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Carcinogenesis Advance Access originally published online on February 6, 2008
Carcinogenesis 2008 29(4):875-879; doi:10.1093/carcin/bgn039
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

p53 codon 72 polymorphism associated with risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never-smokers

Xuemei Ji1, Ana S. Neumann2,3, Erich M. Sturgis1,2, Karen Adler-Storthz4, Kristina R. Dahlstrom1,5, John T. Schiller6, Qingyi Wei2 and Guojun Li1,2,*

1 Department of Head and Neck Surgery
2 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
3 Dental Division of the Royal Children's Hospital, Melbourne 3052, Australia
4 Department of Diagnostic Sciences, The University of Texas Health Science Center-Dental Branch, Houston, TX 77030, USA
5 Department of Genetics and Developmental Medicine, University of Washington, Seattle, WA 98195, USA
6 Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

* To whom correspondence should be addressed. Tel: +1 713 792 0227; Fax: +1 713 794 4662; Email: gli{at}mdanderson.org


   Abstract
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 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 
The tumor suppressor p53 protein can be bound, degraded and inactivated by the human papillomavirus (HPV) E6 oncoprotein. The p53 protein's susceptibility to this oncoprotein may be influenced by the p53 codon 72 polymorphism, but the role of such a polymorphism in the development of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP) has not been established. To investigate the role of the p53 codon 72 polymorphism in the risk of HPV16-associated SCCOP, we conducted a hospital-based case–control study of 188 non-Hispanic white patients with newly diagnosed SCCOP and 342 cancer-free control subjects frequency matched by age (±5 years), sex, tobacco smoking status and alcohol drinking status. We found that HPV16 seropositivity was associated with an increased risk of SCCOP [adjusted odds ratio (OR), 5.7; 95% confidence interval (CI), 3.7–8.7], especially among never-smokers (adjusted OR, 14.1; 95% CI, 6.0–32.9) and among subjects with the p53 codon 72 variant genotypes [Arginine (Arg)/Proline (Pro) and Pro/Pro] (adjusted OR, 9.2; 95% CI, 4.7–17.7). A significant multiplicative interaction on the risk of SCCOP was also found between the p53 codon 72 polymorphism and HPV16 seropositivity (P = 0.05). Among never-smokers, the risk of SCCOP for those who had both HPV16 seropositivity and p53 codon 72 variant genotypes (Arg/Pro + Pro/Pro) was particularly high (adjusted OR, 22.5; 95% CI, 4.8–106.2). These findings suggest that p53 codon 72 variant genotypes modify the risk of HPV16-associated SCCOP and may be markers of genetic susceptibility to HPV16-associated SCCOP, especially among never-smokers.

Abbreviations: Arg, Arginine; CI, confidence interval; HPV, human papillomavirus; MDACC, M. D. Anderson Cancer Center; OR, odds ratio; PCR, polymerase chain reaction; Pro, Proline; SCCOP, squamous cell carcinoma of the oropharynx


   Introduction
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 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 References
 
Squamous cell carcinoma of the head and neck, which includes squamous cell carcinomas of the oral cavity, oropharynx, hypopharynx and larynx, is among the five most common cancers and accounts for >500 000 new cases every year worldwide (1). The leading risk factors for these cancers are tobacco use and alcohol consumption; but over the past decade, oncogenic human papillomavirus (HPV) has been repeatedly detected in squamous cell carcinoma of the oropharynx (SCCOP) (2). In numerous studies, ~50% (39–73%) of SCCOP cases have been found to contain portions of the HPV genome (3–6), suggesting that HPV plays an etiologic role in subset of SCCOP, termed HPV-associated SCCOP. Unlike HPV-negative tumors, HPV-associated tumors tend to have the wild-type p53 gene and HPV DNA, express HPV E6 and/or E7, have decreased expression of cyclin D and pRb and have upregulated p16 (7–9). Of the known HPV types, oncogenic HPV16 is the most frequent, accounting for ~90% of HPV-associated tumors of the oropharynx (5,10,11). The presence of HPV16 antibodies, a marker of past exposure to HPV16, has been positively associated with increased risk of cervical cancer (12,13) and SCCOP (11,14–17). Although HPV infection may be a major risk factor for SCCOP (5,10), the malignant conversion of oropharyngeal infection by oncogenic HPV is uncommon, suggesting an interindividual variation in genetic susceptibility to HPV-associated carcinogenesis.

The p53 protein, as a tumor suppressor, has a highly conserved role as a ‘guardian of the genome’ and is central to cellular anticancer mechanisms (18). In response to genotoxic injuries, p53 can dictate cellular fate (19–21) by initiating cell cycle arrest, promoting DNA repair (22), triggering apoptosis (23) and inducing growth arrest and senescence (24). Although direct mutations can alter or inactivate p53, interactions with the oncogene products of oncogenic viruses (e.g. HPV) can also cause aberrations in the p53 regulation (23,25). The malignant transforming potential of oncogenic HPV is attributed to its oncoproteins, E6 and E7 (26), and the E6 oncoprotein can bind to the tumor suppressor p53, promoting ubiquitination and rapid proteasome-mediated degradation (27,28). Because of the important roles that p53 plays in carcinogenesis and the complex relationship between p53 and HPV oncogenes, it is reasonable to expect that p53 polymorphisms can modify interindividual variations in susceptibility to cancer. To date, 20 non-synonymous polymorphisms have been identified in the human p53 gene (29). Among them, the polymorphism in codon 72 of exon 4, encoding either Proline (Pro) or Arginine (Arg), has been proven to influence functional activity, mutant behavior, susceptibility to SCCOP and response to treatment (30,31). Compared with p53 72Pro, p53 72Arg appears to suppress cellular transformation more effectively, to induce apoptosis more efficiently (32), but to be possibly more susceptible to HPV E6-mediated degradation (33). In addition, some studies have suggested that this polymorphism is correlated with the risk of HPV-associated cervical cancer (20,33,34).

Several studies have examined the effect of p53 codon 72 polymorphism on the risk of HPV-associated squamous cell carcinomas of head and neck (35–37). However, to our knowledge, only one study was restricted to SCCOP, finding that p53 Pro/Pro genotype was a risk factor for HPV-associated SCCOP in a case–control study of 77 SCCOP patients and 141 control subjects without adjustment for other confounders, such as smoking and alcohol consumption (36). To further investigate the possible roles of the p53 codon 72 polymorphism in the risk of HPV-associated SCCOP, we evaluated the relationship between the p53 codon 72 polymorphism and HPV16 serological status and explored the joint effects of p53 genotypes and HPV16 serological status in subgroups of subjects stratified by smoking status in a case–control study of 188 case subjects newly diagnosed with SCCOP and 342 cancer-free control subjects.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 References
 
Study subjects
Consecutive patients with newly diagnosed, histopathologically confirmed and untreated SCCOP were recruited between May 1996 and January 2001 through the Head and Neck Center at The University of Texas, M. D. Anderson Cancer Center (MDACC) in Houston, Texas, as part of a molecular epidemiologic study of squamous cell carcinoma of the head and neck. The controls included two groups of cancer-free subjects. One group were 156 (45.6%) healthy controls who were selected from a control pool of enrollees at the Kelsey-Seybold Clinic, a multi-specialty physician practice with multiple clinics throughout the Houston metropolitan area. The overall response rate was ~75%. The other controls were 186 (54.4%) healthy visitors who were accompanying cancer patients to the outpatient clinics at MDACC but genetically unrelated to the cases. The response rate for this MDACC control group was ~80%. The accrual rate was 81% for the cases. Both control groups had no previous history of any cancer and were not on therapies or treatment for any diseases and were frequency matched to the cases on age (±5 years), gender and smoking status. To avoid confounding due to ethnic characteristics, we included only non-Hispanic whites in both the case and the control groups.

Participants who had smoked >100 cigarettes in their lifetimes were categorized as ‘ever-smokers’ and the rest as ‘never-smokers’. Participants who had drunk alcoholic beverages at least once a week for >1 year were categorized as ‘ever-drinkers’ and the rest as ‘never-drinkers’. ‘Former smokers’ and ‘former drinkers’ were defined as those ever-smokers and ever-drinkers who had quit such behavior for at least 1 year before enrollment in the study and the remaining ever-smokers and ever-drinkers were defined as ‘current smokers’ and ‘current drinkers’. After signing informed consent forms, which had been approved by the institutional review boards of both MDACC and Kelsey-Seybold, study participants completed a questionnaire regarding demographic and relevant risk factors and donated 30 ml of blood.

HPV16 serological testing
HPV16 L1 virus-like particles generated from recombinant baculovirus-infected insect cells were used to test for antibodies against HPV16 in the plasma of study subjects by using a standard enzyme-linked immunosorbent assay, as described previously (12,38). Control sera, known to be positive and negative, were also tested in parallel with the study samples in duplicate on each plate. The cutoff level, above which optical density values were considered positive and below which optical density values were considered negative for HPV16, was based on the absorbance value of a standard pooled serum known to be at the threshold of detection. Samples that were in 15% of the cutoff were tested twice more; those positive in all three runs were considered positive. We also randomly selected 10% of the samples to retest for confirmation of the original findings. To eliminate potential binding interference by heparin, we treated the plasma samples with 43 U/ml heparinase I (Sigma, St Louis, MO) before testing (39). We tested heparinized plasma, as well as serum, obtained from three individuals and did not detect discernible difference between the reactions of the serum samples and the heparinized plasma samples treated with heparinase I.

p53 genotyping
Leukocyte cell pellets were obtained from the buffy coat by centrifugation of 1 ml of each subject's whole blood; then, genomic DNA was extracted from each pellet using the Qiagen DNA Blood Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. We used polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis to identify the p53 polymorphism in codon 72 with the primers 5'-ATCTACAGTCCCCCTTGCCG-3' and 5'-GCAACTGACCGTGCAAGTCA-3'. The PCR reaction was performed in 25 µl volumes containing ~50 ng of genomic DNA template, 12.5 pmol of each primer, 0.1 mM of each deoxynucleoside triphosphate, 1x PCR buffer (50 mM KCl, 10 mM Tris–HCl and 0.1% Triton X-100), 1.5 mM MgCl2 and 1.5 U of Taq polymerase (Promega Corporation, Madison, WI). PCR amplification involved an initial denaturation step at 94°C for 4 min, 35 cycles of 94°C for 40 s, 56°C for 30 s and 72°C for 30 s; and a final extension at 72°C for 10 min. Then, the PCR product (a 296 bp fragment) was digested by BstUI (New England BioLabs, Beverly, MA) overnight at 60°C and resolved on 2.5% NuSieve 3:1 agarose gel (FMC BioProducts, Rockland, ME) with ethidium bromide and photographed with Polaroid film. The p53 72Pro allele, which lacked the BstUI restriction site, had only a single 296 bp band, whereas p53 72Arg, which had the BstUI restriction site, produced 169 and 127 bp bands. More than 10% of the samples were retested randomly, and the results were 100% concordant.

Statistical analysis
All the statistical analyses were performed with Statistical Analysis System software (Version 9.1; SAS Institute, Cary, NC). The differences in the distributions of selected demographic variables, tobacco smoking, alcohol drinking and p53 allele and genotype frequencies between cases and controls were evaluated using the {chi}2 test. Both univariate and multivariate logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for cases and controls who were stratified by age, sex, p53 genotype, smoking, drinking and HPV16 status. In the multivariate logistic regression model, OR and 95% CI were adjusted by age, sex, smoking and drinking. Because only a small number of individuals (11 cases and 23 controls) were homozygous for the Pro allele, precluding meaningful subgroup analyses, p53 genotype data were dichotomized according to a dominant model, in which homozygosity for Arg/Arg was coded as zero and the heterozygous state and homozygosity for Pro/Pro were coded as one. All tests were two sided, and a P value of 0.05 was considered as the cutoff for statistical significance.


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 References
 
The distributions of demographic variables and risk factors of the 188 cases and the 342 cancer-free controls are summarized in Table I. All were non-Hispanic whites and the two groups appeared to be adequately frequency matched for age, sex, smoking and alcohol consumption, but these factors were also adjusted for in later analyses for controlling any residual effects. When comparing p53 codon 72 genotype distributions between cases and controls, no significant differences were found ({chi}2 = 0.356, P = 0.837). The distributions of p53 genotypes among the controls were in agreement with Hardy–Weinberg equilibrium ({chi}2 = 0.391, P = 0.532). The p53 codon 72Pro allele was present in 45.2% of the cases and 47.6% of the cancer-free controls (P = 0.661), and the p53 codon 72Pro allele frequency was 25.5% in the cases and 27.2% in the controls (P = 0.598). We also found that the distribution of p53 72Pro carriers and non-carriers was similar between the cases and controls, and this difference was not statistically significant ({chi}2 = 0.292, P = 0.589). However, the HPV16 seropositivity was significantly more common in cases than in controls (P < 0.001).


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  		Table I. Frequency distribution of demographic and risk factors in SCCOP cases and controls

 
As shown in Table II, HPV16 seropositivity was associated with a >5-fold risk of SCCOP (OR, 5.7; 95% CI, 3.7–8.7) after adjusting for age, sex, smoking status and drinking status. While HPV16 seropositivity among those with the p53 homozygous wild-type (Arg/Arg) genotype was associated with an elevated risk of SCCOP (OR, 3.9; 95% CI, 2.2–7.0), among individuals with the p53 Arg/Pro and Pro/Pro genotypes, HPV16 seropositivity was associated with an even greater risk of SCCOP (adjusted OR, 9.2; 95% CI, 4.7–17.7). Although the 95% CIs of these risk estimates overlap one another, we did find a significant interaction between HPV16 serologic status (seropositive versus seronegative) and p53 codon 72 polymorphism (p53 72Pro carriers versus non-carriers) on the risk of SCCOP, but the interaction is only marginally significant (P = 0.05).


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  		Table II. Adjusted ORs and 95% CIs of selected variables and risk of HPV16-associated SCCOP

 
To identify other factors affecting risk of HPV16-associated SCCOP, we further stratified the associations between the HPV16 status and the cancer risk by age, sex, smoking and alcohol drinking. We found that risk of SCCOP associated with HPV16 seropositivity was evident for all the subgroups, but particularly more pronounced among men (OR, 6.1; 95% CI, 3.8–9.8), individuals <56 years old (OR, 7.3; 95% CI, 3.9–13.4), never-smokers (OR, 14.1; 95% CI, 6.0–32.9) and never-drinkers (OR, 10.9; 95% CI, 4.0–29.5). However, the interaction between HPV16 status and sex, age and alcohol drinking was not statistically significant (P = 0.442 for sex, P = 0.182 for age and P = 0.177 for alcohol drinking, respectively). We did find a significant interaction between HPV16 status and smoking status (P = 0.015) (Table II).

We also found a significant three-way interaction between HPV16 serologic status, p53 codon 72 genotype and smoking status (P = 0.006), and therefore we stratified the risk by HPV16 serological status, p53 genotype and smoking status, with adjustment for age, sex and drinking status (Table III). Those never-smokers who were HPV16 seropositive and had variant p53 genotypes exhibited a >22-fold greater risk of SCCOP (adjusted OR, 22.5; 95% CI, 4.8–106.2) than those never-smokers who were HPV16-negative and had the wild-type genotype, but this result could be caused by chance due to the small sample sizes in each subgroups. We need further studies with larger sample sizes to confirm this finding. However, HPV16 seropositivity in never-smokers with the Arg/Arg genotype conferred only a 5-fold risk of SCCOP (adjusted OR, 4.9; 95% CI, 1.8–13.2). Ever-smokers who had variant p53 genotypes and were HPV16 seropositive exhibited a 4.2-fold greater risk of SCCOP (adjusted OR, 4.2; 95% CI, 2.0–8.6) than ever-smokers who had the wild-type genotype and were HPV16 seronegative. Ever-smokers with the wild-type genotype who were HPV16 seropositive exhibited a similar but slightly less increased risk of SCCOP (adjusted OR, 3.4; 95% CI, 1.7–6.8). In this stratified analysis, we also found that, compared with the p53 Arg/Arg genotype, the variant p53 genotypes (Arg/Pro + Pro/Pro) were protective for never-smokers without evidence of HPV16 exposure (adjusted OR, 0.3; 95% CI, 0.1–0.8), but not for similar ever-smokers (adjusted OR, 0.9; 95% CI, 0.5–1.6).


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  		Table III. Stratification of risk of SCCOP in never- and ever-smokers by p53 genotype and HPV16 exposure

 

   Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 References
 
In this study, we found that the increase in risk of SCCOP associated with HPV16 seropositivity was significantly greater for individuals with p53 codon 72 variant genotypes (Arg/Pro and Pro/Pro) than for those with the p53 Arg/Arg genotype. This finding suggests that p53 variant genotypes are risk genotypes for HPV16-associated SCCOP and that the p53 codon 72 polymorphism may be a marker for genetic susceptibility to HPV16-associated SCCOP. A possible explanation is that the change from Arg to Pro alters the p53 protein, affecting p53's susceptibility to E6-mediated degradation, apoptosis potency and transcriptional activity (32), thereby increasing the carcinogenic potential of HPV16.

Storey et al. (33) were the first to suggest that individuals homozygous for p53 72Arg have a 7-fold greater risk of HPV-associated cancers than the heterozygotes. Since then, several studies have examined the associations between the p53 codon 72 polymorphism, HPV infection and head and neck cancer risk, with inconsistent results (35–37,40). For example, Katiyar et al. (35) found no association between the p53 codon 72 polymorphism and the risk of HPV-associated oral cancer in 13 patients with HPV-positive carcinomas, 31 patients with HPV-negative carcinomas and 20 healthy controls from an Indian population. Another study of 202 patients with oral cancer and 333 healthy controls also found no association between the p53 codon 72 polymorphism and HPV status or between the p53 codon 72 polymorphism and risk of oral cancer (37). Recently, another study, which investigated squamous cell carcinomas of the head and neck in 122 patients (44 with laryngeal cancer, 33 with oropharyngeal cancer, 30 with hypopharyngeal cancer, 13 with oral cavity cancer, one with cancer of the ear and one with cancer of the nose) and 193 healthy individuals also found no significant association between the p53 polymorphism and HPV expression level (40).

However, when Perrone et al. (36) explored the association of the p53 codon 72 polymorphism with HPV-associated SCCOP in 77 cases and 141 cancer-free controls, they found that the p53 Pro/Pro genotype was a risk factor for developing HPV16-associated SCCOP, which is consistent with the results reported here. However, unlike the current study, those results evaluated the risk of SCCOP without adjusting or segregating data for smoking or drinking status. Moreover, several studies found that individuals with the p53 72Pro allele were at higher risk of developing cervical cancers, nearly all of which were HPV-positive, than those with the p53 72Arg allele (20,41,42).

The contradictory results from all these studies may be due to the differences in tumor sites, sample sizes and ethnic groups studied. In fact, yet other previous studies have suggested that environmental risk factors, such as HPV infection, and genetic predispositions, such as the p53 codon 72 polymorphism, may contribute differently to cancer risk depending on the specific anatomic site, even within the head and neck region (40,43,44). For example, compared with squamous cell carcinomas at other head and neck sites, SCCOP is more likely to be associated with HPV (4,5,8) and is therefore more likely to be associated with the p53 codon 72 polymorphism (40). In contrast, cancers of the oral cavity, which are rarely HPV positive, may unlikely to be associated with p53 status, a fact that may have led to negative results of some studies that had mixed oral cavity and SCCOP cases.

Another important finding in our study is that, among never-smokers, p53 variant Pro genotypes were associated with a 22-fold greater risk for the development of HPV16-associated SCCOP, whereas among ever-smokers, the p53 variant genotype was associated with only a 4-fold increase in the risk of developing HPV16-associated SCCOP. This finding implies that the p53 codon 72 polymorphism may have an increased interaction with HPV16 among never-smokers and that smoking and p53 variants may not be cofactors in the etiology of HPV16-associated SCCOP, possibly because tobacco use and HPV infection, the two major etiologic agents for SCCOP, both target p53 and disrupt the p53 pathway through different mechanisms. In other words, the p53 codon 72 polymorphism may be important to carcinogenesis of HPV16-associated oropharyngeal cancers, but not other oropharyngeal cancers. To our knowledge, no studies have investigated the associations between the p53 codon 72 polymorphism and HPV-associated cancers according to the patient's smoking status. Although this study strongly provides evidence of interplay between the p53 codon 72 polymorphism, smoking status and HPV16-associated SCCOP, these findings need to be validated in further studies with larger samples.

Despite these intriguing results in this relatively large group of subjects compared with previously published reports, our study also has some limitations. For instance, because this was a hospital-based case–control study, there may have been some selection bias in that our cases and controls were from different populations: SCCOP cases were enrolled from the MDACC patients, and controls were recruited from outpatient clinics visitors at MDACC and a control pool of enrollees at the Kelsey-Seybold Clinic through the Houston metropolitan area. However, as others have also found (45–48), the difference in the frequency of p53 genotypes between cases and controls was not statistically significant. Also, as in other studies, our findings confirmed that HPV16 infection is a risk factor for SCCOP and that the risk associated with HPV16 seropositivity is higher among men, younger individuals (46), never-drinkers (49) and never-smokers (4,5,11,38). In addition, because our study included only non-Hispanic white subjects, and the cases and controls were frequency matched for age, sex, smoking status and drinking status, the effects of any confounding demographic factors might have been minimized. Another limitation may be that the stratified analyses had a limited number of individuals in each category, so our results should be confirmed in larger studies. Furthermore, HPV16 seropositivity might not reflect actual tumor molecular events, and some patients may be classified as serologically negative when their tumors were actually HPV16 DNA positive. However, Herrero et al. (11) have shown a reasonable concordance between HPV16 seropositivity and SCCOP tumor HPV16 DNA positivity; furthermore, using serologic status allows for the inclusion of a cancer-free control group.

In summary, our study provides evidence that p53 codon 72 variant genotypes are risk factors for HPV16-associated SCCOP in a non-Hispanic white population. We also found that p53 codon 72 variant genotypes were associated with a strikingly higher risk for HPV16-associated SCCOP in never-smokers than in smokers. To our knowledge, this is the largest study to investigate the association between the p53 codon 72 polymorphism and HPV16-associated SCCOP with stratification by smoking status. To advance these findings, we are currently testing other functional polymorphisms of members of the p53 family to elucidate the roles of these genetic variants in the pathology of HPV-positive and HPV-negative SCCOP, and we encourage future studies of these genotypes and their interaction with HPV and smoking in molecular epidemiologic studies restricted to the oropharyngeal subsite.


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
References
 
The University of Texas MDACC to E.M.S.; the National Institutes of Health Head and Neck SPORE Career Development Award (P50CA097007) to E.M.S.; the University of Texas MDACC Institutional Research to E.M.S.; the National Institutes of Health (ES 11740) to Q.W.; the Clinician Investigator Award (K-12 CA88084) to E.M.S.; and the National Institutes of Health Cancer Center Support, MDACC (CA 16672).


   Acknowledgments
 
The authors thank Angelique Siy for manuscript editing; Margaret Lung, Liliana Mugartegui and Angeli Fairly for their help with subject recruitment and Li-E Wang for laboratory management.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 

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Received October 22, 2007; revised January 10, 2008; accepted January 29, 2008.


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X. Chen, E. M. Sturgis, A. K. El-Naggar, Q. Wei, and G. Li
Combined effects of the p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms on the risk of HPV16-associated oral cancer in never-smokers
Carcinogenesis, November 1, 2008; 29(11): 2120 - 2125.
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