Synergistic effect of HLA class II loci and cytokine gene polymorphisms on the risk of gastric cancer in Japanese patients with Helicobacter pylori infection

It has been reported that polymorphisms of human leukocyte antigen (HLA) genes and several cytokine genes are associated with an increased risk of developing gastric cancer (GC). However, the results of studies from different geographic regions, ethnic groups and study groups are inconsistent. The aim of this study was to evaluate the influence of H. pylori infection and host genetic factors on GC susceptibility in Japanese patients with GC. We analyzed genotypes for HLA class I and II, tumor necrosis factor α, interleukin (IL)‐1β, IL‐1 receptor, IL‐4, IL‐4Rα and IL‐10 in 330 H. pylori‐infected noncardia patients with GC and 190 H. pylori‐infected nonulcer dyspeptic controls. Haplotype analyses indicated that the frequencies of the HLA DRB1*0405 and DQB1*0401 alleles were increased in the patients with intestinal‐type GC when compared with controls (both DRB1*0405 and DQB1*0401: p = 0.015, OR = 1.57, 95% CI = 1.09–2.26), but the changes were not statistically significant after correction for multiple comparisons. None of the cytokine gene polymorphisms were associated with GC susceptibility, whether patients with GC were analyzed as a group according to the histological subtype. Of interest was the comparison of controls and patients with intestinal‐type GC. The frequency of an IL‐10‐592AA homozygote showing concomitant carriage of the HLA DRB1*0405‐DQB1*0401 haplotype was significantly higher in patients with intestinal‐type GC (χ² = 6.369, p = 0.0116, p_c = 0.0464, OR = 2.43, 95% CI = 1.21–4.48). Our results suggest that the HLA class II and IL‐10‐592A/C polymorphisms synergistically affect the susceptibility to GC development of H. pylori‐infected individuals in the Japanese population. © 2009 UICC     

HLA class II alleles associated with infection by HPV16 in cervical cancer in situ

HLA class II alleles have been associated with an increased risk of developing cervical cancer through infection with oncogenic forms of human papilloma virus (HPV). We have examined the association of variation at the DRB1 and DQB1 loci with HPV16 infection and risk of development of cervical cancer by analysis of 440 cases diagnosed with cervical cancer in situ and 476 age-matched controls in a retrospective case-control study. The infection history of a woman was studied by analysis of cervical smears taken at multiple times during a period of up to 27 years (1969-95). The frequency of a number of alleles are either increased (DRB1*0801, DRB1*1501, DQB1*0402 and DQB1*0602) or decreased (DRB1*0101, DRB1*1301, DQB1*0501 and DQB1*0603) in the cancer patients compared to the controls. After correction for multiple testing, only the DQB1*0602 and the DRB1*1501 alleles remain associated with cancer and only in HPV16-infected patients (DQB1*0602: 102/264 (39%) vs. 130/476 (28%), p = 0.028 and DRB1*1501: 104/259 (40%) vs. 132/469 (28%), p = 0.027). These alleles are associated primarily with infection by HPV and only indirectly affect the risk of developing cervical cancer in situ. To study the impact of these alleles on persistence of infection, women with short-term infections were compared to those with long-term infections. Carriers of DQB1*0602 and DRB1*1501 were more frequent in the group with long-term HPV infections, indicating that these class II alleles contribute to the inability to clear an HPV infection.     

Modeling HLA associations with EBV‐positive and ‐negative Hodgkin lymphoma suggests distinct mechanisms in disease pathogenesis

HLA genotyping and genome wide association studies provide strong evidence for associations between Human Leukocyte Antigen (HLA) alleles and classical Hodgkin lymphoma (cHL). Analysis of these associations is complicated by the extensive linkage disequilibrium within the major histocompatibility region and recent data suggesting that associations with EBV‐positive and EBV‐negative cHL are largely distinct. To distinguish independent and therefore potentially causal associations from associations confounded by linkage disequilibrium, we applied a variable selection regression modeling procedure to directly typed HLA class I and II genes and selected SNPs from EBV‐stratified patient subgroups. In final models, HLA‐A*01:01 and B*37:01 were associated with an increased risk of EBV‐positive cHL whereas DRB1*15:01 and DPB1*01:01 were associated with decreased risk. Effects were independent of a prior history of infectious mononucleosis. For EBV‐negative cHL the class II SNP rs6903608 remained the strongest predictor of disease risk after adjusting for the effects of common HLA alleles. Associations with “all cHL” and differences by case EBV status reflected the subgroup analysis. In conclusion, this study extends previous findings by identifying novel HLA associations with EBV‐stratified subgroups of cHL, highlighting those alleles likely to be biologically relevant and strengthening evidence implicating genetic variation associated with the SNP rs6903608.     

人类白细胞抗原Ⅰ、Ⅱ类等位基因及单倍体多态性与中国南方汉族白血病的相关性

目的探讨人类白细胞抗原(HLA)Ⅰ类(A、B、C)、Ⅱ类(DRB1、DQB1、DPB1)等位基因和单倍体多态性与中国南方汉族急性淋巴细胞白血病(ALL)、急性髓系白血病(AML)以及慢性粒细胞白血病(CML)的相关性。方法收集深圳市血液中心845例中国南方汉族白血病患者(323例ALL、350例AML及172例CML)和745名中国南方汉族健康献血者的外周血样本。应用聚合酶链反应反向序列特异性寡核苷酸探针杂交(PCR-rSSO)及测序分型(PCR-SBT)方法对HLA-A、-B、-C、-DRB1、-DQB1和-DPB1进行基因分型,鉴定HLA等位基因前4位数。采用Arlequin 3.5软件分析HLA单倍体;从HLA低分辨水平(等位基因前2位数)及高分辨水平(等位基因前4位数)分别统计分析HLA等位基因和单倍体多态性与3种白血病的相关性。结果经Bonferroni校正,ALL组A*02(36.22%比28.26%,χ²=13.41,PC<0.01)及其单倍体A*02-B*46-C*01(15.35%比10.23%,χ²=10.90,PC=0.02)、DRB1*12(15.79%比11.10%,χ²=9.02,PC=0.03)、A*02:03(9.75%比5.32%,χ²=14.25,PC=0.002)及其单倍体A*02:03-B*38:02-C*07:02(3.80%比1.51%,χ²=10.41,PC=0.02)的频率均高于对照组,是ALL易感因素;AML组A*11-B*15-C*08-DRB1*15-DQB1*06-DPB1*02的频率高于对照组(1.34%比0.07%,χ²=12.54,PC=0.003),是AML易感单倍体;CML组A*02(36.63%比28.26%,χ²=9.33,PC=0.02)及其单倍体A*02-B*15-C*04(2.17%比0.29%,χ²=11.74,PC=0.02)、DRB1*03:01-DQB1*02:01-DPB1*02:01(1.86%比0.14%,χ²=13.10,PC=0.01)的频率均高于对照组,是CML易感因素;CML组DRB1*13的频率低于对照组(1.45%比5.25%,χ²=9.29,PC=0.03),是CML拮抗基因。结论在HLA低分辨及高分辨水平发现了白血病易感或拮抗HLA等位基因和单倍体,可为探究中国南方汉族白血病发病机制并制订有效治疗策略提供参考。     

HLA-DRB alleles are differentially expressed by tumor cells in breast carcinoma

The biologic and prognostic significance of HLA-DR expression and T-cell infiltration in breast carcinoma are presently controversial. To test the hypothesis that these factors are influenced by particular HLA-DRB alleles, 52 breast tumor samples, composed of 26 DRB1*04 and 26 non-DRB1*04 tumors, were assessed using immunohistochemistry for expression of DR and its associated invariant chain (Ii) and for infiltrating CD3+ T cells. While DR expression by tumor cells was significantly associated with T-cell infiltration, DRB1*04 tumors were more frequently DR+ Ii+ and contained smaller CD3+ infiltrates than non-DRB1*04 tumors. This difference was largely attributable to DRB1*07 tumors, which were typically DR- Ii-, although they contained similar numbers of T cells to DR+ Ii+ tumors. Further analysis of DR+ tumors using allotype discriminating antibodies revealed that DRB1*04 alleles were always expressed, while non-DRB1*04 alleles were inconsistently expressed. The results of this study provide the first reported evidence that DRB alleles influence DR expression and T-cell infiltration in breast carcinoma and suggest that multiple factors contribute to DR expression. Ongoing studies aimed at elucidating the molecular and immunologic mechanisms controlling differential DR expression and implications for prognosis and outcome should further our understanding of the antitumor immune response and evasion strategies employed by tumor cells.     

Susceptible and Protective Associations of HLA Alleles and Haplotypes with Cervical Cancer in South India

Background: Human leukocyte antigen (HLA) genes have been implicated in cervical cancer in several populations. Objectives: To study the predispositions of HLA alleles/haplotypes with cervical cancer. Materials and Methods: Clinically diagnosed and PAP smear confirmed cervical cancer patients (n 48) and age matched controls (n 47) were genotyped for HLA-A,-B,-DRB1* and DQB1* alleles by PCR-SSP methods. Results: The frequencies of alleles DRB1*04 (OR=2.57), DRB1*15 (OR=2.04), DQB1*0301 (OR=4.91), DQB1*0601 (OR=2.21), B*15 (OR=13.03) and B*07 (OR=6.23) were higher in cervical cancer patients than in the controls. The frequencies of alleles DRB1*10 (OR=0.22) and B*35 (OR=0.19) were decreased. Strong disease associations were observed for haplotypes DRB1*15-DQB1*0601 (OR=6.56; < 3.5.10-4), DRB1*14-DQB1*0501 (OR=6.51; <0.039) and A*11-B*07 (OR=3.95; <0.005). The reduced frequencies of haplotypes DRB1*10-DQB1*0501 (OR=0.45), A*03-B*35 (OR=0.25) and A*11-B*35 (OR= 0.06) among patients suggested a protective association. HLA-C* typing of 8 patients who possessed a unique three locus haplotype 'A*11-B*07-DRB1*04' (8/48; 16.66%; OR=6.51; <0.039) revealed the presence of a four locus haplotype 'A*11-B*07-C*01-DRB1*04' in patients (4/8; 50%). Amino acid variation analysis of susceptible allele DQB1*0601 suggested 'tyrosine' at positions 9 and 37 and tyrosine-non-tyrosine genotype combination increased the risk of cervical cancer. Conclusions: Strong susceptible associations were documented for HLA alleles B*15, B*07, DRB1*04, DRB1*15, DQB1*0301, DQB1*0601 and haplotypes DRB1*15-DQB1*0601 and DRB1*14-DQB1*0501. Further, protective associations were evidenced for alleles B*35 and DRB1*10 and haplotypes A*11-B*35 and DRB1*10-DQB1*0501 with cervical cancer in South India.     

Human leukocyte antigen class II DRB1*1302 allele protects against cervical cancer: At which step of multistage carcinogenesis?

We investigated the role of human leukocyte antigen (HLA) class II alleles in multistage cervical carcinogenesis. Cross‐sectional analysis for HLA association with cervical cancer included 1253 Japanese women: normal cytology (NL, n = 341), cervical intraepithelial neoplasia grade 1 (CIN1, n = 505), CIN grade 2 or 3 (CIN2/3, n = 96), or invasive cervical cancer (ICC, n = 311). The HLA class II allele frequencies were compared by Fisher's exact test or the χ²‐test. The Bonferroni adjustment corrected for multiple comparisons. Among the study subjects, 454 women with low‐grade squamous intraepithelial lesion cytology were prospectively monitored by cytology and colposcopy every 3–4 months to analyze cumulative risk of CIN3 within the next 10 years in relation to HLA class II alleles. HLA class II DRB1*1302 allele frequency was similar between women with NL (11.7%) and CIN1 (11.9%), but significantly decreased to 5.2% for CIN2/3 and 5.8% for ICC (P = 0.0003). Correction for multiple testing did not change this finding. In women with low‐grade squamous intraepithelial lesion cytology, the cumulative risk of CIN3 diagnosed within 10 years was significantly reduced among DRB1*1302‐positive women (3.2% vs. 23.7%, P = 0.03). In conclusion, the two different types of analysis in this single study showed the protective effect of the DRB1*1302 allele against progression from CIN1 to CIN2/3.     

Host genetic control of HPV 16 titer in carcinoma in situ of the cervix uteri

Cervical cancer is strongly associated with infection by oncogenic forms of human papillomavirus (HPV). Although most women are able to clear an HPV infection, some develop persistent infections that may lead to cancer. The determinants of persistent infection are largely unknown. We have previously shown that women developing carcinoma in situ of the cervix uteri have higher titers of HPV 16 long before development of cervical neoplasia, indicating that the immune response to HPV is important in determining the outcome of an infection. The HLA class II alleles DRB1*1501 and DQB1*0602 have previously been associated with an increased risk of HPV infection, and carriers of these alleles also tend to have more long-term infections. Together these results indicate that certain HLA alleles may affect the ability to control the HPV copy number. To evaluate this possibility, we studied the HLA class II DRB1*1501-DQB1*0602 haplotype, as well as the alleles individually, and the HPV 16 titer in 928 women from a retrospective case-control study (441 cases and 487 controls). Carriers of the haplotype DRB1*1501-DQB1*0602 allele have a significantly higher HPV 16 titer compared to noncarriers (t-test with unequal variance, p = 0.017). An association was found between the HLA haplotype carrier frequency and HPV 16 titer (Mantel-Haenszel statistics p = 0.005). To study whether titer is related to the persistency of infection, women were divided into groups with long-term and short-term infection. A strong correlation is seen between long-term infection and high viral load and between short-term infection and low viral load. These results show that host genetic factors, e.g., variation at the HLA class II loci studied, may affect the immune reaction to the virus and thereby indirectly increase the susceptibility to carcinoma in situ of the cervix uteri.     

The investigation of HLA microsatellites influence in predisposition to sarcoidosis among Croatians

The aim of the present study was to analyze the distribution of HLA alleles (A, B, DRB1, DQB1) and HLA microsatellite alleles (TNFa, TNFb, TNFd, D6S273, D6S1014) in the Croatian patients with acute (N=93), as well as chronic sarcoidosis (N=40), in comparison to healthy controls (N=177), and investigate whether the polymorphism within the HLA region could be associated with different forms of sarcoidosis. Genomic DNA was isolated from peripheral blood. Patients were analyzed for HLA class I loci (A, B) by serology, while PCR-SSP method was used for HLA class II loci (DRB1, DQB1). Five HLA microsatellites were analyzed by PCR and electrophoresis in an automated sequencer. No significant deviation in the distribution of frequencies at HLA class I alleles was observed between the two patients' subgroups and controls. Regarding the HLA class II alleles, a statistically significant increase in frequency of HLA-DRB1*03 and DQB1*0201 allele was found among patients with acute sarcoidosis in comparison to controls as well as in comparison to patients with chronic sarcoidosis. The same finding was observed for HLA-DRB1*03/DQB1*0201 haplotype (Pcorr=0.0168; OR=2.83). In the group of patients with chronic sarcoidosis DRB1*11 (P=0.0219; OR=2.44), DRB1*15 (P=0.0414; OR=2.47) demonstrated statistically significant difference in comparison to controls only, while a lower frequency of DRB1*13 (P=0.0156; OR=0.24) in this group was statistically significant when compared to both patients with acute sarcoidosis and controls. None of the alleles at TNFa microsatellite showed significant difference in distribution among both subgroups of patients and controls. Significant difference between patients with acute form of disease and controls was found for the following alleles: TNFd-2 (Pcorr=0.00007; OR=4.89), D6S273-7 (Pcorr=0.0213; OR=2.96), and D6S1014-7 (Pcorr=0.0028; OR=3.97). On the other hand, patients with chronic sarcoidosis differed from control subjects for D6S1014-8 (Pcorr=0.0296; OR=8.35) allele. This study suggests the existence of an association of non-HLA markers with sarcoidosis and the involvement of the region between HLA-DQB1 and D6S273 loci in its pathophysiology.     

Meningioma: is there an association with human leukocyte antigens?

The expression of human leukocyte antigen (HLA) alleles plays an important role in the development and recurrence of benign and malignant diseases. Association of single HLA alleles or haplotypes with neoplastic processes has been investigated previously, and correlation between HLA and solid tumors, such as head and neck cancers or uterine cervical squamous epithelial lesions, were reported. However, there is no published data on the influence of the HLA system on the development of symptomatic cerebral meningioma, a mostly benign intracranial tumor of mesenchymal origin in adults. The present investigation is comparing the frequency of single HLA alleles and haplotypes in 81 adult Caucasian patients with symptomatic central nervous system meningiomas to that of 157 area- and race-matched healthy controls. Both standard serological and molecular genetic (PCR) techniques were used for HLA typing. Our results suggest an association between single HLA alleles and occurrence of clinically symptomatic meningioma. Patients with HLA-A*02 had a 2.5-fold increased risk of meningioma (P = 0.02), and those with HLA-DQB1*05 had a 1.8-fold increased risk of meningioma (P = 0.05). Conversely, HLA-A*01, -B*08, and -DRB1*03 were associated with a 0.4-, 0.5-, and 0.5-fold, respectively, decreased risk of meningioma (P = 0.008, P = 0.05, and P = 0.04). Moreover, the occurrence rate of combinations and estimated haplotypes containing these HLA alleles was strikingly different in meningioma patients compared with controls: significantly increased for the haplotypes HLA-A*02:DRB1*04 (P = 0.02, relative risk = 2.5) and HLA-A*02:DRB1*04:DQB1*0302,DQB1*05 (P = 0.03, RR = 7.5), and significantly decreased for the haplotype HLA-A*01:B*08:DRB1*03 (P = 0.01, relative risk = 0.2). In conclusion, these data suggest that some single HLA alleles and haplotypes may protect from or predispose to developing symptomatic central nervous system meningioma during adult life. These associations may be indicative of the involvement of the immune system in the host antitumor surveillance, recognition, and destruction of de novo arising human tumor cells.     

HLA-A,HLA-B,HLA-DRB1 Polymorphisms and Risk of Cervical Squamous Epithelial Cell Carcinoma: A Population Study in China

Cervical cancer is the second most common cancer in women. HLA class I and II alleles polymorphismshave been shown to be associated with cervical cancer risk, but results have varied among different populations.In this study, the HLA-A, -B, and –DRB1 alleles among 100 southern Chinese women with cervical squamouscell carcinoma (SCC) were compared to 254 controls. Our results showed that B*51:01:02 allele frequencywas significantly higher in patients with SCC than in healthy controls (P = 3.17x 10-5, Pc = 0.005, OR = 26.7).Statistical analysis also revealed a significantly decreased frequency of B*51:01:01 (P = 7.01x 10-4, Pc = 0.03, OR= 0.12) in patients with SCC when compared with healthy controls. These results indicate that HLA-B*51:01:02may confer susceptibility to SCC and HLA-B*51:01:01 may contribute to resistance to the development of SCCin Chinese women. None of the HLA-A-B or HLA-A-B-DRB1 haplotypes were significantly different in casesand controls after multiple testing corrections, indicating the individual allele associations to be independent ofthe identified haplotypes. These results support the hypothesis that some HLA-B alleles could be involved withsusceptibility for developing SCC.     

Associations of human leukocyte antigen class II genotypes with human papillomavirus 18 infection and cervical intraepithelial neoplasia risk

BACKGROUND:

Only a small proportion of women infected with human papillomavirus type 18 (HPV18) may progress to persistent infection and cervical neoplasia. This community‐based cohort study aimed to assess associations with human leukocyte antigen (HLA) class II genotypes for natural infection of HPV18 and subsequent risk of cervical neoplasia.

METHODS:

Among 10,190 cytologically normal participants, 125 with HPV18 infection were identified by HPV blot kit. HPV18 viral load at study entry was examined by real‐time polymerase chain reaction; persistent infection was defined as HPV18 infection at 2 consecutive examinations.

RESULTS:

There was a significant association between HLA‐DRB1*0403 allele and high HPV18 viral load (>1000 copies in 50 ng of total DNA) at study entry (odds ratio [OR], 7.2; 95% confidence interval [CI], 2.0‐25.2). After adjustment for age and viral load at study entry, haplotype HLA‐DRB1*0405‐DQA1*0301‐DQB1*0302 was significantly associated with persistent HPV18 infection (OR, 13.3; 95% CI, 1.7‐105.9). HLA‐DRB1*0403 allele was also associated with a significantly increased risk of high‐grade squamous intraepithelial lesion or cancer, showing a multivariate‐adjusted hazard ratio (95% CI) of 18.1 (2.6‐128.5).

CONCLUSIONS:

HLA‐DRB1*0403 allele and HLA‐DRB1*0405‐DQA1*0301‐DQB1*0302 haplotype may play important roles in determination of high viral load and persistent infection of HPV18 and subsequent cervical neoplasia risk. Cancer 2012;. © 2011 American Cancer Society.     

Association of HLA‐DRB1, interleukin‐6 and cyclin D1 polymorphisms with cervical cancer in the Swedish population—A candidate gene approach

High‐risk human papillomavirus (hrHPV) infection is the major risk factor for cervical cancer (CxCa). The role of genetic susceptibility in the disease has been suggested, but the existing data lack consistency. We conducted a nested case‐control study on 973 CxCa cases and 1,763 matched controls, from two Swedish population‐based cohorts to examine the association of common genetic variants with CxCa risk. Human leukocyte antigen (HLA) alleles and 24 other polymorphisms in 14 genes were selected on the basis of reported association or mechanistic plausibility with an HPV infection or cervical cancer development. Genotyping was conducted using multiplex PCR and Luminex technology. A significant association of CxCa with various polymorphisms was observed: rs1800797 in the IL‐6 gene (odds ratio [OR] = 0.88, 95% confidence intervals [CI]: 0.79–0.99); rs1041981 in the LTA gene (OR = 0.87, 95% CI: 0.78–0.98), and rs9344 in the CCND1 gene (OR = 1.14, 95% CI: 1.02–1.27), for those individuals carrying the rare allele. Additionally, the alleles 0401 and 1501 of the HLA class II DRB1 locus were associated with an increased risk (OR = 1.23, 95% CI: 1.04–1.45 and OR = 1.29, 95% CI: 1.11–1.50, respectively), and allele 1301 was associated with decreased risk (OR = 0.59, 95% CI: 0.47–0.73). The effects of CCND1 and the HLA*DRB1 alleles were independent of the effect of smoking. We did not find any association of risk with polymorphisms in genes related to the innate immune system. In conclusion, our study provides evidence for genetic susceptibility to CxCa due to variations in genes involved in the immune system and in cell cycle. © 2009 UICC     

Association of chronic lymphocytic leukemia with specific alleles of the HLA-DR4:DR53:DQ8 haplotype in German patients

The etiology of chronic lymphocytic leukemia (CLL) remains unknown, though a genetic susceptibility has been suggested. Results of complete DNA typing of HLA alleles in CLL patients are lacking. We compared HLA class I and class II frequencies in 101 German CLL patients and 157 healthy German controls as determined by PCR-SSP/SSO DNA analysis and serologic typing. The most striking difference was the increased frequency of HLA-DRB4*0103 [relative risk (RR) = 2.74, p < 0.0025] among patients. The presence of alleles HLA-DRB1*0401, HLA-DQB1*0302 and HLA-DPB1*0301 as well as of homozygosity for HLA-DQB1 was also associated with a higher risk for CLL, though none of these differences remained significant after correction for multiple comparisons. No association was found for any HLA class I allele. Haplotype analysis revealed a CLL-specific linkage disequilibrium for HLA-DRB1*0401:DRB4*0103 and HLA-DRB4*0103:DQB1*0302. Our results suggest that CLL could be associated with distinct class II alleles of the Caucasian haplotype HLA-DR4:DR53:DQ8, which has also been related to a susceptibility for several auto-immune diseases. The positive, though weak, association of CLL with HLA-DPB1*0301 might represent an independent susceptibility factor since no linkage disequilibrium existed with any of the other CLL-associated alleles. None of the previously reported associations with HLA class I antigens was confirmed. Our results suggest that factors within or close to the human MHC class II region confer susceptibility to CLL.     

Identification of NY‐BR‐1‐specific CD4+ T cell epitopes using HLA‐transgenic mice

Breast cancer represents the second most common cancer type worldwide and has remained the leading cause of cancer‐related deaths among women. The differentiation antigen NY‐BR‐1 appears overexpressed in invasive mammary carcinomas compared to healthy breast tissue, thus representing a promising target antigen for T cell based tumor immunotherapy approaches. Since efficient immune attack of tumors depends on the activity of tumor antigen‐specific CD4⁺ effector T cells, NY‐BR‐1 was screened for the presence of HLA‐restricted CD4⁺ T cell epitopes that could be included in immunological treatment approaches. Upon NY‐BR‐1‐specific DNA immunization of HLA‐transgenic mice and functional ex vivo analysis, a panel of NY‐BR‐1‐derived library peptides was determined that specifically stimulated IFNγ secretion among splenocytes of immunized mice. Following in silico analyses, four candidate epitopes were determined which were successfully used for peptide immunization to establish NY‐BR‐1‐specific, HLA‐DRB1*0301– or HLA‐DRB1*0401‐restricted CD4⁺ T cell lines from splenocytes of peptide immunized HLA‐transgenic mice. Notably, all four CD4⁺ T cell lines recognized human HLA‐DR‐matched dendritic cells (DC) pulsed with lysates of NY‐BR‐1 expressing human tumor cells, demonstrating natural processing of these epitopes also within the human system. Finally, CD4⁺ T cells specific for all four CD4⁺ T cell epitopes were detectable among PBMC of breast cancer patients, showing that CD4⁺ T cell responses against the new epitopes are not deleted nor inactivated by self‐tolerance mechanisms. Our results present the first NY‐BR‐1‐specific HLA‐DRB1*0301– and HLA‐DRB1*0401‐restricted T cell epitopes that could be exploited for therapeutic intervention against breast cancer.     

HLA class II polymorphism: Protective or risk factors to breast cancer in Tunisia?

HLA system plays a key role in the tumor cells’ escape from immune surveillance. Herein is the first report on the correlation of the susceptibility to breast cancer with HLA class II markers in Tunisia. Molecular typing of HLA-DRB1 and -DQB1 loci was undertaken for 70 Tunisian female patients. Comparison of allele and haplotype distribution between patients and 70 female control subjects reveals a negative association between HLA-DRB1*07-DQB1*02 and the incidence of breast cancer in the Tunisian population. (Pathology Oncology Research Vol 12, No 2, 79–81)     

Human leukocyte antigen G polymorphism is associated with an increased risk of invasive cancer of the uterine cervix

Human leukocyte antigen (HLA)-G acts as negative regulator of the immune responses and its expression in tumor cells may enable them to escape immunosurveillance. The purpose of this study was to investigate the influence of HLA-G polymorphism on risk of high-grade cervical intraepithelial neoplasia (HG-CIN) and cervical cancer in a Canadian population. The authors have analyzed 1,372 women from participants recruited between 2001 and 2009 in the ongoing Biomarkers of Cervical Cancer Risk case-control study. A total of 539 women with histologically confirmed HG-CIN and invasive cancer formed the case series, and 833 women with normal cytology served as controls. Cervical specimens were tested for human papillomavirus (HPV) DNA using the MY09/11 PCR protocol and HLA-G alleles where determined using a direct DNA sequencing procedures. HLA-G polymorphisms were not associated with HG-CIN or HPV infection. However, the risk for invasive cancer was significantly increased with the homozygous genotypes HLA-G*01:01:02 [odds ratio (OR) = 3.52, 95% confidence interval (CI): 1.43-8.61, p = 0.006], -G*01:06 (OR = 19.1, 95% CI: 2.29-159, p = 0.005) and -G* 3'UTR 14-bp insertion (OR = 2.17, 95% CI: 1.10-4.27, p = 0.020), whereas, the heterozygotic form of the G*01:01:01 wild-type allele was significantly associated with a reduced risk of invasive cancer (OR = 0.31, 95% CI: 0.16-0.59, p < 0.0001) after adjusting for age, HPV infection and ethnicity. These associations were also observed with progression of disease from HG-CIN to invasive cancer among HPV-positive women. These results suggest that HLA-G polymorphism is an independent risk factor for the development of invasive cervical cancer.     

Human leukocyte antigens in 295 Chinese patients with chronic myeloid leukemia

Experimental studies using synthetic peptides identical to the bcr-abl fusion region in chronic myeloid leukemia (CML) patients have revealed that some specific peptides could bind to human leukocyte antigen (HLA) class I and class II molecules. Previous clinical observations have also reported some significant HLA associations with the development of CML in their populations. Due to high diversity of HLA alleles, the present study assessed the possibility of an association of HLA molecules in CML patients living in Jiangsu province, the eastern part of China. HLA-A, B and DRB1 allele distributions in 295 CML patients (aged 4 - 65 years) were analysed and compared with unrelated healthy hematopoietic stem cell donors from the same ethnic and geographic background. By comparison of the HLA gene distribution characteristics between CML and healthy donor populations, differences with statistical significance were found in HLA-A*30 (5.42% versus 9.13%) with odds ratio (OR) 0.57, DRB1*07 (8.14% versus 12.51%; OR = 0.62), and B*81 (0.51% versus 0.09%, OR = 5.44). These results suggest that expression of HLA-A*30, DRB1*07 might imply a protective effect on CML acquisition, while B*81 might be associated with CML susceptive factors in our population.     

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Human papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45-positive cervical carcinoma. This provides further evidence that the HLA class II-mediated immune response to HPV is important for controlling viral load and outcome of an infection.