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Association Between DQB1 and Cervical Cancer in Patients With Human Papillomavirus and Family Controls

From the Department of Psychiatry, and the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, the Lauren V. Ackerman Laboratory of Surgical Pathology, and the Department of Genetics, Washington University School of Medicine, St. Louis, Missouri; the HLA Laboratory, Barnes-Jewish Hospital, St. Louis, Missouri; and the Department of Pathology, University of Alabama, Birmingham, Alabama.

Address reprint requests to: Rosalind J. Neuman, PhD, Washington University Medical Center, Box 8134, 4940 Children’s Place, St. Louis, MO 63110, E-mail: roz{at}gretta.wustl.edu

	Abstract

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Objective: The role of human leukocyte antigen (HLA) DQB1 alleles and human papillomavirus (HPV) as contributing factors to invasive cervical cancer was investigated. To overcome problems of misleading causal inferences common in traditional case-control studies, a family-based test, the transmission/disequilibrium test, was used.

Methods: Ninety-six patients with pathologically confirmed invasive cervical cancer were ascertained. Human papillomavirus types were determined in 80 patients, of whom 81.25% were HPV-positive, and 18.75% were HPV-negative. Deoxyribonucleic acid was extracted from samples, taken from patients and their parents, and sequenced to determine DQB1 genotypes. Nuclear family data were used to test whether the DQB1 locus is associated with invasive cervical cancer while controlling for high-risk HPV-positive patients. The transmission/disequilibrium test evaluates whether the frequency of transmission of parental marker alleles to their affected offspring deviates from the expected Mendelian frequency of 50%.

Results: The HLA DQB1 locus showed evidence for allelic association with invasive cervical cancer in high-risk HPV-positive patients (P = .006). The transmission/disequilibrium test showed that the DQB1*0303 allele was transmitted to high-risk HPV patients more often than expected by chance, ²₁ = 8.0, P = .005 (P = .035 when correcting for multiple tests). Tests of association were negative when applied to all 96 patients, irrespective of HPV status. No significant differences were found in the distribution of the DQB1 alleles among HPV-positive patients compared with those who were HPV-negative, indicating that HLA alleles are not associated with susceptibility to HPV infection.

Conclusion: These results suggest that the DQB1*0303 allele increases the risk for invasive cervical cancer in women who are HPV-positive.

Cervical cancer is the second leading cause of cancer deaths in women worldwide and the leading cause in many developing countries.¹ The age-adjusted incidence of cervical cancer is estimated to be between ten and 40 per 100,000.² In the United States, the age-adjusted incidence and mortality rates of cervical cancer between 1991 and 1995 were 8.0 and 2.8, respectively, per 100,000,³ with the reduction due to the extensive use of Papanicolaou-stained smears as a screening tool.

Infection with human papillomavirus (HPV) is the risk factor most often associated with cervical neoplasms with the highest risk attributed to HPV types 16 and 18, followed by HPV 31 and 33.⁴ Prevalence estimates of genital HPV infection vary according to the method of HPV diagnosis and the population studied. Estimates ranging from 10% to 40% have been reported for the United States.^1,2,5 Although HPV infection is an important risk factor for development of cervical neoplasms, it is clear that it is neither necessary nor sufficient. Although up to 80% of cervical tumors harbor HPV DNA,^1,6 most infected women do not develop such tumors. Thus, additional environmental or genetic factors must be involved in the predisposition to cervical carcinogenesis.

Compelling evidence has implicated genetic factors as another important risk factor for susceptibility to invasive cervical cancer. Most, but not all, such studies have pointed to specific HLA class II alleles as candidates for involvement in onset of cervical intraepithelial neoplasia (CIN) or invasive cervical cancer. Some have reported a strong positive association with alleles at the DQB1 locus, dependent upon HPV type,^7–12 whereas others report no association.^13,14 Haplotypes formed from the DR and DQ loci have produced positive^15,16 and negative findings.¹² Confounded with the genetic evidence is the increase in high-risk HPV status observed in CIN and invasive cervical cancer patients. The exact relationship between these two risk factors is not well understood. However, it is clear that cervical cancer does not follow a simple Mendelian pattern of inheritance but, rather, is most likely the result of a complex interplay of genetic and environmental risk factors.

Human leukocyte antigen (HLA) genetic studies of cervical cancer have been primarily traditional case-control studies in which the frequencies of alleles among cases and controls are compared. The pitfalls of case-control studies have been well documented. Problems arise from the use of inappropriate control groups giving rise to spurious evidence for association due to artifacts such as population stratification. Furthermore, causal inferences based on genetic differences between cases and controls are often difficult to replicate. In response, family-based controls or haplotype relative-risk (RR) methods^17–19 are recommended for genetic association studies.²⁰

The present study used the transmission/disequilibrium test¹⁹ for a family-based genetic association study of invasive cervical cancer and alleles at the DQB1 locus. This test focuses on transmission of a parental marker allele to an affected offspring, comparing this transmission with those alleles that are not transmitted. Consequently, a perfectly matched control is created for each case. In particular, we applied a likelihood-based form of the transmission/disequilibrium test to these data.²¹ The likelihood form of this statistical test is particularly appropriate because of the large number of alleles at the DQB1 locus, making traditional haplotype RR methods less reliable because statistical problems arise when multiple tests are performed.

	Materials and Methods

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Patients with invasive cervical cancer were identified from medical records at Barnes-Jewish Hospital/Washington University Medical Center in St. Louis, Missouri, between January 1, 1986, and May 1, 1997. Patients were contacted to identify those with living parents who were willing to participate in the study. When possible, blood was obtained from the proband and her parents for DQB1 analysis. In 50 individuals, buccal cells instead of blood were used. Samples were obtained by scraping the inner cheek for 5 seconds with a cytology brush and transferring the cells obtained to a tube containing 10 mM Tris-Cl, pH 8.0. Specimens were obtained at the hospital or transported by airmail to the laboratory within 48 hours and stored at -20C until DNA extraction. This study was approved by the Human Studies committee at Washington University in St. Louis.

Deoxyribonucleic acid was extracted from whole blood by first lysing the red cells in a solution containing 0.32 M sucrose, 10 mM Tris-Cl pH 7.5, 5 mM MgCl2, and 1% Triton X-100 (Sigma, St. Louis, MO). White blood cells were pelleted and washed twice in the same solution to remove hemoglobin. The cell pellet was then resuspended and incubated in 100 µL 10 mM Tris-Cl, 1 mM ethylenediaminetetracetic acid (EDTA), pH 8.0, 20 µg/mL proteinase K, and 0.5% NP40 at 50C for 2 hours. The proteinase K was inactivated by boiling for 20 minutes. The buccal cells were scraped from the brush, pelleted, and resuspended in 20–40 µL of 10 mM Tris-Cl, pH 8.0. Four µL of buccal cell solution was added to 10 mM Tris-HCl pH 9.0, 50 mM KCl, 2.0 mM MgCl₂, and 14.8 µg of proteinase K for a total volume of 50 µL. The tube was incubated at 60C for 20 minutes and then the proteinase K was inactivated by boiling for 20 minutes. Five µL of this solution was used for polymerase chain reaction (PCR) amplification.

Deoxyribonucleic acid from blood or buccal cells was amplified by PCR using the DQB1 exon-2-specific primers DQBAMP-A and DQBAMP-4 or DQBAMP-6.²² The DQBAMP-4 and DQBAMP-6 primers selectively amplified the *05 and *06 or *02, *03, and *04 alleles, respectively. Therefore, two amplifications were done for each individual. The 20–30 µL PCR reaction contained 20–50 ng of blood DNA or 4 µL of buccal cell solution, 10 mM Tris-HCl pH 9.0, 50 mM KCl, 2.0 mM MgCl₂, 0.2 mM deoxyribonucleotide triphosphates, 3.2 pmole of each primer, and 0.25 units Taq (Promega, Madison, WI) or AmpliTaq (Perkin-Elmer, Applied Biosystems Division, Foster City, CA) DNA polymerase and .1% Triton X-100 (when Taq polymerase was used). The reaction mixture was held at 94C for 10 minutes, followed by 35 cycles at 93C for 1 minute, 60C for 1 minute, and 72C for 1 minute in an Omnigene Thermal Cycler (Hybaid, Middlesex, UK). Five µL of each PCR was run on a 2% agarose gel and the presence of a DNA fragment was detected by ethidium bromide staining. Amplified samples were then used as sequencing templates.

Purification of PCR products was done by adding 2 to 8 µL of the PCR reaction to 10 units of exonuclease I and 2 units of shrimp alkaline phosphatase (Amersham Life Science/United States Biochemical, Cleveland, OH). The reaction was held at 37C for 25 minutes and 80C for 15 minutes. The sequencing reaction was done using the ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit (Perkin-Elmer) with AmpliTaq DNA polymerase, FS, according to instructions. After purifying the reaction product by spinning it through a Sephadex G50 column, the column effluent was precipitated, dried, and denatured before it was loaded on an ABI model 373 or 377 sequencing gel system (Perkin-Elmer). Genotypes for DQB1 were determined by reading one or two 180 bp sequence from exon 2 on each individual. By this method, 21 alleles could be identified. There were no discriminating sequences to distinguish between the 06011–06012, 06051–0609, 0201–0202, 03031–03032, or 0401–0402 alleles. Because the polymorphism is high at this locus, typing served as a check for paternity. In cases of nonpaternity, if the transmitted or nontransmitted alleles from the mother could be resolved unambiguously, they were used in the analysis. Homozygous samples and samples that could not be sequenced were also typed by dot-blot assay. Briefly, genomic DNA was amplified by PCR using DQB1-specific primers and hybridized with 16 oligonucleotide probes.²³ Detection of the DQB1 alleles was performed by colorimetric reverse-dot-blot hybridization ( Duffy BF, Begovich AB, Novotny JF, Mohanakumar T. Allele level HLA DRB typing with Amplicor typing kit using an extended panel of primers and probes [abstract]. Hum Immunol 1997;55:137). This method also distinguished the genotypes 0301/0302 from 03032/0304 and 0603/0604 from 0607/0608 because heterozygous peaks in the sequencing trace could not be discerned as distinct alleles.

Tumor specimens were obtained for pathologic evaluation and HPV typing. One to three 25 µm sections of formalin-fixed paraffin-embedded tumors were added to 200 µL of digestion buffer (50 mM Tris-Cl pH 8.5, 1 mM EDTA, 0.5% Tween 20, 200 µg proteinase K/mL) and incubated overnight at 65C. After incubation, 100 µL of Chelex 100 (BioRad, Richmond, CA), as a deionized water slurry, was added and the samples were boiled for 10 minutes and spun at 14,000 rpm in a microcentrifuge for 5 minutes. The aqueous phase (DNA) above the Chelex beads and below the paraffin surface was removed and transferred to sterile micro-centrifuge tubes. Human papillomavirus typing was done by PCR amplification of the E6-E7 gene using the degenerate consensus primers pU-1M/pU-2R and restriction-fragment-length polymorphism analysis (RFLP).^24,25

We used family-based data to test for association or linkage disequilibrium between the DQB1 locus and invasive cervical cancer. The term family-based indicates that the data consist of nuclear families rather than unrelated individuals designated as cases and controls. In the family-based design, the transmission of each parental allele is tracked to affected offspring, and the alleles that are not transmitted are considered to belong to the control. Figure 1 indicates that the A alleles were transmitted to the affected offspring and the B alleles were not transmitted. The strength of the family-based design is that it provides a perfectly matched control to the affected offspring. Traditional case-control designs may give rise to spurious disease associations because of ethnic admixture within a population or other problems relating to inappropriate controls. A family-based test neatly circumvents these problems by providing a pseudo or internal control perfectly matched to the affected offspring.

View larger version (12K): [in this window] [in a new window]   Figure 1. Transmitted and nontransmitted alleles.

To avoid multiple statistical tests, one for each allele at a highly polymorphic marker such as at the DQB1 locus (resulting in loss of power), we used a multi-allelic likelihood-ratio based approach to test for linkage disequilibrium.²¹ This multi-allelic approach jointly tests whether any of the alleles is excessively transmitted by formulating the likelihood of the data in terms of one parameter which, under the null hypothesis of no allelic excess transmission, would be equal to zero. The advantage of this statistic is that it has only one degree of freedom, irrespective of the number of alleles of the marker, and therefore, provides a more powerful test of linkage disequilibrium than traditional tests. This test was first applied to all 96 nuclear families and then applied only to those families in which the proband had a high-risk HPV type.

	Results

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More than 150 patients with invasive cervical cancer, identified from medical records, were contacted to participate in our study. At least one parent for each of 96 patients was available for genotyping. Seventy-two families (75%) had genotyping information on both parents, 21 families contained genotype information on the mother but not the father, and three families had information on the father only. Table 1 displays the sample characteristics. Eighty-eight families (92%) were white, seven were black, and one family was Hispanic. Human papillomavirus typing showed that 57 probands had high-risk HPV types 16 or 18, whereas seven had types 31 or 33. Five cancers contained a mixture of HPV 16 with other HPV types. Fifteen probands (15.6%) were HPV-negative and 16 probands were unknown. The age range of the probands was 21–55 years. Sixty-four (90.1%) of the squamous cell tumors contained HPV 16, 18, 31, or 33, with most containing HPV 16 (n = 52). High-risk HPV types were detected in 66.7% (n = 12) of the adenocarcinomas.

To eliminate the possibility that the HLA locus conferred susceptibility to HPV infection, we examined the distribution of the DQB1 alleles in HPV-positive compared with negative cases. We found no significant difference in the distribution of alleles between groups (P = .12).

	Discussion

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Our results confirm an association between DQB1*0303 and cervical cancer in patients whose tumors contain high-risk HPV types. Evidence for this finding came from applying a likelihood-based transmission/disequilibrium test to the nuclear family data of 64 patients with invasive cervical cancer who tested positive for HPV types 16, 18, 31, or 33. The association was not present when the total sample of 96 patients and their families were tested together. The transmission/disequilibrium test is a family-based method of analysis in which internal controls are used to eliminate misleading associations that are due to population or ethnic stratification. Potential problems can arise with this type of test because of the multiple-comparison problem in which statistical tests are applied to each allele of a polymorphic marker. To circumvent this problem, we used a likelihood-based method that has one degree of freedom, providing a more powerful test.

These findings are consistent with those of other studies in which a positive association was detected between DQB1*03 and either invasive cervical cancer or the precursor lesion, CIN. Wank and Thomssen⁷ first reported an association between DQw3 antigens and cervical squamous cell carcinoma in a German population. A predominance of DQB1*0301 and DQB1*0303 alleles were then found in the same set of patients when the initial study was extended using molecular typing.²⁶ These results have also been replicated in populations from Norway,¹⁰ Japan,⁹ England,²⁷ and France,²⁸ as well as in a black sample.¹¹ In white British patients, Odunsi et al^12,29 found a significant association between DQB1*03 and CIN. Vandenwelde et al³⁰ reported a significantly elevated frequency of the DQB1*03 alleles in high-risk HPV-positive Belgian women diagnosed with CIN grades I and II, but not in those with CIN-III. However, David et al³¹ found a strong association between DQB1*03 and CIN-III in a British sample. Moderate increases of DQB1*0303 among HPV16-positive cases have been reported in a New Mexico Hispanic population³² and in a French population.²⁸

The next most frequent allele found to be associated with cervical cancer is DQB1*0602, which has been reported in women from Tanzania⁸ and Hispanics from the United States.³² Sanjeevi et al³³ found DQB1*0602 to be strongly associated with CIN in HPV16-positive Swedish patients compared with HPV16-positive controls. Several haplotypes containing the DQB1*0602 allele also have been found to be over-represented in patient populations. In a Norwegian study, Helland et al¹⁶ found an increase of the DQA1*0102-DQB1*0602 haplotype among HPV-positive CIN grade II and III cases compared with controls. Apple et al^32,15 found a significant increase in haplotype DRB1*1501-DQB1*0602 in a New Mexico Hispanic population diagnosed with invasive cervical cancer and CIN, particularly in HPV16-positive patients. Sanjeevi et al³³ found the DQA1*0102-DQB1*0602 haplotype significantly increased among HPV16-positive CIN patients compared with HPV16-positive controls. Similarly, a study from Norway showed the same DQA1*0102-DQB1*0602 haplotype associated with an increased risk of developing CIN when infected with HPV16 without influencing progression to cancer.¹⁶ It should be noted that linkage disequilibrium exists among many of the HLA class II haplotypes³⁴ and therefore, the increased haplotype frequency, in fact, may be due to only one of the loci.

Several negative findings have been reported. Helland et al¹⁶ found no increase in DQB1*03 alleles in a British population of CIN patients. No association between cervical carcinoma with alleles encoding the DQ3 antigen was found in a population of Swedish patients.³⁵ Glew et al^13,14 found no positive correlation between invasive cervical cancer and HLA DR-DQ haplotypes in their British population samples, irrespective of HPV status. The conflicting reports on HLA associations with invasive cervical cancer and CIN may be due to differences in the ethnic origin of patients and controls among the many various studies, selection of poorly matched control groups within each study, differences in methods of HLA typing, interacting environmental factors, genetic heterogeneity, and differences in statistical methodologies.

In general, overwhelming evidence indicates that, in addition to high-risk HPV types, the HLA complex contains genetic factors that increase the propensity for invasive cervical cancer among some populations. However, many women infected with high risk HPV types never progress to invasive cervical cancer. This phenomenon may be partially explained by the dependence of the immune system’s response to HPV infections on specific genotypes at the DQB1 locus or on as yet undefined additional genetic or environmental factors. There are also some women with cervical cancer, albeit a small minority, who do not show any detectable signs of HPV infections. These cases may represent an etiologically separate group of patients with unknown genetic or environmental or both agents that cause invasive cervical malignancies. Consequently, it has become increasingly clear that invasive cervical cancer arises from a complex interplay between genetic and environmental factors, which may differ across disparate populations.

	Footnotes

 
This work was supported by NIH grants MH31302 and CA62009, ACS #IN 36-34, and the Wendy Will Case Cancer Fund.

PII S0029-7844(99)00501-3

Received March 15, 1999. Received in revised form June 23, 1999. Accepted July 1, 1999.

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