Genetics and Molecular Biology, 40, 4, 751-758 (2017)

Copyright © 2017, Sociedade Brasileira de Genética. Printed in Brazil

DOI: [Link]

Research Article

Relationship between XPD, RAD51, and APEX1 DNA repair genotypes and
prostate cancer risk in the male population of Rio de Janeiro, Brazil

Ana Sheila Cypriano1*, Gilda Alves2, 7*, Antonio Augusto Ornellas2,3, José Scheinkman4, Renata Almeida5,
Luciano Scherrer6 and Claudia Lage1
1
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal de Rio de Janeiro (UFRJ), Rio de
Janeiro, RJ, Brazil
2
Instituto Nacional de Câncer, Hospital do Câncer I, Rio de Janeiro, RJ, Brazil
3
Hospital Mário Kroeff, Rio de Janeiro, RJ, Brazil
4
Hospital Universitário Antônio Pedro, Niteroi, RJ, Brazil
5
Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
6
Faculdades Kennedy, Belo Horizonte, MG, Brazil
7
Laboratório de Marcadores Circulantes, Departamento de Patologia, Faculdade de Ciências Médicas,
Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

Abstract
Susceptibility to cancer ensues in individuals carrying malfunctioning DNA repair mechanisms. The impact of Single
Nucleotide Polymorphisms (SNPs) in key DNA repair mechanisms on risk for prostate cancer was investigated in
this case-control study. Samples consisted of 110 patients with confirmed prostate cancer and 200 unaffected men,
from Rio de Janeiro, Brazil. XPD/Lys751Gln (rs13181), APEX1/Asp148Glu (rs1130409), and RAD51/G135C
(rs1801320) SNPs were analyzed by PCR-RFLP. Allelic and genotypic frequencies were calculated and compared
by Chi-Square test. The association between SNPs and clinical/epidemiological data was considered significant by
Odds Ratio analysis, with IC95% and a p-value£0.05. Only the XPD/Lys751Gln SNP significantly increased suscep-
tibility to disease in southeastern Brazilian men, with p£0.001 [OR=2.36 (1.46-3.84)], with no association with APEX1
or RAD51 SNPs. Combined XPD+RAD51 SNPs were highly associated with the disease, p£0.005 [OR=3.40
(1.32-9.20)]. A Chi-Square significant association between XPD/Lys751Gln and Gleason score was also observed
(OR=9.31; IC95%=1.19–428.0; p=0.022). Epidemiological inquiries revealed that exposure to pesticides signifi-
cantly impacted the risk for prostate cancer in this population. DNA repair dysfunctions seem to prevail among work-
ers exposed to chemical byproducts to cancer in this specific tissue. Non-invasive genotyping SNPs may help
assessment of prostate cancer risk in environmentally exposed populations.
Keywords: Prostate cancer, single nucleotide polymorphism, XPD, DNA repair, gene-environment interaction.
Received: Fevereiro 20, 2017; Accepted: Julho 24, 2017.

Introduction genetic history were identified as top risk factors for PCa
An increasing incidence of prostate cancer (PCa) has (Bostwick et al., 2004).
been observed in Brazil, associated with longer lifetimes Oxidative stress seems to influence the prostatic car-
and due to improved diagnosis methods in countrywide in- cinogenic process because of its expressive association
formation databases. The Brazilian National Cancer Insti- with aging and accumulating damage (Platz and Giovan-
tute (INCA) estimates approximately 61,200 new cases in nucci, 2006). Likewise, environmentally-borne carcino-
2016, with a risk of 61.82 cases per 100,000 men (INCA, genic agents can also damage DNA, and different DNA
2016). Factors such as hypertension, smoking, alcohol con- repair mechanisms have been implicated in alleviating such
sumption, sedentarism/obesity, hypercholesterolemia, and harmful damages (Pramanik et al., 2011). Single Nucleo-
tide Polymorphisms (SNPs) result from single-nucleotide
changes in these genes, influencing expression or function
Send correspondence to Claudia Lage. Laboratório de Radiações of the affected genes. These changes could be critical con-
em Biologia, Carlos Chagas Filho Institute of Biophysics, CCS –
cerning DNA repair functions.
Bldg G, Federal University of Rio de Janeiro (UFRJ) 21941-902 Rio
de Janeiro, RJ, Brazil. E- mail: lage@[Link] The XPD (Xeroderma pigmentosum
* both authors contributed equally for this study complementation group D) gene encodes one of the pro-
752 Cypriano et al.

teins involved in the Nucleotide Excision Repair (NER) The control group consisted of 200 men (61.6 ± 10.3 mean
pathway (O’Donovan and Wood, 1993). One of XPD’s im- age) undergoing routine tests, without suspicion of PCa, at
portant SNPs is XPD/Lys751Gln (rs13181), in which an A the Antonio Pedro University Hospital (APUH, Niterói, RJ,
® C base substitution at exon 23 causes a Lys ® Gln sub- Brazil), sampled between 2009-2010. The study was ap-
stitution in codon 751, compromising part of the C-terminal proved by the Ethics Committees of INCA (#91/05) and
domain of the XPD protein and its full DNA repair capacity APUH (#48/09). All participants signed a written informed
(White, 2009). consent. The recruited patients carried T1, T2, or T3 pros-
The APE1 endonuclease removes abasic sites from tate tumors, according to the TNM scoring system (tumor
DNA, and is the top enzyme initiating recognition of dam- extension and metastasis).
aged sites in human Base Excision Repair (BER), along
Individuals included in the study met the clinical cri-
with its 3’ ® 5’ exonuclease, DNA 3’-repair diesterase and
teria of having a palpable mass by digital rectal examina-
DNA 3’-phosphatase activities. APE1 plays a major 3’-
tion (DRE) and/or elevated PSA serum levels (C > 2.5
phosphodiesterase role in initiating the repair of oxida-
ng/mL) indicative of the occurrence of a tumor, followed
tive-generated single-strand breaks (Ramana et al., 1998).
by histopathological confirmation of PCa. All patients were
A missense G ® T substitution SNP in the APEX1 gene in treated with radical prostatectomy. Gleason scoring was
exon 5 (rs1130409) changes a critical Asp ® Glu residue at obtained by a pathologist’s biopsy evaluation and PSA lev-
codon 148. An up to date report connects this SNP to the els by clinical blood tests.
development of PCa in Asian descendents (Chen et al.,
2016). Patients and controls were interviewed following a
The human RAD51 gene codes for a bacterial RecA structured individual questionnaire covering educational
recombinase homolog, central to the Homologous Recom- level, familial cancer and medical history, place and date of
bination Repair (HRR) mechanism (Galkin et al., 2006). birth, place of birth of father and mother, weight, height,
The RAD51 protein is critical for maintaining genomic in- and place of residence. We also profiled the occurrence of
tegrity by repairing DNA double-strand breaks. The prostate and other cancers in first-degree relatives, smoking
RAD51 polymorphism (rs1801320) implies in a G ® C status, and alcohol consumption. Patients and controls were
substitution mapping upstream the 5’ untranslated pro- asked to self-declare skin color, which is a normal question
moter region at -135 bp from the transcription start. Al- in such inquiries in Brazil. Controls and patients were ex-
though the functional consequences of this SNP remain to cluded if they showed genetic syndromes and past cancer
be clarified, a single nucleotide change in this CpG pro- history.
moter island may up-regulate gene expression, thus affect-
ing RAD51 mRNA levels (Antoniou et al., 2007). This SNP Genotyping
has been linked to breast and ovarian cancer susceptibility
due to the supposed interaction of RAD51 with BRCA1 Genomic DNA was isolated from 4-5 mL peripheral
and BRCA2 proteins, with an especially higher risk for car- blood by proteinase K digestion and phenol-chloroform ex-
riers of BRCA2 mutations (Levy-Lahad et al., 2001). traction (Sambrook, 1989). The selected SNPs were geno-
The investigation on this assembly of SNPs was de- typed by polymerase chain reaction-restriction fragment
signed because they significantly impact main DNA repair length polymorphism (PCR-RFLP). The XPD/Lys751Gln
mechanisms (NER, BER and HRR, respectively) and ge- (rs13181), RAD51/G-135C (rs1801320), and APEX1
netic instability and, under this perspective, had never been Asp148Glu (rs1130409) SNPs were determined following
addressed in a Brazilian population before. Considering the conditions described by Baccarelli et al. (2004), Wang et
importance of DNA repair failures in cancer development, al. (2001), and Hu et al. (2001), respectively.
the aim of this work was to investigate the contribution of
XPD and APEX1 amplicons were digested by 10 U of
SNPs in key genes XPD/Lys751Gln, APEX1/Asp148Glu
the specific restriction endonucleases (37 oC, 2 h). The
and RAD51/G-135C in the susceptibility to PCa in a
XPD/Lys751Gln genotypes A/A, A/C, or C/C were pro-
case-control study in Rio de Janeiro, Brazil.
filed as PstI digestion products of 100/224,
66/100/158/224, or 66/100/158 bp bands, respectively. The
Subjects and Methods APEX1/Asp148Glu genotypes T/T, T/G, or G/G were pro-
filed as BfaI digestion products of 164, 164/144/20, or
Study population
144/20 bp bands, respectively. For RAD51/G-135C ampli-
For this study, 110 patients (62.0 ± 6.5 mean age at di- cons, digestions were performed with 10U of BstNI (60ºC,
agnostic) who had undergone radical prostatectomy and 1 h). The genotypes G/G, G/C, or C/C were profiled as di-
subsequent chemo- and/or radiotherapy were recruited be- gestion products of 71/87, 71/87/157, and 157 bp bands, re-
tween 2006-2008 from the National Cancer Institute spectively. All samples were resolved on 3% agarose gels
(INCA) and Mario Kroeff Hospital (Rio de Janeiro, Brazil). and visualized by ethidium bromide staining.
DNA repair SNPs in prostate cancer 753

Statistical analyses The sampled populations were native to southeastern

Genotypic frequencies between patient/control Brazil, mainly from the Rio de Janeiro metropolitan region
groups were analyzed by Chi-Square Test and Odds Ratios (80%). The majority self-declared as ethnically white
with CI=95%. Contingency tables were used to compare (53.8%), followed by brown or mulatto (30.7%) and black
groups concerning age, socio-economical and life style as- (15.5%). PSA values were obtained for 79 patients, ranging
pects by Chi-Square Test. Data were analyzed with Statisti- from 0.78-38.0 ng/mL (median 7.2 ± 5.4 ng/mL) (Table 2).
cal Package 17.0 for Social Sciences (SPSS). Levels of Additional comparisons of SNP with age, prognosis, PSA
significance p£0.05, corresponding to 95.0% confidence, level, and Gleason score unveiled two extra implications:
were considered in all analyses. All polymorphisms were (a) a Chi-Square significant association between XPD SNP
regarded as potential markers by using the collective crite- and Gleason score (OR=9.31; 95%CI=1.19–428.0;
ria of sensibility, specificity, positive and negative predic- p=0.022); (b) the RAD51 SNP related with unclear progno-
tive values, and test accuracy. sis (p=0.031).

Prostate cancer risk and DNA repair genotyping

Results
Genotypes of XPD, RAD51, and APEX1 were deter-
Population profiling and clinical records mined for 110 patients and 200 controls. The most common
Regarding age, there was no significant difference allele was considered as the reference one, whereas the less
between patients (62.0±6.5) and control groups common ones were grouped as variants (risk polymor-
(61.6±10.3). Age-pairing between groups was essential phism) (Table 3). Neither RAD51 (OR=1.13;
concerning duration of exposure to environmental carcino- 95%CI=0.64–1.96) nor APEX1 polymorphic genes
gens. Case and control populations were also profiled simi- (OR=0.88; 95%CI=0.55–1.42) were associated with risk
larly for basic items listed in Table S1 (geographic origin, for PCa. Only for XPD (OR=2.36; 95%CI=1.46–3.84) a
education level, ethnic profile, familial cancer history, positive association was found for variant C/C or A/C ge-
chronic diseases). When exposure to risk factors was notypes. Wild-type RAD51 patients were significantly as-
weighted (tobacco, alcohol, or drug consumption), no sig- cribed as the poorer prognosis (Table 2).
nificant differences were found between groups, with Among the SNPs, the combined polymorphisms
smokers and drinkers prevailing in both. Exposure to envi- XPD/RAD51 were found to have a harmful association
ronmentally-borne agents (pesticides) was the only remark- (OR=3.40; 95% CI=1.32–9.20; p£0.05). Other combina-
able difference between case and control populations, and tions such as RAD51/APEX1 SNPs (OR=0.86;
that caused a significant difference to appear (p<0.0001) to- 95%CI=0.28–2.60), XPD/APEX1 (OR=2.30;
wards the patient’s group. While 21.1% of patients de- 95%CI=0.76–8.08), or XPD/RAD51/APEX1 (OR=1.43;
clared having manipulated pesticides, only 3.5% of 95%CI=0.34–5.07) resulted in non-significant risks for
controls were subjected to this occupational hazard (Table PCa (Table S2).
1). In a comparative analysis with the International
HapMap database ([Link]), only the XPD poly-
morphic allele and genotypic frequencies were statistically
Table 1 - Exposure to occupationally-borne and other risk factors between
different in relation to Chinese (CHB) and Japanese (JPT)
case and control groups.
populations, calculated by the Chi-Square test (Table
Risk Factors Groups p value S3).The variant allele frequency ranged from 0.076 for Jap-
anese (JPT) to 0.358 for Native American Indians (GIH).
Controls, n (%) Cases, n (%)
In order to estimate whether these polymorphic genes
Organic solvents 43 (21.3) 9 (8.3)
could fulfill the role of diagnostic/prognostic markers, we
Chronic diseases 91 (45.7) 45 (41.3) performed a data performance diagnostic test for available
Pesticides 7 (3.5) 23 (21.1) a genotypes. As shown in Table 4, the combination
Combustion products 5 (2.5) 10 (9.2) p < 0.0001 XPD/RAD51 SNPs scored better for sensitivity, specificity,
Combustion + solvent 3 (1.5) 1 (0.9) and accuracy.
None 50 (25.2) 21 (19.2)
Totals 199* (100) 109* (100) Discussion
Notes: p-value: descriptive level of the chi-square (Pearson). Only one The association between three dysfunctional SNPs
p-value refers to a statistical model that indistinguishably compares all (Asp148Glu/APEX1, G-135C/RAD51 and
variables listed between control and patients’ groups.
a Lys751Gln/XPD) and PCa susceptibility was evaluated in
this particular environmental agent was highly significant (p < 0.05) in
terms of risk for prostate cancer in exposed men. this case-control study. This is the first Brazilian study to
*each patient was allocated in just one category, the one to which he de- cover SNPs in genes implicated in three main DNA repair
clared to have been exposed to for longer periods. pathways in a PCa population in Brazil. The present study
 754

Table 2 - SNPs and clinic-pathological characteristics in prostate cancer patients. Results shown in bold were statistically significant.

XPD RAD51 APEX1

Clinical record wild-type polymorphic OR wild-type polymorphic OR wild-type polymorphic OR
(95% CI) (95% CI) (95% CI)
Age (n=110)
0.82 0.47 0.90
(0.32 - 2.04) (0.17 - 1.28) (0.37 - 2.21)
< 60 12(30%) 24(34.3%) X2=0.212 24(28.6%) 12(46.2%) X2=2.788 21(31.8%) 15(34.1%) X2=0.062
p=0.645 p=0.095 p=0.804
> 60 28(70%) 46(65.7%) 60(71.4%) 14(53.8%) 45(68.2%) 29(65.9%)
Prognosis (n=43) X2=3.055 p=0.217
Good 1(11.2%) 5(14.3%) 5(13.9%) 1(14.3%) X2=6.954 2(9.5%) 4(18.2%) X2=0.897
Bad 4(44.4%) 24(68.6%) 26(72.2%) 2(28.6%) p=0.031 15(71.4%) 13(59.1%) p=0.638
Uncertain 4(44.4%) 6(17.1%) 5(13.9%) 4(57.1%) 4(19.1%) 5(22.7%)
Gleason Score (n=57)
9.31 0.40 1.13
(1.19 – 428.0) (0.06 - 1.85) (0.33 - 3.82)
X2=5.907 X2=1.711 X2=0.053
<7 15(93.8%) 25(61%) p=0.015 25(56.8%) 10(76.9%) p=0.191 20(64.5%) 16(61.5%) p=0.816
³7 1(6.2%) 16(39%) 19(43.2%) 3(23.1%) 11(35.5%) 10(38.5%)
PSA (n=79)
1.74 0.53 0.57
(0.54 - 5.46) (0.17 - 1.64) (0.19 - 1.69)
X2=1.174 X2=1.600 X2=1.289
< 5ng/mL 9(39.1%) 15(26.8%) p=0.278 14(25.9%) 10(40%) p=0.206 12(25.5%) 12(37.5%) p=0.256
³ 5ng/mL 14(60.9%) 41(73.2%) 40(74.1%) 15(60%) 35(74.5%) 20(62.5%)
Cypriano et al.
DNA repair SNPs in prostate cancer 755

Table 3 - Genotypic frequencies of XPD, RAD51 and APEX1 genotypes in 110 prostate cancer patients and 200 controls. Results shown in bold were sta-
tistically significant.

XPD RAD51 APEX1 Totals

A|A A|C C|C G|G G|C C|C T|T T|G G|G

Patients n (%) 40 (36.4) 55 (50.0) 15 (13.6) 84 (76.4) 24 (21.8) 2 (1.8) 66 (60.0) 33 (30.0) 11 (10.0) 110
(100)
Control group n (%) 115 (57.5) 68 (34.0) 17 (8.5) 157 (78.5) 40 (20.0) 3 (1.5) 114 (57.0) 84 (42.0) 2 (1.0) 200 (100)
Totals 155 (50.0) 123 (39.7) 32 (10.3) 241 (77.7) 64 (20.6) 5 (1.6) 180 (58.1) 117 (37.7) 13 (4.2) 310 (100)
OR 2.36 1.13 0.88
(1.46 – 3.84) (0.64 – 1.96) (0.55 – 1.42)
(95% CI) p<0.001 p=0.766 p=0.696
Hardy-Weinberg Equilibrium p=0.345 p=0.788 p=0.337

n: number of individuals

Table 4 - Data performance diagnostic test calculated for each polymorphism alone and combined

Parameters Probabilities
XPD RAD51 APEX1 XPD + RAD51
Sensitivity (%) 63.6 (54.3-72.0) 23.6 (16.7-32.4) 40.0 (31.3-49.3) 62.1 (44.0-77.3)
Specificity (%) 57.5 (50.5-64.1) 78.5 (72.3-83.6) 57.0 (50.0-63.7) 68.0 (54.2-79.2)
Positive predictive value (%) 45.2 (37.5-53.0) 37.7 (27.2-49.5) 33.8 (26.3-42.3) 52.9 (36.7-68.5)
Negative predictive value (%) 74.2 (66.7-80.4) 65.1 (58.9-70.8) 63.3 (56.1-70.0) 75.6 (61.3-85.7)
Accuracy (%) 59.7 (54.1-65.0) 59.0 (53.5-64.3) 50.1 (45.4-56.5) 65.8 (54.8-75.3)

was, thus, designed to improve the genetic profiling of PCa between cases and controls, a remarkable positive
patients by mapping a panel of DNA repair SNPs and as- correlation was found only for exposure to pesticides. The
sess its correlation with clinical parameters. A comparative expressive amount of XPD AC and CC polymorphic pa-
epidemiological inquiry on known cancer risk factors was tients exposed to pesticides implies that they can steeply ac-
applied to cases and controls. The collected data revealed cumulate damages because of NER malfunction, leading to
that exposure to environmental factors, as well as the increased PCa risk.
XPD/Lys751Gln (rs13181) polymorphism appeared to be
associated with increased risk for PCa. Extensive DNA damage was detected in exposed
floriculturists compared to non-exposed ones, and expo-
Major areas of research on PCa have focused on three
sure to pesticides appeared as the primary genotoxic factor
main points: (1) assessment of how life style/environmen-
for long-term carcinogenesis (Bolognesi et al., 2004).
tal factors/diet can influence carcinogenesis; (2) strategies
Theophilou et al. (2015) followed-up transgenerational al-
to delay disease onset and progression; and (3) finding ac-
terations in human prostate tissue samples over 30 years,
curate biomarkers to distinguish between indolent and ag-
correlated with geographic distribution and exposure to
gressive forms (Shen and Abate-Shen, 2010). The present
risk factors. Indeed, genotoxic agents seem to ensue long-
study was designed to target items (1) and (3).
lasting genetic/epigenetic alterations, imprinting pheno-
The roles of XPD and RAD51 SNPs in prostate typic pro-malignant changes.
cancer proneness
Although the association of lifestyle and cancer risk
A significantly increased risk for lymphohemato- had already been highlighted in a number of studies, none
poietic, prostate, melanoma, and brain neoplasms has been of the other noxious habits (smoking, drug use), or social
surveyed among pesticide handlers and industry workers aspects could be ascribed to PCa risk in the studied group.
(Koutros et al., 2010). Moreover, the NER pathway was re- Here, only the XPD SNP was related to the risk of develop-
cently shown to repair damage induced by carcinogens, in- ing PCa. It is worthy of note that XPD-mediated NER cor-
cluding pesticides (Barry et al., 2012). Accordingly, data rects damages caused by environmental agents and reactive
from the present study associated an NER dysfunction oxygen species (Mitra et al., 2001), these being important
(XPD) with high risk for PCa (Table 3), especially in men triggers of PCa. This supports the complex genetic basis of
exposed to pesticides. When risk factors were compared PCa involving multiple susceptibility genes.
756 Cypriano et al.

Sulfolobus acidocaldarius XPD (SaXPD protein) Studies about ethnically-linked differences strengthen the
harbors a catalytic site for its SaRAD51 protein, and all need to continue research on new confident biomarkers.
SaXPD helicase domains were conserved in human XPD
(Fan and Wilson, 2005). Four domains comprise the The APEX1 SNP counteracting risky genotypes
SaXPD’s catalytic core: two RAD51/RecA-like domains Interestingly, the APEX1 deficiency caused the risk
(HD1-HD2) and two additional HD1 domains inserted to- for PCa to drop (Table S2), and this result is interpreted as
gether. Twenty-two out of the known 26 point mutations re- deriving from the simultaneous knockdown of three key
lated to XPD-linked human diseases mapped there routes of DNA repair: HRR, NER, and BER. This probably
(Xeroderma pigmentosum, Cockayne syndrome, and drives prostatic cells to death, protecting the prostatic tissue
Trichothiodystrophy). Aloyz et al. (2002) showed that the from the outbreak of potentially malignant clones.
physical association between human XPD and RAD51 pro- The APEX1/Asp148Glu (rs1130409) SNP was re-
teins acting to remove DNA crosslinks maybe assembled in corded in another Brazilian population (Kuasne et al.,
a larger complex. They appear to be recombination coun- 2011), which appeared to be more susceptible to PCa. In
terparts, modulating the HRR-mediated resistance to our group, however, no susceptibility was connected with
crosslinks. this SNP, maybe because of other genetic background dif-
By playing an important role in recovering damaged ferences between the sampled populations and the low
DNA in vertebrates, the RAD51 hyper-recombination phe- penetrance of this SNP for cancer development.
notype can potentiate genomic instability (Klein, 2008).
Schild and Wiese (2010) suggest that RAD51 overexpres- Genetic instability assessment and decision making
sion can contribute to carcinogenic progression. Since XPD in prostate cancer
and RAD51 are counterparts in the repair of DNA breaks, Data compiled for this Brazilian group revealed the
their double malfunctions appeared statistically related to need for a clinical follow-up, along with a panel of key
high risk for PCa, perhaps because of the triggered genomic DNA repair dysfunctions, instead of just one or two genes.
instability. Noteworthy, wild-type RAD51 patients under- Moreover, biomarker research has mainly targeted diagno-
went worse prognoses, probably because of better repair of sis, rather than prognosis and outcomes (Prensner et al.,
therapy-induced DNA damages by HRR, while 2012), which are capable of tailoring individual therapeu-
XPD/Lys751Gln patients displayed higher Gleason scores tics. For instance, Chantre-Justino et al. (2015) reported
(Table 2). Despite the small number of cases analyzed, that patients with lower transcript levels of the APE1 gene
these correlations were highly significant. belonged to the cohort with 100% lethality from aggressive
Regarding general clinical findings, both specificity bladder cancer. In prostate cancer, the expression of a panel
and sensitivity tests also revealed that XPD and of 17 genes belonging to nine different DNA damage and
XPD+RAD51 genotypes scored good negative predictive repair (DDR) pathways was determined in prostatectomy
values (Table 4). Regarding the potential validity of our samples in a cohort study by Evans et al. (2016), where
proposed panel, since XPD and RAD51 SNPs significantly high expression of NER and BER genes significantly re-
scored the top OR in a small population, they would proba- lated to metastasis and lower overall survival. The authors
bly reach a much more relevant status as risk markers when envisaged the screening of individual “DDR signatures” to
assessing a larger group. track aggressive prostate cancers on the basis of their dif-
ferential response to therapy. These two studies on genetic
A Spanish multicenter group revealed that genes in- markers in tumors of two urinary-related organs point out
volved in HRR could be associated with poor prognosis in how tissue-specific the neoplastic process can be driven.
PCa (Henriquez-Hernandez et al., 2014). Their findings In this study, we observed that patients with a poly-
corroborate ours, regarding the association of HRR SNPs morphic XPD genotype significantly ranked at higher
with unclear prognosis. The same group reported that DNA Gleason scores, indicating that NER-deficient individuals
repair genetic variants (XRCC6 and MVP) were associated seem to bear genetically more instable tumors. In the ab-
with more aggressive outcomes (Henriquez-Hernandez et sence of the error-free NER pathway, other concurrent er-
al., 2016). ror-prone mechanisms could take control of less accurately
Our genetic analysis is endorsed by the HapMap data- repair of DNA damages. In support of this finding, XPD
base, i.e., the Southeast Brazilian population is quite differ- SNPs rs13181 and rs1799793 (XPD/Asp312Asn) tended to
ent from the Japanese and Chinese. The European coloniza- group under high Gleason scores and advanced tumor
tion remains strongly imprinted in Brazilian ethnicity, stages, although results were not statistically significant
remaining genetically distant from Eastern populations. (Agalliu et al., 2010). Altogether, these findings help to un-
Accordingly, the genotypic profiling seen by Henriquez- veil genetic features on how this disease is triggered and
Hernandez et al. (2014) in a Spanish population and a progresses in different populations, whose heterogeneity
meta-analysis performed by Mi et al. (2012) with Asian and can render even more complex outcomes due to gene-
African populations matches our HapMap assessments. environment interactions. Present findings await corrobo-
DNA repair SNPs in prostate cancer 757

ration by other studies, focusing on environmental and eth- the survival of patients with urothelial carcinoma of the
nic factors impacting this important male cancer. bladder). Oncol Rep 34:1667-1674.
Complimentary tests, such as ultrasonography and bi- Chen Y, Li J and Mo Z (2016) Association between the APEX1
Asp148Glu polymorphism and prostate cancer, especially
opsy should be included in more precise diagnostics, al-
among Asians: A new evidence-based analysis. Oncotarget
though the lower cutoff of 4.1 ng/ml of PSA protein, for 7:52530-52540.
example, is consensually taken as a good negative predic- Evans JR, Zhao SG, Chang SL, Tomlins SA, Erho N, Sboner A,
tion (Van den Broeck et al., 2015). If early cancer detection Schiewer MJ, Spratt DE, Kothari V, Klein EA, et al. (2016)
by current tests is the desired target in cancer prevention, Patient-level DNA damage and repair pathway profiles and
genotyping instability-prone DNA repair SNPs can be en- prognosis after prostatectomy for high-risk prostate cancer.
visaged as the earliest informative test amongst all. JAMA Oncol 2:4710480.
Fan J and Wilson DM (2005) Protein-protein interactions and post
translational modifications in mammalian base excision re-
Acknowledgments
pair. Free Radic Biol Med 38:1121-1138.
Financial support was provided by CAPES (Coor- Galkin VE, Wu Y, Zhang XP, Qian X, He Y, Yu X, Heyer WD,
denação de Aperfeiçoamento de Pessoal de Nível Superior) Luo Y and Egelman EH (2006) The Rad51/RadA N-ter-
and a fellowship to CL by Conselho Nacional de Desenvol- minal domain activates nucleoprotein filament ATPase ac-
tivity. Structure 14:983-992.
vimento Científico e Tecnológico (CNPq). We also wish to
Gangwar R, Manchanda PK and Mittal RD (2009) Implications of
acknowledge the assistance of Dr. Ana Hatagima (FioCruz,
XRCC1, XPD and APE1 gene polymorphism in North In-
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The following online material is available for this article:
Ramana CV, Boldogh I, Izumi T and Mitra S (1998) Activation of
Table S1 - Distribution of patients and controls among dif-
apurinic/apyrimidinic endonuclease in human cells by reac-
tive oxygen species and its correlation with their adaptive re-
ferent socio-economical and life style groups.
sponse to genotoxicity of free radicals. Proc Natl Acad Sci Table S2 - Frequencies of the combined genotypes in 110
USA 95:5061-5066. prostate cancer patients and 200 controls.
Table S3 - Allelic and genotype frequencies of XPD
Sambrook J (1989) Molecular Cloning: A Laboratory Manual.
Lys751Gln in HapMap and Brazilian populations.
2nd edition. Cold Spring Harbor Laboratory Press, New
York, 1659 p.
Associate Editor: Mara H. Hutz
Schild D and Wiese C (2010) Overexpression of RAD51 sup-
License information: This is an open-access article distributed under the terms of the
presses recombination defects: A possible mechanism to re- Creative Commons Attribution License (type CC-BY), which permits unrestricted use,
verse genomic instability. Nucleic Acids Res 38:1061-1070. distribution and reproduction in any medium, provided the original article is properly cited.