HPV prevalence and genetic predisposition to cervical cancer in Saudi Arabia
© Alsbeih et al.; BioMed Central Ltd. 2013
Received: 31 December 2012
Accepted: 17 April 2013
Published: 4 May 2013
Cervical cancer incidence is low in Saudi Arabian women, suggesting low prevalence to HPV infection due to environmental, cultural and genetic differences. Therefore, we investigated HPV prevalence and genotype distribution in cervical cancer as well as the association with 9 genetic single nucleotide polymorphisms (SNPs): CDKN1A (p21) C31A, TP53 C72G, ATM G1853A, HDM2 promoter T309G, HDM2 A110G, LIG4 A591G, XRCC1 G399A, XRCC3 C241T and TGFβ1 T10C, presumed to predispose to cancer.
One hundred cervical cancer patients (90 squamous cell carcinoma and 10 adenocarcinoma) and 100 age/sex-matched controls were enrolled. SNPs were genotyped by direct sequencing and HPV was detected and typed in tumors using the HPV Linear Array Test.
Eighty-two cases (82%) were positive for HPV sequences. Seven HPV genotypes were present as single infections (16, 18, 31, 45, 56, 59, 73) and five double infections (16/18, 16/39, 16/70, 35/52, 45/59) were detected. Most common genotypes were HPV-16 (71%), 31 (7%), and 18, 45, 73 (4% each). Only XRCC1 SNP was significantly associated with cervical cancer (P=0.02, OD=1.69; 95% CI= 1.06–2.66). However, nested analysis revealed a preponderance of HPV-positivity in patients harboring the presumed risk allele TP53 G (P=0.06). Both XRCC1 and TP53 SNPs tended to deviate from Hardy-Weinberg equilibrium (HWE; P=0.03-0.07).
HPV prevalence (82%) in cervical cancer is at the lower range of the worldwide estimation (85 - 99%). While XRCC1 G399A was significantly associated with cervical cancer, TP53 G72C showed borderline association only in HPV-positive patients. Deviation from HWE in HPV-positive patients indicates co-selection, hence implicating the combination of HPV and SNPs in cancer predisposition. Thus, SNPs could be more relevant biomarkers of susceptibility to cervical cancer when associated with HPV infection.
KeywordsCervical cancer Human papillomavirus (HPV) Predisposition Single nucleotide polymorphism (SNP)
Cancer of the uterine cervix is the 3rd most frequent malignancy affecting women worldwide and the seventh overall, with an estimated 530,000 new cases in 2008 [1, 2]. Among all the known risk factors, human papillomavirus (HPV) stands as a main cause, and high-risk HPV infections play a major role in the pathogenesis of cervical cancer with an estimated prevalence between 85% to 99% [3–7]. More than 85% of the global burden occurs in developing countries, where it accounts for 13% of all female cancers. This is due to the lack of proper screening program that has helped reducing cervical cancer incidence and mortality rates by 70% in developed countries [8, 9].
In contrast to the global view, the incidence of cervical cancer is very low in Saudi Arabia, ranking number 11 between all cancers in females and accounts only for 2.4% of all new cases , despite the lack of national screening programs. The actual reason for this low incidence is unknown. The closed society and standards of mores could reduce women exposure to HPV infection [11–14]. In addition, male circumcision is associated with a reduced risk of penile HPV infection and a reduced risk of cervical cancer in their female partners . The prevalence of HPV infection among women and its association with cervical cancer in Saudi Arabia and in similar socio-cultural societies is scanty [14, 16–20]. In a limited study performed on 120 women attending routine gynecological examination, Al-Muammar et al. reported a prevalence of 31.6% infection with HPV-16/18 . In addition, early reports are discordant [22, 23], particularly that some show high incidence, such as in Indonesia, where cervical cancer ranks number 3 after breast and colorectal tumors .
One hundred patients with histopathologically proven, locally advanced, cervical cancer were enrolled in this study out of 218 patients followed at King Faisal Specialist Hospital and Research Centre (KFSHRC) from 2009 to 2012. There was no restriction on patients’ age or histological type of cervix cancer (squamous cell carcinoma, adenocarcinoma or other). The cervix tumor samples were obtained during routine procedure for regular biopsy or from paraffin embedded tissues. One hundred age-matched women without history of cancer were enrolled and served as normal controls. Upon signing an institutionally approved informed consent, 5-ml blood samples were withdrawn for the genetic study. The KFSHRC Research Ethics Committee has approved the study (RAC # 2060 029).
DNA extraction, PCR amplification, DNA sequencing and SNP genotyping
DNA was extracted using Puregene DNA Purification Kit (Gentra System). The PCR primers used for amplification were published previously . Relevant segments of DNA were amplified by thermal cycling (95°C for 15 min, 39 rounds of 95°C for 1 min, 56°C for 1 min and 72°C for 1 min and final extension at 72°C for 7 min) using HotStarTaq DNA polymerase (Qiagen), and 50 ng template DNA in 25 micro-litter volume with standard reaction conditions. The amplified fragment was directly sequenced using the DYEnamic ET Dye Terminator Cycle Sequencing Kit (Amersham Biosciences) and were run on the MegaBase 1000 sequencer (Applied Biosystems). Sequencing results were aligned to the corresponding reference sequence and the SNPs were genotyped using SeqManII sequence analysis software (DNASTAR Inc.).
HPV detection and genotyping
We used the Linear Array HPV Genotyping Test ( LA HPV GT; Roche Diagnostics). The LA HPV GT is based on four major processes including DNA extraction, PCR amplification of target DNA, hybridization of amplified products to oligonucleotide probes and finally, the colorimetric determination using the Linear Array Detection Kit (LA DK). It enables the concurrent detection and genotyping of 37 most common anogenital HPV DNA genotypes [6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 64, 66, 67, 68, 69, 70, 71, 72, 73 (MM9), 81, 82 (MM4), 83 (MM7), 84 (MM8), 89 (CP6108) and IS39]. The test has the betaglobin gene as an internal control to show adequacy of the sample. The manufacturer states a sensitivity of 96% (95% CI: 92-98%) and a specificity of 99% (95% CI: 98-100%) and has included 3 controls, 2 negatives and 1 positive for HPV-16. The kit also enables detection of multiple infections. The primers and PCR reaction conditions were provided with the test kit. The manufacturer’s recommended methodology was strictly followed as also described previously . Positive reactions appear as blue bands on the test strip. The strips were interpreted using the HPV reference guide provided with the kit. Results were considered negative if no HPV band was detected after at least two repeated testing.
Statistical analysis and ethical considerations
A total of 100 patients and 100 controls subjects were included in the project following signing an informed consent. Samples were coded with no identifiable personal data. HPV status was compared between the patients in 5-year age groups. The association between SNPs and cervical cancer was evaluated by the odd ratio (OR) with its confidence interval. The degree of significance was calculated using the Chi-Squares method. A p-value of 0.05 or less was considered statistically significant. Statistical analysis was carried out using the SigmaPlot platform (Version 12.0, SPSS Science, IL, USA) and the free online software: Case Control Studies, Tests for Association, Institute of Human Genetics, Helmholtz Center Munich, Germany (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl).
Results and discussion
Subjects and clinical data
HPV detection and genotyping
HPV detection and genotyping showed that 82 patients (82%) were positive for HPV infection while 18 specimens proved to be negative (18%) after at least two independent testing. This prevalence of HPV infection in Saudi cervical cancer patients is at the lower range of the estimated 85% to 99% worldwide [5, 7, 30], and also contrasting with the high burden estimated from previously published data from the extended Middle East and North Africa that showed up to 98% positivity in women with preinvasive and invasive lesions . Khorasanizadeh et al. has reported slightly lower prevalence (76%) in a nearby Country .
Detection and Prevalence of different HPV genotypes in 100 cervical cancer patients
Number of patients
The most common HPV genotypes were HPV-16 (71%), followed by HPV-31 (7%), HPV-18, 45, 73 (4% each). Seven patients had double infections involving HPV-16/18 (4%), HPV-16/39, 16/70, 35/52, and 45/59 (1% each). In agreement with other studies, the most common HPV genotype was HPV-16  with an overall prevalence, including co-infections, of 77% compared to 54% in the world . In addition, HPV-16 and/or HPV-18 were present in 66% (66/100) of all patients and formed together 80% (66/82) of all HPV positive patients. This is slightly higher than the prevalence observed in Europe (74.5%), North America (76.5%) and in the whole world (70.9%). These results are close to those reported in another neighboring Country where HPV-16 (54%), HPV-18 (14%), and HPV-31 (6%) were the most commonly detected in cervical cancer patients . However, our results seem to be different from those obtained in other Middle Eastern Country where the most common HPV genotype was HPV-33, which was not detected in our patients, followed by HPV-16 and HPV-18 .
Genetic polymorphic variations
Genotypes’ and alleles’ frequencies of 7 assessed polymorphisms in 100 cervix carcinoma patients in addition to 100 age-and-gender matched control volunteers without cancers
Gene, genotype and allele
Cancer patients’ frequency
Normal volunteers’ frequency
(%, n= 100)
(%, n= 100)
CDKN1A (p21) codon 31 C>A Ser/Arg rs1801270
TP53 (p53) codon 72 G>C Arg/Pro rs1042522
ATM codon 1853 G>A Asp/Asn rs1801516
HDM2 promoter 309 T>C rs2279744
TGFβ1 codon 10 T>C Leu/Pro rs1982073
XRCC1 codon 399 G>A Arg/Gln rs25487
XRCC3 codon 241 C>T Thr/Met rs861539
Genotypes’ association with HPV status and test for deviation from Hardy-Weinberg Equilibrium
Gene, genotype and allele
HPV+/− n( %)
Deviation from HWE
(HPV+) (n= 82)
(HPV-) (n= 18)
XRCC1 codon 399 G>A Arg/Gln (rs25487)
Armitages’ trend test
Common OR= 1.67
Significance level (P-value) for deviation from HWE
TP53 (p53) codon 72 G>C Arg/Pro (rs1042522)
Armitages’ trend test:
Common OR= 0.48
Significance level (P-value) for deviation from HWE
In contrast, no association was found for TP53 G72C where cancer patients and controls without cancer have showed similar frequencies (Table 3). Nonetheless, nested analysis showed that 90% of patients with majority (G/G) allele were HPV-positive compared to 74% of heterozygous (G/C), and 68% of homozygous (C/C) variant allele, revealing a preponderance of HPV-positivity in patients harboring the majority (G) allele. In fact, this allele has been suggested to be more susceptible to high-risk HPV E6 degradation . In addition, statistical analysis showed a trend towards an association between TP53 G72C SNP genotype and HPV infection (P = 0.06; Table 3). Furthermore, testing for deviation from HWE also showed a borderline significant deviation (P = 0.07) for HPV-positive cases, meanwhile no significant deviation was observed for HPV-negative controls. Again, these results suggest that cervical cancer occurrence is not random in the population and that certain factors such as genetic SNPs, for instance having the XRCC1 A-allele or the TP53 G-allele in connection with HPV infection, favors its development. To answer the question whether these 2 SNPs exhibit cumulative effect towards HPV mediated cervical cancer, , we have computed the number of risk alleles for XRCC1 and TP53 in patients and controls. Although the patients had higher median number of risk alleles (2 compared to 1), the difference was not statistically significant (Mann–Whitney rank sum test, P = 0.12) suggesting independent effects.
Since the first identification of the potential role of Arg/Arg genotype as a risk marker for uterine cervix neoplasia , there have been many studies that investigated the association between the TP53 codon 72 polymorphism and cervical cancer in various populations; however, results were inconsistent . Although several factors were proposed as contributing factors to the discrepancies, the deviation from the Hardy-Weinberg equilibrium was identified as a principal source of divergent results . Nonetheless, there is sufficient evidence to support a positive association particularly when HPV status and/or histopathology is known. Thus, while Sousa et al. failed to confirm the association in most European countries, except Italy and United Kingdom, two other meta-analyses confirmed the association of homozygous Arg with invasive cervical cancer [39, 41], In line with our results, a recent family-based association study where HPVs status was also determined, Hu et al. confirmed that the TP53 codon 72 G (arginine) is significantly overtransmitted in Caucasian cervical cancer subjects, especially in cases infected with HPV16- and/or HPV-18 .
The prevalence of HPV infection in invasive cervical cancer in Saudi Arabia (82%) is at the lower range of that observed in the world (85%-99%), the most common HPV genotype was by far HPV-16 (71%), followed by HPV-31 (7%), HPV-18, 45, and 73 (4% each) with double infections were present in 8.5% of HPV-positive patients. Genetic predisposition showed that among the nine SNPs studied, only XRCC1 G399A was significantly (P = 0.02) associated with cervical cancer, while TP53 G72C showed borderline association (P = 0.06) only in HPV-positive patients. In addition, both SNPs showed degrees of deviation from Hardy-Weinberg equilibrium only in HPV-infected tumors, indicative of non-random distribution, hence implicating the combination of HPV and SNPs in cancer predisposition. Thus, SNPs could be more relevant biomarkers of susceptibility to cervical cancer when associated with HPV infection. Further studies with larger cohort are needed to confirm these results and better postulate the use of SNPs as biomarkers of susceptibility to cervical cancer.
Single nucleotide polymorphism
Human papilloma virus
c yclin-dependent kinase inhibitor 1A
Tumor protein p53
Human double minutes 2 (also known as MDM2)
DNA ligase IV
X-ray repair cross-complementing 1
X-ray repair cross-complementing 3
Transforming Growth Factor Beta 1
We would like to thank: Asma Tulbah (Pathology & Laboratory Medicine), Hani Salem, Osama AlOmar, Murad Al-Aker (Obstetrics & Gynecology), Khalid Balaraj, Raef Ahmad, Rana Mahmood, Mohamed Al-Dehaim, Ehab Khalil (Radiation Oncology), Belal Moftah, Khaled Al-Hadyan, Muneera Al-Buhairi, Sarah Al-Qahtani (Radiation Biology) for helping in collecting samples and clinical data; Brian Meyer (Genetics) for DNA sequencing and Mohamed Shoukri for statistical advice. This project was supported by King Abdulaziz City for Science and Technology (KACST) grant # ARP-27-12 (RAC# 2060 029).
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