Research IndicatorsGraph generated 16 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: HLA-DPB1 (cancer-related)
Zhang X, Zheng C, Zhou ZH, et al.Relationship between HLA-DP gene polymorphisms and the risk of hepatocellular carcinoma: a meta-analysis.
Genet Mol Res. 2015; 14(4):15553-63 [PubMed
] Related Publications
The association between the HLA-DP single nucleotide polymorphisms (SNPs) rs3077 and rs9277535 and hepatocellular carcinoma (HCC) has been reported, but results have been inconclusive and controversial. Therefore, to investigate the relationship between these HLA-DP SNPs and HCC susceptibility, a meta-analysis of studies published before January 2014 was carried out using the PubMed and Google Scholar databases. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated for HLA-DP alleles, and for co-dominant, dominant, and recessive genotype models of each SNP, based on fixed- or random-effects models. A total of nine studies from six published articles were included. The association study between rs3077 and HCC susceptibility was performed in four independent comparisons that contained 1871 cases with hepatitis B virus (HBV)-related HCC and 3207 carriers with persistent HBV. Association between rs9277535 and HCC susceptibility was examined in five separate comparisons that contained 2017 cases and 3930 carriers. Our analysis indicated a significant association of rs3077 and rs9277535 with HCC susceptibility, suggesting that rs3077 might act beneficially against HCC susceptibility (A vs G: OR = 0.884, 95%CI = 0.803-0.973, P = 0.012; GA vs GG: OR = 0.842, 95%CI = 0.733-0.967, P = 0.015; AA+GA vs GG: OR = 0.848, 95%CI = 0.744-0.968, P = 0.014), and that rs9277535 might promote HCC susceptibility (AA vs GA: OR = 1.202, 95%CI = 1.011-1.428, P = 0.037). This study suggested that HLA-DP rs3077 and rs9277535 polymorphisms are associated with HCC susceptibility in the Asian population.
Hirabayashi K, Kurata T, Horiuchi K, et al.Loss of Mismatched HLA on the Leukemic Blasts of Patients With Relapsed Lymphoid Malignancies Following Bone Marrow Transplantation From Related Donors With HLA Class II Mismatches in the Graft Versus Host Direction.
Pediatr Blood Cancer. 2016; 63(4):709-11 [PubMed
] Related Publications
Mechanisms of relapse of acute lymphoblastic leukemia (ALL) after human leukocyte antigen (HLA) class II mismatched hematopoietic stem cell transplantation (HSCT) remain unclear. We report two children with relapsed ALL after HSCT from related donors with HLA-DRB1 and -DQB1 mismatches in the graft versus host direction. One lost HLA-DRB1, DQB1, and DPB1 alleles, and the other lost one HLA haplotype of the leukemic blasts at relapse. HLA class II loss may be a triggering event for ALL relapse after partially HLA-mismatched-related HSCT. In addition, HLA typing of relapsed leukemic blasts could be vital in the selection of retransplant donors.
Delahaye-Sourdeix M, Urayama KY, Gaborieau V, et al.A Novel Risk Locus at 6p21.3 for Epstein-Barr Virus-Positive Hodgkin Lymphoma.
Cancer Epidemiol Biomarkers Prev. 2015; 24(12):1838-43 [PubMed
] Related Publications
BACKGROUND: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein-Barr virus (EBV) status, particularly within the MHC region.
METHODS: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls.
RESULTS: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83-2.97; P = 7 × 10(-12)], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92-1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10(-8)). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL.
CONCLUSIONS: rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL.
IMPACT: This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease.
PURPOSE: We carried out this study to find out the relevance between rs2281388 T/C polymorphism of human leukocyte antigen (HLA) gene and hepatocellular carcinoma (HCC) risk in Chinese Han population.
METHODS: The method of polymerase chain reaction (PCR) was applied to amplify the genomic DNA. Then the PCR products were sequenced to test the HLA-DP gene rs2281388T/C polymorphism of the case and control groups. Odds ratios (ORs) and 95% confidence interval (95% CIs) were utilized to evaluate the potential correlation between rs2281388 variants and HCC risk.
RESULTS: We analyzed the rs2281388 polymorphism distribution among the clinical pathological features. The results showed that there existed a significant statistic correlation between rs2281388T/C polymorphism of HLA-DP gene and HBsAg feature, and no significant correlation was found between rs2281388 and other clinical features. Further analysis showed that the TT genotype of rs2281388 was significantly correlated with HCC risk, and the same to T allele, but there was no significant difference of CT genotype distribution in case and control groups.
CONCLUSION: TT genotype and T allele of HLA-DP gene rs2281388 polymorphism may increase the risk of HCC.
Yang YC, Chang TY, Chen TC, et al.Genetic susceptibility to cervical squamous cell carcinoma is associated with HLA-DPB1 polymorphisms in Taiwanese women.
Cancer Immunol Immunother. 2015; 64(9):1151-7 [PubMed
] Related Publications
Cervical cancer is a multifactorial disease, and increasing evidence suggests that host immunogenetic background may contribute to its pathogenesis. Genetic variations in human leukocyte antigen (HLA) genes may alter the efficiency of immune response to human papillomavirus (HPV) antigens and have been implicated in the risk of cervical cancer. We investigated whether polymorphisms in the HLA-DPB1 gene were associated with cervical cancer risk in a Taiwanese population. HLA-DPB1 alleles and +550 G/A polymorphism were genotyped in a case-control study of 473 women with cervical squamous cell carcinoma (CSCC) and 676 healthy controls. The presence and genotypes of HPV in CSCC were determined. We found that the DPB1*05:01 and +550 A alleles were associated with decreased and increased risk of CSCC, respectively [odds ratio (OR) = 0.72, Pc = 0.001; OR = 1.25, Pc = 0.03]. In subgroup analysis based on HPV type 16 positivity, significant associations were shown in the DPB1*05:01 and *13:01 alleles (OR = 0.65, Pc = 0.0007; OR = 1.83, Pc = 0.004). Furthermore, the DPB1*05:01-G and *13:01-G haplotypes conferred decreased and increased risk of both CSCC and HPV-16 positive CSCC women, respectively (OR = 0.72, Pc = 0.0009; OR = 0.63, Pc = 0.0004 for DPB1*05:01-G; OR = 1.55, Pc = 0.03; OR = 1.84, Pc = 0.004 for DPB1*13:01-G). A risk haplotype DPB1*02:01-A was also observed in the HPV-16 positive CSCC women (OR = 1.51, Pc = 0.05). These findings suggest that HLA-DPB1 gene is involved in the CSCC development.
Wang L, Wei B, Hu G, et al.Screening of differentially expressed genes associated with human glioblastoma and functional analysis using a DNA microarray.
Mol Med Rep. 2015; 12(2):1991-6 [PubMed
] Related Publications
Glioblastoma multiforme (GBM) is the most malignant type of human glioma, and has a poor prognosis. Screening differentially expressed genes (DEGs) in brain tumor samples and normal brain samples is of importance for identifying GBM and to design specific-targeting drugs. The transcriptional profile of GSE30563, containing three genechips of brain tumor samples and three genechips of normal brain samples, was downloaded from Gene Expression Omnibus to identify the DEGs. The differences in the expression of the DEGs in the two different samples were compared through hierarchical biclustering. The co-expression coefficient of the DEGs was calculated using the information from COXPRESdb, the network of the DEGs was constructed and functional enrichment and pathway analysis were performed. Finally, the transcription factors of important DEGs were predicted. A total of 1,006 DEGs, including 368 upregulated and 638 downregulated DEGs, were identified. A close correlation was demonstrated between six important genes, associated with immune response, HLA-DQB1, HLA-DRB1, HLA-DPA1, HLA-B, HLA-DMA and HLA-DRA, and the immune response. Allograft rejection was selected as the most significant pathway. A total of 17 transcription factors, including nuclear factor (NF)-κB and NF-κB1, and their binding sites containing these six DEGs, were also identified. The DEGs, including major histocompatibility complex (MHC) class II, DQβ1, MHC class II, DRβ1, MHC class IB, MHC class II, DMα, MHC class II, DPα1, MHC class II, DRα, may provide novel targets for the diagnosis and treatment of GBM. The transcription factors of these six genes and their binding sites may also provide evidence and direction for identifying target-specific drugs.
Zsiros E, Duttagupta P, Dangaj D, et al.The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28-Costimulated T Cells Prepared for Adoptive Therapy.
Clin Cancer Res. 2015; 21(12):2840-50 [PubMed
] Free Access to Full Article Related Publications
PURPOSE: Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)-vaccine primed T cells in the context of cell-based immunotherapy.
EXPERIMENTAL DESIGN: The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer.
RESULTS: The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumor-infiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine-primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer.
CONCLUSIONS: DC-primed tumor-specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines. Clin Cancer Res; 21(12); 2840-50. ©2015 AACR.
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.
How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic data sets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
We hypothesized that the compatibility of each HLA loci between donor and patient induced divergent transplant-related immunologic responses, which attributed to the individualized manifestation of clinical outcomes. Here, we analyzed 7898 Japanese pairs transplanted with T-cell-replete marrow from an unrelated donor with complete HLA allele typing data. Multivariable competing risk regression analyses were conducted to evaluate the relative risk (RR) of clinical outcomes after transplantation. A significant RR of HLA allele mismatch compared with match was seen with HLA-A, -B, -C, and -DPB1 for grade III-IV acute graft-versus-host disease (GVHD), and HLA-C for chronic GVHD. Of note, only HLA-C and HLA-DPB1 mismatch reduced leukemia relapse, and this graft-versus-leukemia effect of HLA-DPB1 was independent of chronic GVHD. HLA-DRB1 and HLA-DQB1 double (DRB1_DQB1) mismatch was revealed to be a significant RR for acute GVHD and mortality, whereas single mismatch was not. Thus, the number of HLA-A, -B, -C, -DPB1, and DRB1_DQB1 mismatches showed a clear-cut risk difference for acute GVHD, whereas the number of mismatches for HLA-A, -B, -C, and DRB1_DQB1 showed the same for mortality. In conclusion, we determined the biological response to HLA locus mismatch in transplant-related immunologic events, and provide a rationale for use of a personalized algorithm for unrelated donor selection.
Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (HLA-DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of HLA-DRB1 and HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in cancer adjacent normal (ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of HLA-DRB1 and hypermethylation of HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in HLA-DQB1 (P < 0.01). Moreover, hypomethylation of HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of HLA-DRB1 CpG16 and hypomethylation of HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant HLA-DRB1 and HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific tumor epitopes, promoting the occurrence and progression of Kazakh ESCC.
BACKGROUND: Though HLA-DP/DQ is regarded to associate with HBV susceptibility and HBV natural clearance, its role in hepatocellular carcinoma (HCC) development is obscure. And the role of STAT4 in HBV susceptibility and clearance as well as HCC development is still contentious. Therefore, we conducted this study, aiming to clarify these obscure relationships.
METHODS: We recruited 1312 Chinese Han subjects including healthy controls, HBV carriers and HCC patients in the experiment stage. The meta-analysis included 3467 HCC patients and 5821 HBV carriers to appraise the association with HCC development.
RESULTS: Consistent with previous studies, HLA-DP/DQ associated with HBV susceptibility and HBV natural clearance (p<0.05). However, the experiment showed that HLA-DP rs3077, rs9277535 and rs7453920 did not associate with HCC development (dominant model, rs3077, OR = 0.86, 95%CI = 0.62-1.18; rs9277535, OR = 0.94, 95%CI = 0.68-1.30; rs7453920, OR = 0.75, 95%CI = 0.44-1.27). Meta-analysis again consolidated this conclusion (allele model, rs3077, OR = 0.94, 95%CI = 0.87-1.02; rs9277535, OR = 1.04, 95%CI = 0.97-1.11; rs7453920, OR = 0.89, 95%CI = 0.76-1.02). As for STAT4 rs7574865, we did not find any significant association with HBV susceptibility (OR = 0.91, 95%CI = 0.66-1.26) or HBV natural clearance (OR = 1.13, 95%CI = 0.86-1.49). Moreover, current data failed to acquire positive connection of rs7574865 with HCC development (experiment, OR = 0.86, 95%CI = 0.62-1.19; meta-analysis, OR = 0.87, 95%CI = 0.74-1.03), which may be due to the small sample size.
CONCLUSIONS: HLA-DP/DQ polymorphisms (rs3077, rs9277535, rs7453920) did not associate with HCC development, but did correlate with HBV susceptibility and HBV natural clearance. STAT4 rs7574865 seemed not to correlate with HBV susceptibility or natural clearance. And it seemed rather ambiguous in its role on HCC development at present.
Leite FA, Lira RC, Fedatto PF, et al.Low expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 is associated with poor prognosis in pediatric adrenocortical tumors (ACT).
Pediatr Blood Cancer. 2014; 61(11):1940-8 [PubMed
] Related Publications
BACKGROUND: Low expression of HLA class II antigens has been associated with more aggressive disease in several human malignancies including adult adrenocortical tumors (ACT), but their clinical relevance in pediatric ACT needs to be investigated.
PROCEDURE: This study analyzed the expression profile of three class II histocompatibility genes (HLA-DRA, HLA-DPA1, and HLA-DPB1) in 58 consecutive pediatric ACT (13 adenomas and 45 carcinomas) by quantitative real time PCR and their association with clinical and biological features. HLA-DPA1 protein level was determined by immunohistochemistry.
RESULTS: A significant association (P < 0.01) was observed between lower expression levels of the three genes analyzed and poor prognostic factors such as age ≥ 4 years, tumor size ≥ 200 cm(3), tumor weight ≥ 100 g, and metastatic disease; the presence of an unfavorable event and death. Underexpression of the HLA-DRA, HLA-DPA1, and HLA-DPB1 genes were associated with lower 5-year event-free survival (EFS) (P = 0.017, P < 0.001, and P = 0.017, respectively). Cox multivariate analysis showed that HLA-DPA1 was an independent prognostic factor (P = 0.029) when analyzed in association with stage IV, age and tumor size. Significantly lower EFS was also observed in patients with negative/weak immunostaining for HLA-DPA1 (P = 0.002). Similar results were observed when only patients classified as having carcinomas were analyzed.
CONCLUSION: Our results suggest that lower expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 genes may contribute to more aggressive disease in pediatric ACT. HLA-DPA1 immunostaining may represent potential aggressiveness marker in this tumor.
Thompson P, Urayama K, Zheng J, et al.Differences in meiotic recombination rates in childhood acute lymphoblastic leukemia at an MHC class II hotspot close to disease associated haplotypes.
PLoS One. 2014; 9(6):e100480 [PubMed
] Free Access to Full Article Related Publications
Childhood Acute Lymphoblastic Leukemia (ALL) is a malignant lymphoid disease of which B-cell precursor- (BCP) and T-cell- (T) ALL are subtypes. The role of alleles encoded by major histocompatibility loci (MHC) have been examined in a number of previous studies and results indicating weak, multi-allele associations between the HLA-DPB1 locus and BCP-ALL suggested a role for immunosusceptibility and possibly infection. Two independent SNP association studies of ALL identified loci approximately 37 kb from one another and flanking a strong meiotic recombination hotspot (DNA3), adjacent to HLA-DOA and centromeric of HLA-DPB1. To determine the relationship between this observation and HLA-DPB1 associations, we constructed high density SNP haplotypes of the 316 kb region from HLA-DMB to COL11A2 in childhood ALL and controls using a UK GWAS data subset and the software PHASE. Of four haplotype blocks identified, predicted haplotypes in Block 1 (centromeric of DNA3) differed significantly between BCP-ALL and controls (P = 0.002) and in Block 4 (including HLA-DPB1) between T-ALL and controls (P = 0.049). Of specific common (>5%) haplotypes in Block 1, two were less frequent in BCP-ALL, and in Block 4 a single haplotype was more frequent in T-ALL, compared to controls. Unexpectedly, we also observed apparent differences in ancestral meiotic recombination rates at DNA3, with BCP-ALL showing increased and T-ALL decreased levels compared to controls. In silico analysis using LDsplit sotware indicated that recombination rates at DNA3 are influenced by flanking loci, including SNPs identified in childhood ALL association studies. The observed differences in rates of meiotic recombination at this hotspot, and potentially others, may be a characteristic of childhood leukemia and contribute to disease susceptibility, alternatively they may reflect interactions between ALL-associated haplotypes in this region.
Jiang X, Ma Y, Cui W, Li MDAssociation of variants in HLA-DP on chromosome 6 with chronic hepatitis B virus infection and related phenotypes.
Amino Acids. 2014; 46(8):1819-26 [PubMed
] Related Publications
Hepatitis B virus (HBV) infection affects more than 2 billion people throughout the world. Among them, more than 240 million have chronic infection. Every year, 0.5-1.2 million people die of chronic hepatitis B virus infection (CHBVI), and approximately 60% of liver cancers are related to CHBI and subsequent liver cirrhosis (LC). These HBVI-related diseases impose a considerable economic burden as well as morbidity on patients, families, and society. Family and twin studies have indicated that the host genetic constitution greatly influences the clinical outcomes of HBV infection. During the past several years, genome-wide association studies (GWAS) have identified susceptibility variants for various HBVI-related diseases. Of these variants, SNPs rs3077 and rs9277535 in HLA-DP on chromosome 6 show the strongest evidence for association with CHBVI and with viral clearance. However, whether there exists an association between HLA-DP variants and the progression of CHBVI remains to be determined. Thus, further study should focus not only on identifying more variants in HLA-DP that are associated with various HBVI-related diseases but also on characterizing any newly discovered functional variants at the molecular level. Further, given the complexity of CHBV infection and its progression, gene-gene and gene-environment interactions should also be taken into consideration. Moreover, because both smoking and alcohol affect HBV infection and progression, it is important to understand how these factors interact with genetics to influence HBV-related diseases.
Chen D, Gyllensten USystematic investigation of contribution of genetic variation in the HLA-DP region to cervical cancer susceptibility.
Carcinogenesis. 2014; 35(8):1765-9 [PubMed
] Related Publications
Compared with the other human leukocyte antigen (HLA) genes, few studies have evaluated the role of HLA-DP genes in cervical cancer pathogenesis. A recent genome-wide association study (GWAS) in the Swedish population has identified a susceptibility locus for cervical cancer within the HLA-DP region. To further study this locus, we imputed classic HLA alleles using single-nucleotide polymorphism (SNP) data and analysed 449 genotyped and 3066 imputed SNPs in 1034 cervical cancer patients and 3948 controls. We confirmed that the strongest signal came from a SNP located at HLA-DPB2 [rs3117027, odds ratio (OR) = 1.29, 95% confidence interval (CI) = 1.16-1.43, P = 1.9 × 10(-6) for A allele] and that this effect is not driven by associations with classic HLA alleles. In silico analysis further revealed that this SNP is highly correlated with rs3129294 (D' = 1, r(2) = 0.95 in controls), which may have a putative regulatory function. We also identified an independent association at DPB1*0402, which conferred decreased risk of cervical cancer (OR = 0.75, 95% CI = 0.63-0.89, P = 7.0 × 10(-4)) and is independent of previously described associations with HLA-B*0702, DRB1*1501-DQB1*0602, and DRB1*1301-DQA1*0103-DQB1*0603. No association was found with the two SNPs (rs4282438 or rs9277952) that were recently identified within the HLA-DP region in a cervical cancer GWAS in the Chinese population. Our study provides the first systematic investigation of the association of genetic variants in the HLA-DP region with cervical cancer susceptibility and provides further insight into the contribution of polymorphisms in the HLA-DP region to risk of cervical cancer.
Puig-Butille JA, Escámez MJ, Garcia-Garcia F, et al.Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer.
Oncotarget. 2014; 5(6):1439-51 [PubMed
] Free Access to Full Article Related Publications
Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson's, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development.
The goal of this study was to determine the frequency of HLA class II antigen expression in colorectal carcinoma (CRC) tumors, its association with the clinical course of the disease, and the underlying mechanism(s). Two tissue microarrays constructed with 220 and 778 CRC tumors were stained with HLA-DR, DQ, and DP antigen-specific monoclonal antibody LGII-612.14, using the immunoperoxidase staining technique. The immunohistochemical staining results were correlated with the clinical course of the disease. The functional role of HLA class II antigens expressed on CRC cells was analyzed by investigating their in vitro interactions with immune cells. HLA class II antigens were expressed in about 25% of the 220 and 21% of the 778 tumors analyzed with an overall frequency of 23%. HLA class II antigens were detected in 19% of colorectal adenomas. Importantly, the percentage of stained cells and the staining intensity were significantly lower than those detected in CRC tumors. However, HLA class II antigen staining was weakly detected only in 5.4% of 37 normal mucosa tissues. HLA class II antigen expression was associated with a favorable clinical course of the disease. In vitro stimulation with interferon gamma (IFNγ) induced HLA class II antigen expression on two of the four CRC cell lines tested. HLA class II antigen expression on CRC cells triggered interleukin-1β (IL-1β) production by resting monocytes. HLA class II antigen expression in CRC tumors is a favorable prognostic marker. This association may reflect stimulation of IL-1β production by monocytes.
BACKGROUND: Previous studies showed that single nucleotide polymorphisms (SNPs) in the HLA-DP, TCF19 and EHMT2 genes may affect the chronic hepatitis B (CHB). To predict the degree of risk for chronicity of HBV, this study determined associations with these SNPs.
METHODS: The participants for this study were defined into 4 groups; HCC (n = 230), CHB (n = 219), resolved HBV infection (n = 113) and HBV uninfected subjects (n = 123). The HLA-DP SNPs (rs3077, rs9277378 and rs3128917), TCF19 SNP (rs1419881) and EHMT2 SNP (rs652888) were genotyped.
RESULTS: Due to similar distribution of genotype frequencies in HCC and CHB, we combined these two groups (HBV carriers). The genotype distribution in HBV carriers relative to those who resolved HBV showed that rs3077 and rs9277378 were significantly associated with protective effects against CHB in minor dominant model (OR = 0.45, p<0.001 and OR = 0.47, p<0.001). The other SNPs rs3128917, rs1419881 and rs652888 were not associated with HBV carriers.
CONCLUSIONS: Genetic variations of rs3077 and rs9277378, but not rs3128917, rs1419881 and rs652888, were significantly associated with HBV carriers relative to resolved HBV in Thai population.
Hepatitis B virus (HBV) infection is a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. Human leukocyte antigens (HLAs) play an important role in the regulation of immune response against infectious organisms, including HBV. Recently, several genome-wide association (GWAS) studies have shown that genetic variations in HLA genes influence disease progression in HBV infection. The aim of this study was to investigate the role of HLA genetic polymorphisms and their possible role in HBV infection in Saudi Arabian patients. Variations in HLA genes were screened in 1672 subjects who were divided according to their clinical status into six categories as follows; clearance group, inactive carriers, active carriers, cirrhosis, hepatocellular carcinoma (HCC) patients and uninfected healthy controls. Three single nucleotide polymorphisms (SNPs) belonged to HLA-DQ region (rs2856718, rs7453920 and rs9275572) and two SNPs belonged to HLA-DP (rs3077 and rs9277535) were studied. The SNPs were genotyped by PCR-based DNA sequencing (rs2856718) and allele specific TaqMan genotyping assays (rs3077, rs7453920, rs9277535 and rs9275572). The results showed that rs2856718, rs3077, rs9277535 and rs9275572 were associated with HBV infection (p = 0.0003, OR = 1.351, CI = 1.147-1.591; p = 0.041, OR = 1.20, CI = 1.007-1.43; p = 0.045, OR = 1.198, CI = 1.004-1.43 and p = 0.0018, OR = 0.776, CI = 0.662-0.910, respectively). However, allele frequency of rs2856718, rs7453920 and rs9275572 were found more in chronically infected patients when compared to clearance group infection (p = 0.0001, OR = 1.462, CI = 1.204-1.776; p = 0.0178, OR = 1.267, CI = 1.042-1.540 and p = 0.010, OR = 0.776, CI = 0.639-0.942, respectively). No association was found when polymorphisms in HLA genes were compared in active carriers versus cirrhosis/HCC patients. In conclusion, these results suggest that variations in HLA genes could affect susceptibility to and clearance of HBV infection in Saudi Arabian patients.
van Besien KAllogeneic transplantation for AML and MDS: GVL versus GVHD and disease recurrence.
Hematology Am Soc Hematol Educ Program. 2013; 2013:56-62 [PubMed
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Allogeneic transplantation constitutes curative treatment for acute myeloid leukemia and myelodysplastic syndrome. Its therapeutic effects are to a large extent mediated by GVL effects, but partially offset by treatment-related mortality and loss of quality of life caused by acute and chronic GVHD. Although severe acute and chronic GVHD are associated with a reduction in relapse risk, they are not associated with improved survival. Recent efforts to modulate the GVL-GVH balance include novel methods of in vitro or in vivo T-cell depletion that are associated with a minimal impact on rates of disease recurrence and a dramatically decreased risk for GVHD. Donor selection algorithms may also have a significant impact on transplantation outcomes. Low-expression HLA alleles, particularly HLA-DP, should be incorporated in selection of adult unrelated donors. Evolving data suggest that KIR typing may also be important. High-resolution HLA typing and the importance of fetal-maternal interactions in umbilical cord blood transplantation are also briefly discussed. A combination of donor selection strategies and GVHD prophylaxis methods will favorably affect long-term outcomes and create an environment suitable for effective posttransplantation interventions.
Chiu BL, Li CH, Chang CCSelective modulation of MHC class II chaperons by a novel IFN-γ-inducible class II transactivator variant in lung adenocarcinoma A549 cells.
Biochem Biophys Res Commun. 2013; 440(1):190-5 [PubMed
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Class II transactivator (CIITA) plays a critical role in controlling major histocompatibility complex (MHC) class II gene expression. In this study, two novel alternatively spliced variants of human interferon (IFN)-γ-inducible CIITA, one missing exon 7 (CIITAΔE7), the other with TAG inserted at exon 4/5 junction (CIITA-TAG), were identified and characterized. Both variants are naturally occurring since they are present in primary cells. Unlike CIITA-TAG, CIITAΔE7 is expressed more abundantly in lung adenocarcinoma A549 cells than in the non-transformed counterpart BEAS-2B cells following IFN-γ stimulation. Transfection experiments showed that CIITAΔE7 induced a markedly lower level of surface HLA-DR, -DP, -DQ expression than CIITA-TAG in A549 cells but not in BEAS-2B cells, although both variants elicited similar amounts of total DR, DP, and DQ proteins. This differential effect was correlated with, in A549 cells, decreased expression of Ii and HLA-DM genes, along with increased expression of HLA-DO genes. Ii and HLA-DM are chaperons assisting in HLA class II assembly, while HLA-DO functions to inhibit endosomal peptide loading and HLA class II membrane transport. These findings raise the possibility that CIITAΔE7 interacts with unknown cancer-associated factors to selectively modulate genes involved in the assembly and transport of HLA class II molecules.
Lin Y, Fujiki F, Katsuhara A, et al.HLA-DPB1*05: 01-restricted WT1332-specific TCR-transduced CD4+ T lymphocytes display a helper activity for WT1-specific CTL induction and a cytotoxicity against leukemia cells.
J Immunother. 2013; 36(3):159-70 [PubMed
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Wilms tumor gene 1 (WT1) is overexpressed in various malignant neoplasms, and has been demonstrated as an attractive target for cancer immunotherapy. We previously reported the identification of a WT1 protein-derived, 16-mer helper peptide WT1332 that could elicit Th1-type CD4+ T-cell response and bind to multiple HLA class II molecules. In this study, we examined the feasibility of adoptive therapy using CD4+ T cells that were transduced an HLA-DPB1*05:01-restricted, WT1332-specific T-cell receptor (TCR). HLA-DPB1*05:01-restricted, WT1332-specific TCR-transduced CD4+ T cells were successfully generated using lentiviral vector and exhibited strong proliferative response and Th1-type cytokine production in response to WT1332 peptide, WT1 protein, or WT1-expressing tumor cell lysate. Furthermore, the WT1332-specific TCR-transduced CD4+ T cells lysed HLA-DPB1*05:01-positive, WT1-expressing human leukemia cells through granzyme B/perforin pathway. Furthermore, stimulation of peripheral blood mononuclear cells with both HLA-A*24:02-restricted cytotoxic T lymphocytes-epitope peptide (modified 9-mer WT1235 peptide, WT1235m) and WT1332 helper peptide in the presence of WT1332-specific TCR-transduced CD4+ T cells strikingly enhanced the induction of WT1235m-specific cytotoxic T lymphocytes. Thus, these results demonstrated the feasibility of immunotherapy based on adoptive transfer of WT1332-specific TCR-transduced CD4+ T cells for the treatment of leukemia.
Chen D, Juko-Pecirep I, Hammer J, et al.Genome-wide association study of susceptibility loci for cervical cancer.
J Natl Cancer Inst. 2013; 105(9):624-33 [PubMed
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BACKGROUND: Cervical carcinoma has a heritable genetic component, but the genetic basis of cervical cancer is still not well understood.
METHODS: We performed a genome-wide association study of 731 422 single nucleotide polymorphisms (SNPs) in 1075 cervical cancer case subjects and 4014 control subjects and replicated it in 1140 case subjects and 1058 control subjects. The association between top SNPs and cervical cancer was estimated by odds ratios (ORs) and 95% confidence intervals (CIs) with unconditional logistic regression. All statistical tests were two-sided.
RESULTS: Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were associated with cervical cancer: the first is adjacent to the MHC class I polypeptide-related sequence A gene (MICA) (rs2516448; OR = 1.42, 95% CI = 1.31 to 1.54; P = 1.6×10(-18)); the second is between HLA-DRB1 and HLA-DQA1 (rs9272143; OR = 0.67, 95% CI = 0.62 to 0.72; P = 9.3×10(-24)); and the third is at HLA-DPB2 (rs3117027; OR=1.25, 95% CI = 1.15 to 1.35; P = 4.9×10(-8)). We also confirmed previously reported associations of B*0702 and DRB1*1501-DQB1*0602 with susceptibility to and DRB1*1301-DQA1*0103-DQB1*0603 with protection against cervical cancer. The three new loci are statistically independent of these specific human leukocyte antigen alleles/haplotypes. MICA encodes a membrane-bound protein that acts as a ligand for NKG2D to activate antitumor effects. The risk allele of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) of MICA, which results in a truncated protein. Functional analysis shows that women carrying this mutation have lower levels of membrane-bound MICA.
CONCLUSIONS: Three novel loci in the MHC may affect susceptibility to cervical cancer in situ, including the MICA-A5.1 allele that may cause impaired immune activation and increased risk of tumor development.
BACKGROUND: B-cell non-Hodgkin lymphoma represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is one of the most common subtypes. Family and epidemiological studies suggest an important genetic role in the etiology of FL. In recent genome-wide association studies (GWAS) of FL, several genetic susceptibility loci have been identified on chromosome 6p21.33 (rs6457327) and 6p21.32 (rs10484561, rs2647012) in the human leukocyte antigen class I and class II regions. To identify new genetic variants and further elucidate the genetic basis of FL, a meta-analysis was performed of the top 1000 SNPs associated with FL risk from two GWAS in the US, Denmark and Sweden (592 cases, 1541 controls), with independent validation in 107 cases and 681 controls.
RESULTS: rs9275517 and rs3117222 in the HLA class II region were validated and inversely associated with FL risk (rs9275517: OR = 0.63, 95% CI = 0.55-0.73, p = 4.03 × 10(-11); rs3117222: OR = 0.66, 95% CI = 0.57-0.77, p = 1.45 × 10(-7)). rs9275517, which is in high linkage disequilibrium with rs2647012 (r2 = 0.9), was no longer associated with FL after conditioning on rs2647012. The rs3117222 association was independent of established FL SNPs, but not of the HLA-DPB1*0301 allele. Using publicly available gene expression profiles with matching genotype information, we found that rs3117222 also was significantly correlated with increased HLA-DPB1 expression.
CONCLUSIONS: By performing a meta-analysis of two GWAS of FL, we further validated the relevance of HLA-DPB1*0301 as a protective allele in the pathogenesis of FL. Moreover, the protective rs3117222 A allele correlated with increased levels of HLA-DPB1, suggesting a possible disease mechanism involving HLA-DPB1 expression regulation. Our results add further support to the major role of HLA genetic variation in the pathogenesis of FL.
The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA-DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only non-Hispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis. Logistic regression analyses showed an increased risk of ALL associated with HLA-DPB1*01:01 (odds ratio [OR] = 1.43, 95% CI, 1.01-2.04) with no heterogeneity by Hispanic ethnicity (P = .969). Analyses of DPB1 supertypes showed a marked childhood ALL association with DP1, particularly for high-hyperdiploid ALL (OR = 1.83; 95% CI, 1.20-2.78). Evidence of interaction was found between DP1 and older sibling (P = .036), and between DP1 and breastfeeding (P = .094), with both showing statistically significant DP1 associations within the lower exposure categories only. These findings support an immune mechanism in the etiology of childhood ALL involving the HLA-DPB1 gene in the context of an insufficiently modulated immune system.
Touzeau C, Gagne K, Sébille V, et al.Investigation of the impact of HLA-DPB1 matching status in 10/10 HLA matched unrelated hematopoietic stem cell transplantation: results of a French single center study.
Hum Immunol. 2012; 73(7):711-4 [PubMed
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The impact of HLA-DPB1 mismatches after unrelated hematopoietic stem cell transplantation (HSCT) remains controversial. We retrospectively analyzed the impact of permissive/non-permissive HLA-DPB1 mismatches on the outcome of 141 patients who underwent 10/10 HLA allelic-matched unrelated HSCT. Each pair was classified according to the 3 (TCE3) and 4-group (TCE4) algorithm based on DPB1 alleles immunogenicity. Outcome analysis revealed that TCE3 and TCE4 non-permissive HLA-DPB1 disparities were not associated with worsened overall survival, relapse risk neither risk of acute GvHD. Overall, this single center retrospective study does not confirm the adverse prognostic of non-permissive HLA-DPB1 mismatches.
Adoptive therapy with TCR gene-engineered T cells provides an attractive and feasible treatment option for cancer patients. Further development of TCR gene therapy requires the implementation of T-cell target epitopes that prevent "on-target" reactivity towards healthy tissues and at the same time direct a clinically effective response towards tumor tissues. Candidate epitopes that meet these criteria are MAGE-C2(336-344)/HLA-A2 (MC2/A2) and MAGE-A3(243-258)/HLA-DP4 (MA3/DP4). We molecularly characterized TCRαβ genes of an MC2/A2-specific CD8 and MA3/DP4-specific CD4 T-cell clone derived from melanoma patients who responded clinically to MAGE vaccination. We identified MC2/A2 and MA3/DP4-specific TCR-Vα3/Vβ28 and TCR-Vα38/Vβ2 chains and validated these TCRs in vitro upon gene transfer into primary human T cells. The MC2 and MA3 TCR were surface-expressed and mediated CD8 T-cell functions towards melanoma cell lines and CD4 T-cell functions towards dendritic cells, respectively. We intend to start testing these MAGE-specific TCRs in phase I clinical trial.
Follicular lymphoma (FL) is an indolent, sometimes, fatal disease characterized by recurrence at progressively shorter intervals and is frequently refractive to therapy. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region on chromosome 6p21.32-33 that are statistically significantly associated with FL risk. Low to medium resolution typing of single or multiple HLA genes has provided an incomplete picture of the total genetic risk imparted by this highly variable region. To gain further insight into the role of HLA alleles in lymphomagenesis and to investigate the independence of validated SNPs and HLA alleles with FL risk, high-resolution HLA typing was conducted using next-generation sequencing in 222 non-Hispanic White FL cases and 220 matched controls from a larger San Francisco Bay Area population-based case-control study of lymphoma. A novel protective association was found between the DPB1*03:01 allele and FL risk [odds ratio (OR) = 0.39, 95% confidence interval (CI) = 0.21-0.68]. Extended haplotypes DRB1*01:01-DQA1*01:01-DQB1*05:01 (OR = 2.01, 95% CI = 1.22-3.38) and DRB1*15-DQA1*01-DQB1*06 (OR = 0.55, 95% CI = 0.36-0.82) also influenced FL risk. Moreover, DRB1*15-DQA1*01-DQB1*06 was highly correlated with an established FL risk locus, rs2647012. These results provide further insight into the critical roles of HLA alleles and SNPs in FL pathogenesis that involve multi-locus effects across the HLA region.