Gene Summary

Gene:HLA-B; major histocompatibility complex, class I, B
Aliases: AS, HLAB, SPDA1
Summary:HLA-B belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from the endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exon 2 and 3 encode the alpha1 and alpha2 domains, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. Hundreds of HLA-B alleles have been described. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:major histocompatibility complex, class I, B
Source:NCBIAccessed: 11 August, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 11 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 August, 2015 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).

Latest Publications: HLA-B (cancer-related)

Morishima Y, Kashiwase K, Matsuo K, et al.
Biological significance of HLA locus matching in unrelated donor bone marrow transplantation.
Blood. 2015; 125(7):1189-97 [PubMed] Free Access to Full Article Related Publications
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.

Djajadiningrat RS, Horenblas S, Heideman DA, et al.
Classic and nonclassic HLA class I expression in penile cancer and relation to HPV status and clinical outcome.
J Urol. 2015; 193(4):1245-51 [PubMed] Related Publications
PURPOSE: Loss of expression of HLA class I is a mechanism of immune evasion in various cancers that is often associated with a worse patient outcome. We analyzed HLA expression in a large cohort with penile cancer in relation to clinical outcome.
MATERIALS AND METHODS: We used penile cancer tissue blocks from 168 patients who underwent surgical resection between 2000 and 2009 to construct tissue microarrays. Immunohistochemical staining was done with antibodies directed against classic and nonclassic HLA molecules. HLA expression was scored semiquantitatively, divided into 3 expression groups and correlated with clinicopathological variables, including HPV and survival. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards models.
RESULTS: Complete and partial loss of total classic HLA class I was observed in 32% and 50% of cases, and up-regulation of HLA-E and G in 16% and 13%, respectively. When corrected for relevant clinical parameters, partial HLA-A loss was significantly associated with decreased survival overall (HR 2.3, 95% CI 1.1-4.6) and in HPV negative patients alone (HR 3.4, 95% CI 1.4-8.4). Abnormal HLA-B/C, E or G expression levels were not associated with survival.
CONCLUSIONS: To our knowledge this is the first study to describe a link between HLA expression and the clinical outcome of penile cancer. HLA down-regulation occurs frequently and partial loss of HLA-A is an independent predictor of poor survival in HPV negative patients. Complete understanding of the mechanisms and relevance of HLA down-regulation and immune evasion in regard to the clinical outcome will contribute to the future design of immunotherapy interventions.

Jahn L, Hombrink P, Hassan C, et al.
Therapeutic targeting of the BCR-associated protein CD79b in a TCR-based approach is hampered by aberrant expression of CD79b.
Blood. 2015; 125(6):949-58 [PubMed] Related Publications
Immunotherapy of B-cell malignancies using CD19-targeted chimeric antigen receptor-transduced T cells or CD20-targeted therapeutic monoclonal antibodies has shown clinical efficacy. However, refractory disease and the emergence of antigen-loss tumor escape variants after treatment demonstrate the need to target additional antigens. Here we aimed to target the B-cell receptor-associated protein CD79b by a T-cell receptor (TCR)-based approach. Because thymic selection depletes high-avidity T cells recognizing CD79b-derived peptides presented in self-HLA molecules, we aimed to isolate T cells recognizing these peptides presented in allogeneic HLA. Peptide-HLA tetramers composed of CD79b peptides bound to either HLA-A2 or HLA-B7 were used to isolate T-cell clones from HLA-A*0201 and B*0702-negative individuals. For 3 distinct T-cell clones, CD79b specificity was confirmed through CD79b gene transduction and CD79b-specific shRNA knockdown. The CD79b-specific T-cell clones were highly reactive against CD79b-expressing primary B-cell malignancies, whereas no recognition of nonhematopoietic cells was observed. Although lacking CD79b-cell surface expression, intermediate reactivity toward monocytes, hematopoietic progenitor cells, and T-cells was observed. Quantitative reverse transcriptase polymerase chain reaction revealed low CD79b gene expression in these cell types. Therefore, aberrant gene expression must be taken into consideration when selecting common, apparently lineage-specific self-antigens as targets for TCR-based immunotherapies.

Liu D, Zhao ZG, Jiao ZL, Li HJ
Identifying differential expression genes and single nucleotide variations using RNA-seq in metastatic melanoma.
Genet Mol Res. 2014; 13(4):8153-62 [PubMed] Related Publications
Melanoma is a malignant tumor and one of the most frequent metastatic cancers. This study was conducted to identify differential expression genes (DEGs) and single nucleotide variations (SNVs) in metastatic melanoma. We analyzed microarray data of GSE23056 downloaded from the Gene Expression Omnibus, including two normal samples (skinN1 and skinN2) and 2 metastatic melanoma samples (skinT and lymphT). We not only compared DEGs in metastatic melanoma samples with normal samples (lymphT_skinN and skinT_skinN), but also compared DEGs between two metastatic melanoma types (lymphT_skinT). SNVs were identified by using Burrows-Wheeler Aligner and Cufflinks in metastatic melanoma samples using RNA-seq. Sequence Alignment/Map tools and the ANNOVAR software were used to analyze and annotate SNVs. We identified 18 significantly common DEGs in lymphT_skinN and skinT_skinN and one common gene, YBX1, in lymphT_skinN, skinT_skinN, and lymphT_skinT. We identified 49,534, 48,118, 63,812, and 33,096 SNVs in skinN1, skinN2, skinT, and lymphT, respectively. Twenty-nine SNVs were located in exonic regions of two DEGs, HLA-B and TSPAN10. SNVs that exist only in tumors were located in MARVELD1, SLC16A3, and VAV3. The DEGs screened in our study are potential biomarkers for metastatic melanoma therapy.

Yoon J
Acute myeloid leukemia is a disease associated with HLA-C3.
Acta Haematol. 2015; 133(2):164-7 [PubMed] Related Publications
BACKGROUND: We aimed to observe human leukocyte antigen (HLA) associations with human acute myeloid leukemia (AML) in a large population, in order to investigate the roles of HLA in leukemogenesis. Furthermore, we examined the HLA association according to morphological, cytogenetic, immunological, and clinical classifications.
MATERIALS AND METHODS: We performed HLA genotyping, bone marrow studies, cytogenetic analyses, and fluorescence-activated cell sorting analyses. A clinical outcome database was constructed, and the HLA frequency, gene frequency, relative risk (RR), linkage disequilibrium, and the 2-locus and 3-locus haplotype frequency using the Mattiuz formula were calculated. For the healthy controls, Korean HLA data published by Park and co-workers were used.
RESULTS: AML was found to be associated with HLA-C3 (RR = 1.46; p < 0.001). In the French-American-British (FAB) classification, acute myelomonocytic leukemia (AML-M4) was associated with HLA-C3 (47.2 vs. 74.1%; RR = 3.13; p = 0.005), in cytogenetic classification, del(9), which is frequently observed in AML-M4, was also associated with HLA-C3 (47.2 vs. 100%; RR = 13.43; p = 0.024), and in clinical classification, incomplete remission was associated with HLA-C3 as well (47.2 vs. 63.2%; RR = 1.92; p = 0.002). No correlations between AML and immunological classifications were observed. Moreover, and in terms of 2-locus haplotypes, AML was found to be associated with HLA-C3/B62 (HLA-C3 gene frequency 0.3415; HLA-B62 gene frequency 0.1361; linkage disequilibrium 0.0136; haplotype frequency 4.15 vs. 6.0%; p < 0.05). In clinical classification, incomplete remission (linkage disequilibrium 0.0136; haplotype frequency 4.15 vs. 13.6%; p = 0.013) and relapse (linkage disequilibrium 0.0136; haplotype frequency 4.15 vs. 71.0%; p = 0.044) were associated with HLA-C3/B62, whereas no association was observed for FAB, cytogenetic and immunological classifications. No association was observed for the 3-locus haplotype.
CONCLUSION: The HLA-C3 antigen and the 2-locus haplotype are associated with AML.

Gokhale P, Mania-Pramanik J, Sonawani A, et al.
Cervical cancer in Indian women reveals contrasting association among common sub-family of HLA class I alleles.
Immunogenetics. 2014; 66(12):683-91 [PubMed] Related Publications
We studied the relationship between human leukocyte antigen (HLA) class I alleles and cervical cancer among Indian women. Seventy-five cervical cancer cases were compared with 175 noncancer controls. Cervical biopsy tissue specimen from cancer cases and cervical swab specimen from controls were collected for HPV detection and typing. Blood was taken for HLA typing by PCR-SSOP method. The impact of HLA class I alleles on cervical cancer risk was evaluated using StatCalc program (Epi Info version 6.0.4. CDC Atlanta, GA, USA), and confirmed with Bonferroni correction. Results revealed HLA-B*37, HLA-B*58 were associated significantly with increased risk while HLA-B*40 with decreased risk for cervical cancer. At high-resolution analysis after Bonferroni correction, HLA-B*37:01 allele was associated with increased risk, whereas HLA-B*40:06 was with decreased risk for cervical cancer. HLA-B*37:01 and HLA-B*40:06 belong to the same superfamily of HLA-B44. In silico analysis revealed different binding affinities of HLA-B*37:01 and HLA-B*40:06 for the epitopes predicted for E6 and L1 proteins of HPV16. The higher binding affinity of epitopes to B*40:06, as revealed by docking studies, supports the hypothesis that this allele is able to present the antigenic peptides more efficiently than B*37:01 and thereby can protect the carriers from the risk of cervical cancer. Thus, there is a clear indication that HLA plays an important role in the development of cervical cancer in HPV-infected women. Identification of these factors in high-risk HPV-infected women may help in reducing the cervical cancer burden in India.

Zhao XY, Chang YJ, Xu LP, et al.
HLA and KIR genotyping correlates with relapse after T-cell-replete haploidentical transplantation in chronic myeloid leukaemia patients.
Br J Cancer. 2014; 111(6):1080-8 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
BACKGROUND: Conflicting results have been reported regarding the predicative roles of alloreactive natural killer (NK) cells on the outcomes of transplantation in leukaemia patients.
METHODS: We prospectively analysed the human leukocyte antigen (HLA) typing of donor-recipient pairs and the KIR typing of the donors in 97 CML patients to address the predictive roles of NK cells in relapse undergoing T-cell-replete haploidentical transplantation.
RESULTS: Patients with class I ligands for the donor-inhibitory KIR gene exhibited decreased molecular and haematologic relapse rates (P=0.003 and P=0.015, respectively). There was a significantly reduced risk of molecular and haematologic relapse in patients with HLA-C1C2 or C2C2 who accepted donors with KIR2DS1 or in patients with HLA-Bw4 who accepted donors with KIR3DS1 ('recipient with relevant KIR ligand for donor-activating KIR', n=25), compared with the remaining transplants (n=72, P=0.009 and P=0.009, respectively). In addition, the presence of class I ligand in the recipients of donor-activating KIR contributed to a decreased relapse rate in patients lacking class I ligand in the recipient of donor-inhibitory KIR (P=0.04 and P=0.03, respectively).
CONCLUSIONS: This study suggests that the presence of class I ligands for the donor-activating or donor-inhibitory KIR gene in the recipient might confer some protection against leukaemic relapse in T-cell-replete haploidentical transplantation.

Sayad A, Akbari MT, Mehdizadeh M, et al.
The association of HLA-class I and class II with Hodgkin's lymphoma in Iranian patients.
Biomed Res Int. 2014; 2014:231236 [PubMed] Article available free on PMC after 09/09/2015 Related Publications
The Hodgkin's lymphoma disease (HD) is a common malignant neoplasm with germinal centre B-cell origin. It has been suggested that the HLA class I and class II regions have susceptibility effects on HD. In different ethnic groups, different HLA class I and class II alleles affect HD. As a result, there is no consensus which of the different HLA alleles confers susceptibility to HD. In this study, we aimed to ascertain the role of HLA class I and class II alleles in association with Hodgkin's lymphoma in Iranian patients. We performed a case-control genotyping study in 85 Iranian HD patients which were selected from the Bone Marrow Transplantation Department of Taleghani Hospital and 150 controls using the SSP-PCR. Our results demonstrated that the HLA-A*68, HLA-B*51, and HLA-DRB1*15 alleles were significantly more frequent in HD patients in comparison to controls (P = 0.026; OR = 6.188, P = 0.00008; OR = 2.86, P = 0.00006; OR = 5.315, resp.) and they have significant susceptibility effects on HD in Iranian population. There are reports of other populations with regard to consistency and inconsistency to our results. Further studies with large sample size or the meta-analysis are needed to explain the exact associations of HLA gene with HD.

Arons E, Adams S, Venzon DJ, et al.
Class II human leucocyte antigen DRB1*11 in hairy cell leukaemia patients with and without haemolytic uraemic syndrome.
Br J Haematol. 2014; 166(5):729-38 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Frequencies of human leucocyte antigens (HLA) were determined in 287 classic hairy cell leukaemia (HCL) patients. With respect to both population (n = 287) and allele (2n = 574) frequency respectively, the most common HLA class I and II antigens expressed were HLA-A*02 (49·1% and 28·6%), HLA-B*07 (21·3% and 11·1%), HLA-C*07 (46·7 and 28·2%), HLA-DQB1*03 (62·7% and 37·3%), HLA-DRB1*11 (30·0% and 16·0%) and HLA-DRB4*01 (45·3% and 29·6%). In comparing 6-14 databases of control Caucasians to 267 Caucasian HCL patients, only HLA-DRB1*11 was consistently over-represented in HCL, 31·1% of patients vs. 17-19·9% of controls (P = 0·0055 to <0·0001) and 16·5% of alleles vs. 6·5-12·3% of control alleles (P = 0·022 to <0·0001). HLA-DRB1*11 is a known risk factor for acquired thrombotic microangiopathy. Anti-CD22 recombinant immunotoxin BL22 in HCL was associated with a 12% incidence of completely reversible grade 3-4 haemolytic uraemic syndrome (HUS), mainly during the second or third retreatment cycle. Of 49 HCL patients receiving ≥2 cycles of BL22, 7 (14%) had HUS and HLA-DRB1*11 was expressed in 71% of 7 with HUS compared with only 21% of 42 without (P = 0·015). These data suggest that DBR1*11 may be a marker for increased susceptibility to HCL and, among HCL patients, could be a risk factor for BL22-induced HUS.

Jung JW, Kim JY, Yoon SS, et al.
HLA-DR9 and DR14 are associated with the allopurinol-induced hypersensitivity in hematologic malignancy.
Tohoku J Exp Med. 2014; 233(2):95-102 [PubMed] Related Publications
Allopurinol, a widely used urate-lowering agent, is a leading cause of severe cutaneous adverse reactions (SCARs), especially in patients with HLA-B*58:01. Despite its routine use for the prevention of tumor lysis-related hyperuricemia prior to chemotherapy, the risk of allopurinol-induced hypersensitivity has not been investigated in patients with hematologic malignancies. This retrospective cohort study was conducted to investigate the incidence and risk factors of allopurinol-induced hypersensitivity in patients at least 18 years of age with hematologic malignancies. We reviewed 463 patients who had ever taken allopurinol for the prevention of hyperuricemia prior to chemotherapy and had undergone serologic HLA typing as a pre-transplant evaluation from January 2000 to May 2010. Thirteen (2.8%) patients experienced maculopapular eruptions (MPE) and none experienced SCARs. Among subtypes of underlying hematologic malignancies, percentage of chronic myeloid leukemia was significantly higher in the allopurinol hypersensitivity group compared with the tolerant group (23.1% (3/13) vs. 5.9% (26/440), P = 0.044). According to HLA subtypes, the incidence of allopurinol-induced MPE was 4.0% in HLA-B58 (+) patients (2/50) and 2.7% in HLA-B58 (-) patients (11/403) but this difference was statistically insignificant. In contrast to HLA-B58, the frequencies of DR9 and DR14 were significantly higher in the allopurinol-induced MPE group compared with the allopurinol tolerant group (38.5% (5/13) vs. 13.6% (53/443), P = 0.019, and 38.5% (5/13) vs. 15.6% (41/440), P = 0.038, respectively). In conclusion, HLA-DR9 and DR14, but not HLA-B58, are associated with hypersensitivity reaction by allopurinol when administered in patients with hematologic malignancy prior to chemotherapy.

Vejbaesya S, Sae-Tam P, Khuhapinant A, Srinak D
Killer cell immunoglobulin-like receptors in Thai patients with leukemia and diffuse large B-cell lymphoma.
Hum Immunol. 2014; 75(7):673-6 [PubMed] Related Publications
Natural killer (NK) cells are key components of the innate immune system that have been implicated in the immune response against tumor cells. Killer cell immunoglobulin-like receptors (KIR) regulate NK cell activity by interaction with specific human leukocyte antigen (HLA) class I. In this study, KIR gene polymorphisms and their HLA ligands were investigated in Thai patients with chronic myelogenous leukemia (CML) (n=60), acute myelogenous leukemia (AML) (n=60), acute lymphoblastic leukemia (ALL) (n=55), and diffuse large B-cell lymphoma (DLBCL) (n=60) compared with 150 healthy controls. The frequency of KIR3DL1 with HLA-Bw4 was significantly lower in DLBCL patients than in controls (P=0.0006, Pc=0.02), whereas no significant differences were seen in KIR gene frequencies and their ligands between leukemia patients and controls. This study suggest a role of inhibitory KIR with its ligand in the protection against DLBCL.

Chen D, Gyllensten U
Systematic 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.

Klar R, Schober S, Rami M, et al.
Therapeutic targeting of naturally presented myeloperoxidase-derived HLA peptide ligands on myeloid leukemia cells by TCR-transgenic T cells.
Leukemia. 2014; 28(12):2355-66 [PubMed] Related Publications
T cells have been proven to be therapeutically effective in patients with relapsed leukemias, although target antigens on leukemic cells as well as T-cell receptors (TCRs), potentially recognizing those antigens, are mostly unknown. We have applied an immunopeptidomic approach and isolated human leukocyte antigen (HLA) ligands from primary leukemia cells. We identified a number of ligands derived from different genes that are restrictedly expressed in the hematopoietic system. We exemplarily selected myeloperoxidase (MPO) as a potential target and isolated a high-avidity TCR with specificity for a HLA-B*07:02-(HLA-B7)-restricted epitope of MPO in the single HLA-mismatched setting. T cells transgenic for this TCR demonstrated high peptide and antigen specificity as well as leukemia reactivity in vitro and in vivo. In contrast, no significant on- and off-target toxicity could be observed. In conclusion, we here demonstrate, exemplarily for MPO, that leukemia-derived HLA ligands can be selected for specific effector tool development to redirect T cells to be used for graft manipulation or adoptive T-cell therapies in diverse transplant settings. This approach can be extended to other HLA ligands and HLA molecules in order to provide better treatment options for this life-threatening disease.

Jiang YZ, Li QH, Zhao JQ, Lv JJ
Identification of a novel fusion gene (HLA-E and HLA-B) by RNA-seq analysis in esophageal squamous cell carcinoma.
Asian Pac J Cancer Prev. 2014; 15(5):2309-12 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is the most common histologic subtype of esophageal cancer and is characterized by a poor prognosis. Determining gene changes in ESCCs should improve understanding of putative risk factors and provide potential targets for therapy. We sequenced about 55 million pair-end reads from a pair of adjacent normal and ESCC samples to identify the gene expression level and gene fusion. Sanger sequencing was used to verify the result. About 17 thousand genes were expressed in the tissues, of which approximately 2400 demonstrated significant differences between tumor and adjacent non tumor tissue. GO and KEGG pathway analysis revealed that many of these genes were associated with cellular adherence and movement, simulation responses and immune responses. Notably we identified and validated one fusion gene, HLA-E and HLA-B, located 1 MB apart. We also identified thousands of remarkably expressed transcripts. In conclusion, a novel fusion gene HLA-E and HLA-B was identified in ESCC via whole transcriptome sequencing, which would be a biomarker for ESCC diagnosis and target for therapy, shedding new light for better understanding of ESCC tumorigenesis.

Brazzelli V, Rivetti N, Badulli C, et al.
Immunogenetic factors in mycosis fungoides: can the HLA system influence the susceptibility and prognosis of the disease? Long-term follow-up study of 46 patients.
J Eur Acad Dermatol Venereol. 2014; 28(12):1732-7 [PubMed] Related Publications
BACKGROUND: Mycosis fungoides (MF) is the most common and one of the least aggressive forms of cutaneous T-cell lymphoma. Several studies have demonstrated the influence of human leucocyte antigen (HLA) genes on the susceptibility of MF, highlighting the importance of certain alleles but, until today, no studies have evaluated the relationship between HLA alleles and the prognosis of patients with MF.
OBJECTIVE: The aim of this retrospective cohort study was to evaluate the polymorphism of HLA class I and class II alleles in a group of 46 MF Caucasian patients, looking for their influence in susceptibility and prognosis of the disease.
METHODS: Study population included a case-cohort sample of 46 Caucasian patients with MF that, between 1993 and 1997, underwent HLA class I and II genomic typing. All patients were diagnosed and followed up from 1977 to 2012 (mean follow-up of 11 years) and they were divided into three groups according to the evolution of the disease.
RESULTS: Molecular typing at low-resolution level revealed that HLA-A*24, A*68, A*69, B*35 and DQB1*05:02 alleles were involved in susceptibility to MF. Correspondence analysis underlined that long-lasting remission was characterized by HLA-A*24 and HLA-A*25 alleles, frequent relapse by HLA-DRB1*01, DQA1*01:01, DQB1*05:01 alleles and death by HLA-A*68, HLA-B*08, HLA-B*35, HLA-C*03 alleles.
CONCLUSION: This study suggests that the prognosis of MF patients is not only correlated with clinical/pathological/serological/immunological variables but it also relies on specific HLA alleles.

Chen D, Gyllensten U
A cis-eQTL of HLA-DRB1 and a frameshift mutation of MICA contribute to the pattern of association of HLA alleles with cervical cancer.
Cancer Med. 2014; 3(2):445-52 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The association of classic human leukocyte antigen (HLA) alleles with risk of cervical cancer has been extensively studied, and a protective effect has consistently been found for DRB1*1301, DQA1*0103, and/or DQB1*0603 (these three alleles are in perfect linkage disequilibrium [LD] and often occur on the same haplotype in Europeans), while reports have differed widely with respect to the effect of HLA-B*07, DRB1*1501, and/or DQB1*0602 (the last two alleles are also in perfect LD in Europeans). It is not clear whether the reported HLA alleles are responsible for the differences in cervical cancer susceptibility, or if functional variants at other locations within the major histocompatibility complex (MHC) region may explain the effect. In order to assess the relative contribution of both classic HLA alleles and single-nucleotide polymorphisms (SNPs) within the MHC region to cervical cancer susceptibility, we have imputed classic HLA alleles in 1034 cervical cancer patients and 3948 controls in a Swedish population for an integrated analysis. We found that the protective haplotype DRB1*1301-DQA1*0103-DQB1*0603 has a direct effect on cervical cancer and always occurs together with the C allele of a HLA-DRB1 cis-eQTL (rs9272143), which increases the expression of HLA-DRB1. The haplotype rs9272143C-DRB1*1301-DQA1*0103-DQB1*0603 conferred the strongest protection against cervical cancer (odds ratio [OR] = 0.41, 95% confidence interval [CI] = 0.32-0.52, P = 6.2 × 10(-13)). On the other hand, the associations with HLA-B*0702 and DRB1*1501-DQB1*0602 are attributable to the joint effects of both the HLA-DRB1 cis-eQTL (rs9272143) and a frameshift mutation (G inserion of rs67841474, also known as A5.1) of the MHC class I polypeptide-related sequence A gene (MICA). Variation in LD between the classic HLA loci, rs9272143 and rs67841474 between populations may explain the different associations of HLA-B*07 and DRB1*1501-DQB1*0602 with cervical cancer between studies. The mechanism suggested may also explain similar inconsistent results for other HLA-associated diseases.

de Smith AJ, Walsh KM, Ladner MB, et al.
The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia.
Blood. 2014; 123(16):2497-503 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Killer cell immunoglobulin-like receptors (KIRs), via interaction with their cognate HLA class I ligands, play a crucial role in the development and activity of natural killer cells. Following recent reports of KIR gene associations in childhood acute lymphoblastic leukemia (ALL), we present a more in-depth investigation of KIR genes and their cognate HLA ligands on childhood ALL risk. Genotyping of 16 KIR genes, along with HLA class I groups C1/C2 and Bw4 supertype ligands, was carried out in 212 childhood ALL cases and 231 healthy controls. Frequencies of KIR genes, KIR haplotypes, and combinations of KIR-HLA ligands were tested for disease association using logistic regression analyses. KIR A/A genotype frequency was significantly increased in cases (33.5%) compared with controls (24.2%) (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.04-2.39). Stratifying analysis by ethnicity, a significant difference in KIR genotype frequency was demonstrated in Hispanic cases (34.2%) compared with controls (21.9%) (OR = 1.86; 95% CI, 1.05-3.31). Homozygosity for the HLA-Bw4 allele was strongly associated with increased ALL risk exclusively in non-Hispanic white children (OR = 3.93; 95% CI, 1.44-12.64). Our findings suggest a role for KIR genes and their HLA ligands in childhood ALL etiology that may vary among ethnic groups.

De Re V, Caggiari L, De Zorzi M, et al.
Genetic diversity of the KIR/HLA system and outcome of patients with metastatic colorectal cancer treated with chemotherapy.
PLoS One. 2014; 9(1):e84940 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
OBJECTIVE: To explore genes of the killer-cell immunoglobulin-like receptor (KIR) and of the HLA ligand and their relationship with the outcome of metastatic colorectal cancer (mCRC) patients treated with first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI).
METHODS: A total of 224 mCRC patients were screened for KIR/HLA typing. The determination of the KIR/HLA combinations was based upon the gene content and variants. Genetic associations with complete response (CR), time to progression (TTP) and overall survival (OS) were evaluated by calculating odds and hazard ratios. Multivariate modeling with prognostic covariates was also performed.
RESULTS: For CR, the presence of KIR2DL5A, 2DS5, 2DS1, 3DS1, and KIR3DS1/HLA-Bw4-I80 was associated with increased CR rates, with median ORs ranging from 2.1 to 4.3, while the absence of KIR2DS4 and 3DL1 was associated with increased CR rates (OR 3.1). After univariate analysis, patients that underwent resective surgery of tumor, absence of KIR2DS5, and presence of KIR3DL1/HLA-Bw4-I80 showed a significant better OS (HR 1.5 to 2.8). Multivariate analysis identified as parameters independently related to OS the type of treatment (surgery; HR 2.0) and KIR3DL1/HLA-Bw4-I80 genotype (HR for T-I80 2.7 and for no functional KIR/HLA interaction 1.8). For TTP, no association with KIR/HLA genes was observed.
CONCLUSION: This study, for the first time, evidences that the genotyping for KIR-HLA pairs are found predictive markers associated with complete response and improves overall survival prediction of FOLFIRI treatment response in metastatic colorectal cancer. These results suggest a role of the KIR/HLA system in patient outcome, and guide new research on the immunogenetics of mCRC through mechanistic studies and clinical validation.

van Esch EM, Tummers B, Baartmans V, et al.
Alterations in classical and nonclassical HLA expression in recurrent and progressive HPV-induced usual vulvar intraepithelial neoplasia and implications for immunotherapy.
Int J Cancer. 2014; 135(4):830-42 [PubMed] Related Publications
Immunotherapy of usual vulvar intraepithelial neoplasia (uVIN) is promising; however, many patients still fail to show clinical responses, which could be explained by an immune escape through alterations in human leukocyte antigen (HLA) expression. Therefore, we analyzed a cohort of patients with a primary (n = 43) and subsequent recurrent uVIN lesion (n = 20), vaccine-treated uVIN patients (n = 12), patients with human papillomavirus (HPV)-induced vulvar carcinoma (n = 21) and healthy controls (n = 26) for the expression of classical HLA-class I/II and nonclassical HLA-E/-G and MHC class I chain-related molecule A (MICA). HLA-class I was downregulated in 70% of uVIN patients, including patients with a clinical response to immunotherapy. Downregulation of HLA-class I is probably reversible, as only 15% of the uVIN cases displayed loss of heterozygosity (LOH) and HLA-class I could be upregulated in uVIN keratinocyte cultures by interferon γ. HLA-class I downregulation is more frequently associated with LOH in vulvar carcinomas (25-55.5%). HLA-class II was found to be focally expressed in 65% of uVIN patients. Of the nonclassical molecules, MICA was downregulated in 80% of uVIN whereas HLA-E and -G were expressed in a minority of cases. Their expression was more prominent in vulvar carcinoma. No differences were found between the alterations observed in paired primary and recurrent uVIN. Importantly, downregulation of HLA-B/C in primary uVIN lesions was associated with the development of recurrences and progression to cancer. We conclude that downregulation of HLA is frequently observed in premalignant HPV-induced lesions, including clinical responders to immunotherapy, and is associated with worse clinical outcome. However, in the majority of cases downregulation may still be reversible.

Ojesina AI, Lichtenstein L, Freeman SS, et al.
Landscape of genomic alterations in cervical carcinomas.
Nature. 2014; 506(7488):371-5 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.

Su WH, Yao Shugart Y, Chang KP, et al.
How genome-wide SNP-SNP interactions relate to nasopharyngeal carcinoma susceptibility.
PLoS One. 2013; 8(12):e83034 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
This study is the first to use genome-wide association study (GWAS) data to evaluate the multidimensional genetic architecture underlying nasopharyngeal cancer. Since analysis of data from GWAS confirms a close and consistent association between elevated risk for nasopharyngeal carcinoma (NPC) and major histocompatibility complex class 1 genes, our goal here was to explore lesser effects of gene-gene interactions. We conducted an exhaustive genome-wide analysis of GWAS data of NPC, revealing two-locus interactions occurring between single nucleotide polymorphisms (SNPs), and identified a number of suggestive interaction loci which were missed by traditional GWAS analyses. Although none of the interaction pairs we identified passed the genome-wide Bonferroni-adjusted threshold for significance, using independent GWAS data from the same population (Stage 2), we selected 66 SNP pairs in 39 clusters with P<0.01. We identified that in several chromosome regions, multiple suggestive interactions group to form a block-like signal, effectively reducing the rate of false discovery. The strongest cluster of interactions involved the CREB5 gene and a SNP rs1607979 on chromosome 17q22 (P = 9.86×10(-11)) which also show trans-expression quantitative loci (eQTL) association in Chinese population. We then detected a complicated cis-interaction pattern around the NPC-associated HLA-B locus, which is immediately adjacent to copy-number variations implicated in male susceptibility for NPC. While it remains to be seen exactly how and to what degree SNP-SNP interactions such as these affect susceptibility for nasopharyngeal cancer, future research on these questions holds great promise for increasing our understanding of this disease's genetic etiology, and possibly also that of other gene-related cancers.

Fernández-Torres J, Flores-Jiménez D, Arroyo-Pérez A, et al.
HLA-B*40 allele plays a role in the development of acute leukemia in Mexican population: a case-control study.
Biomed Res Int. 2013; 2013:705862 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
UNLABELLED: Among oncohematological diseases, acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) are characterized by the uncontrolled production and accumulation of blasts that can lead to death. Although the physiopathology of these diseases is multifactorial, a genetic factor seems to be at play. Several studies worldwide have shown association of ALL and AML with several alleles of the major histocompatibility complex (MHC).
OBJECTIVE: To determine gene frequencies of HLA-B alleles in Mexicans (individuals with Native American genetic background admixed with European descent) with ALL and AML.
METHODS: We compared the HLA-B alleles in 213 patients with ALL and 85 patients with AML to those present in 731 umbilical cord blood (UCB) samples as a control group; this was done by means of the PCR-SSP technique.
RESULTS: We found an increased frequency of the HLA-B*40 allele in ALL patients as compared to the control group (14.5% versus 9.84%, P = 0.003, OR = 1.67); this was particularly evident in a subgroup of young (less than 18 years old) ALL patients (P = 0.002, OR = 1.76); likewise, a decreased frequency of HLA-B*40 allele in AML patients was observed as compared to the control group (4.70% versus 9.84%, P = 0.02, OR = 0.42).
CONCLUSIONS: These results might suggest opposing effects of the HLA-B*40 in the genetic susceptibility to develop ALL or AML and offer the possibility to study further the molecular mechanisms of cell differentiation within the bone marrow lineage.

Shuxian J, Xiaoyun C, Zhihui F, et al.
Association of HLA-B*51:01 with papillary thyroid carcinoma in the Chinese Han population of the Shandong coastal areas.
Thyroid. 2014; 24(5):867-71 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: A lot of work has been done to study the association between human leukocyte antigen (HLA) and papillary thyroid carcinoma (PTC) in various populations. But the results of the currently available studies are not consistent. The aim of this study was to evaluate the association of HLA-A, -B, -C, -DRB1, and -DQB1 with PTC in the Chinese Han population of the coastal areas of Shandong Province with respect to age and sex.
METHODS: A total of 154 patients diagnosed with PTC were analyzed for HLA-A, -B, -C, -DRB1, and -DQB1 alleles by using a polymerase chain reaction sequence-based typing (PCR-SBT) method. Two hundred unrelated healthy individuals were typed as controls.
RESULTS: Compared with the controls, the HLA-B*51:01 (8.8% vs. 4.5%, p=0.029, OR 2.039 [CI 1.101-3.775]) and HLA-C*07:06 (2.6% vs. 0.5%, p=0.024, OR 5.307 [CI 1.119-25.171]) allele frequencies were higher in the PTC patients, while the HLA-C*07:01 (1.3% vs. 6.0%, p=0.001, OR 0.206 [CI 0.071-0.601]) allele frequency was lower in the PTC patients that did not persist after Bonferroni correction for multiple tests. This showed no statistically significant correlation of the HLA-A, -DRB1, and -DQB1 alleles and PTC. The incidence of PTC was more frequent in females between 30 and 60 years old. There were no significant differences in the age and sex distributions between the total and the HLA-B*51:01 positive PTC patients.
CONCLUSIONS: The HLA associations in this Chinese Han population differ markedly from studies done in Europeans and Caucasians. The results reveal that HLA-B*51:01 is more likely to be a susceptible allele for PTC in addition to age and sex in the coastal areas of Shandong Province.

Hojjat-Farsangi M, Razavi SM, Sharifian RA, Shokri F
Frequency analysis of HLA class I alleles in Iranian patients with progressive and non-progressive chronic lymphocytic leukemia.
Hum Immunol. 2014; 75(2):170-5 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a malignant disorder of B cell origin, with low incidence in Asian populations. In this study we investigated the HLA-class I A and B allele frequencies in 87 Iranian CLL patients and 64 healthy controls using sequence specific primer-polymerase chain reaction (SSP-PCR) technique. Our results showed increased frequencies of HLA-A11:01 (p=0.02) and HLA-B35:01 (p=0.002) alleles and HLA-A11:01/B35:01 haplotype (p=0.036) and decreased frequencies of HLA-A01:01 (p=0.02), HLA-A26:01 (p=0.03), HLA-B65:01 (p=0.03) and HLA-B53:01 (p<0.00001) alleles in CLL patients compared to the control group. Classification of the patients into non-progressive and progressive groups did not reveal significant differences for the frequency of any of the HLA-A and -B alleles or haplotypes between these two subtypes. Comparison between patients with immunoglobulin heavy chain variable region genes (IGHV) mutated (n=56) and unmutated (n=31) subtypes showed a significant increase in HLA-A32:01 (p=0.05) and HLA-A33:01 (p=0.05) alleles in IGHV unmutated patients compared to IGHV mutated patients. Similarly, a higher frequency of HLA-B52:01 (p=0.037) alleles was observed in CD38(+) compared with CD38(-) patients. Our results obtained from an Iranian population indicate that CLL is associated with distinct HLA class I alleles and haplotypes some of which are linked to disease prognostic factors.

Turcotte S, Gros A, Tran E, et al.
Tumor-reactive CD8+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy.
Clin Cancer Res. 2014; 20(2):331-43 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
PURPOSE: To evaluate whether patients with metastatic gastrointestinal adenocarcinomas refractory to chemotherapy harbor tumor-reactive cytotoxic T cells.
EXPERIMENTAL DESIGN: Expansion of CD8(+) tumor-infiltrating lymphocytes (TIL) and cancer cell lines was attempted from gastrointestinal cancer metastases in 16 consecutive patients for the study of antitumor immune recognition. Retroviral transduction of genes encoding T-cell receptors (TCR) was used to define HLA-restriction elements and specific reactivity.
RESULTS: TIL were expanded from metastases in all patients, and new tumor cell lines were generated in 5 patients. Autologous tumor recognition without cross-reactivity against allogeneic HLA-matched gastrointestinal tumors was found in CD8(+) TIL from 3 of these 5 patients. In a patient with gastric cancer liver metastases, the repertoire of CD8(+) TIL was dominated by cytolytic sister clones reactive to 2 out of 4 autologous cancer cell lines restricted by HLA-C*0701. From the same patient, a rare CD8(+) TIL clone with a distinct TCR recognized all four cancer cell lines restricted by HLA-B*4901. In a patient with bile duct cancer, two distinct antitumor cytolytic clones were isolated from a highly polyclonal CD8(+) TIL repertoire. TCRs isolated from these clones recognized epitopes restricted by HLA-A*0201. In a third patient, CD8(+) TIL reactivity was progressively lost against an autologous colon cancer cell line that displayed loss of HLA haplotype.
CONCLUSIONS: This study provides a basis for the development of immunotherapy for patients with advanced gastrointestinal malignancies by first establishing the presence of naturally occurring tumor-reactive CD8(+) TIL at the molecular level.

Miyazono T, Shiina T, Michino J, et al.
A novel HLA-B allele, HLA-B*39:01:16, identified by super high-resolution single-molecule sequence-based typing in a Japanese individual.
Tissue Antigens. 2013; 82(3):205-6 [PubMed] Related Publications
HLA-B*39:01:16 differs from B*39:01:03 by one nucleotide 348 (codon 116) T to C.

Tremante E, Ginebri A, Lo Monaco E, et al.
A melanoma immune response signature including Human Leukocyte Antigen-E.
Pigment Cell Melanoma Res. 2014; 27(1):103-12 [PubMed] Related Publications
Paired cultures of early-passage melanoma cells and melanocytes were established from metastatic lesions and the uninvolved skin of five patients. In this stringent autologous setting, cDNA profiling was used to analyze a subset of 1477 genes selected by the Gene Ontology term 'immune response'. Human Leukocyte Antigen E (HLA-E) was ranked 19th among melanoma-overexpressed genes and was embedded in a transformation signature including its preferred peptide ligand donors HLA-A, HLA-B, HLA-C, and HLA-G. Mostly undetectable in normal skin and 39 nevi (including rare and atypical lesions), HLA-E was detected by immunohistochemistry in 17/30 (57%) and 32/48 (67%) primary and metastatic lesions, respectively. Accordingly, surface HLA-E was higher on melanoma cells than on melanocytes and protected the former (6/6 cell lines) from lysis by natural killer (NK) cells, functionally counteracting co-expressed triggering ligands. Although lacking HLA-E, melanocytes (4/4 cultures) were nevertheless (and surprisingly) fully protected from NK cell lysis.

Alcoceba M, Sebastián E, Marín L, et al.
HLA specificities are related to development and prognosis of diffuse large B-cell lymphoma.
Blood. 2013; 122(8):1448-54 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n = 64, 26%) or with (n = 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P = .0008, Pc = .0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P < .0005, Pc = .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P = .019) and 5-year overall (71% vs 92%, P = .001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.

Jobim MR, Jobim M, Salim PH, et al.
Analysis of KIR gene frequencies and HLA class I genotypes in breast cancer and control group.
Hum Immunol. 2013; 74(9):1130-3 [PubMed] Related Publications
Breast cancer is the main cause of cancer-related death among women, with a 0.5% increase in incidence per year. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA alleles in patients with breast cancer and healthy controls. Two hundred thirty patients with breast cancer and 272 healthy controls were typed for HLA class I and KIR genes by PCR-SSO. When both groups were compared, the presence of inhibitory KIR2DL2 receptors was significantly higher in breast cancer patients than in healthy controls. No significant differences were found for HLA-C2 and HLA-Bw4. However, a higher frequency of HLA-C1 in breast cancer patients was observed. These findings suggest a potential role for the KIR gene system in breast cancer. Further studies to confirm this observation are warranted.

Santana-Codina N, Carretero R, Sanz-Pamplona R, et al.
A transcriptome-proteome integrated network identifies endoplasmic reticulum thiol oxidoreductase (ERp57) as a hub that mediates bone metastasis.
Mol Cell Proteomics. 2013; 12(8):2111-25 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Bone metastasis is the most common distant relapse in breast cancer. The identification of key proteins involved in the osteotropic phenotype would represent a major step toward the development of new prognostic markers and therapeutic improvements. The aim of this study was to characterize functional phenotypes that favor bone metastasis in human breast cancer. We used the human breast cancer cell line MDA-MB-231 and its osteotropic BO2 subclone to identify crucial proteins in bone metastatic growth. We identified 31 proteins, 15 underexpressed and 16 overexpressed, in BO2 cells compared with parental cells. We employed a network-modeling approach in which these 31 candidate proteins were prioritized with respect to their potential in metastasis formation, based on the topology of the protein-protein interaction network and differential expression. The protein-protein interaction network provided a framework to study the functional relationships between biological molecules by attributing functions to genes whose functions had not been characterized. The combination of expression profiles and protein interactions revealed an endoplasmic reticulum-thiol oxidoreductase, ERp57, functioning as a hub that retained four down-regulated nodes involved in antigen presentation associated with the human major histocompatibility complex class I molecules, including HLA-A, HLA-B, HLA-E, and HLA-F. Further analysis of the interaction network revealed an inverse correlation between ERp57 and vimentin, which influences cytoskeleton reorganization. Moreover, knockdown of ERp57 in BO2 cells confirmed its bone organ-specific prometastatic role. Altogether, ERp57 appears as a multifunctional chaperone that can regulate diverse biological processes to maintain the homeostasis of breast cancer cells and promote the development of bone metastasis.

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