GSTP1 protein plays important roles against apoptosis

and acts as repressor of JNK and other kinase proteins

involved in stress responses, cell proliferation and apop-

tosis (Adler et al. 1999; Laborde 2010; Dusinska et al.

2012), besides acting in the detoxification of ROS.

Associations of the XPC CC variant genotype plus TP53

ArgArg wild genotype and TP53 ArgArg wild genotype

plus GSTP1 IleIle wild genotype with increased risk for

CM were seen in our study, suggesting a synergic action of

the genes in CM development. The XPC and TP53 genes

encode proteins that act in the NER pathway: the P53

protein acts in the transcriptional activation of the XPC

protein, which is the initial step to repair the damage

caused by the UV component in sunlight (Ford 2005). On

the other hand, the association with the GSTP1 IleIle

genotype and an increased risk for CM in our cases was

unexpected because the protein encoded by the Val variant

allele has a reduced ability to detoxify compounds.

Moreover, the protein encoded by the Ile wild allele seems

to be more efficient in protecting cells from ROS damage

than that produced by the variant allele (Henderson et al.

1998), besides acting against apoptosis (Laborde 2010).

Additionally, we assessed only among patients whether

these polymorphisms were associated with various phe-

notypic and tumour characteristics, and as far as our

knowledge reaches, this is the first study to describe the

influence of these polymorphisms in phenotypic and CM

characteristics.

We found that the TP53 ArgArg genotype was more

common in patients highly exposed to sunlight than in

those with standard sun exposure and that individuals with

this genotype and highly exposed to sunlight were under

increased risk of CM. Excesses of the TP53 ArgArg ?

ArgPro, XPC AC ? CC plus TP53 ArgArg ? ArgPro and

XPF TC ? CC plus TP53 ArgArg ? ArgPro genotypes

were also seen in patients with light skin compared to

patients with non-light skin. Finally, we observed that the

XPC CC and the GSTP1 IleIle genotypes were more

common in patients with advanced tumours than in patients

with localized tumours and that individuals with the

respective genotypes had consistent increased risks for

advanced tumour than others.

In conclusion, the data present preliminary evidence that

the XPC A2920C, the XPF T30028C, the TP53 Arg72Pro

and the GSTP1 Ile105Val polymorphisms alter the risk and

clinical characteristics of CM in a heterogeneous popula-

tion from south-eastern Brazil. However, we recognize that

our conclusions are based on relatively small numbers of

individuals and will require confirmation in additional

larger studies. If the associations with the genetic poly-

morphisms and increased risk in CM in our tropical

country be confirmed, we might be able to identify a high-

risk subset of the population, who could benefit from

a more rigorous control of sun exposure and skin

surveillance.

Acknowledgments This work was supported by Fundacao a Pes-

quisa do Estado de Sao Paulo (FAPESP) and Conselho Nacional de

Desenvolvimento Cientıfico e Tecnologico (CNPq).

Conflict of interest The authors declare no competing interests.

1204 J Cancer Res Clin Oncol (2013) 139:1199–1206

123

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