567

B2M

beta-2-microglobulin;B2M;beta-2-microglobulin

beta chain of MHC class I molecules|beta-2-microglobin

15q21.1

protein-coding

Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI-H) phenotype. MSI-H cancers may develop either sporadically or in the context of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI-H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI-H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the beta2-microglobulin (beta2m) gene. To examine the implications of beta2m mutations during MSI-H colorectal tumor development, we analyzed the prevalence of beta2m mutations in MSI-H colorectal adenomas (n=38) and carcinomas (n=104) of different stages. mutations were observed in 6/38 (15.8%) MSI-H adenomas and 29/104 (27.9%) MSI-H CRCs. A higher frequency of beta2m mutations was observed in MSI-H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of beta2m mutations in HNPCC-associated MSI-H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI-H cancers. beta2m mutations were positively related to stage in tumors without distant metastases (UICC I-III), suggesting that loss of beta2m expression may promote local progression of colorectal MSI-H tumors. However, no beta2m mutations were observed in metastasized CRCs (UICC stage IV, p=0.04). These results suggest that functional beta2m may be necessary for distant metastasis formation in CRC patients.

Colorectal cancer (CRC) is the fourth most common non-cutaneous malignancy in the United States and the second most frequent cause of cancer-related death. One of the most important determinants of CRC survival is lymph node metastasis. To determine whether molecular markers might be prognostic for lymph node metastases, we measured by quantitative real-time RT-PCR the expression levels of 15 cancer-associated genes in formalin-fixed paraffin-embedded primary tissues derived from stage I-IV CRC patients with (n=20) and without (n=18) nodal metastases. Using the mean of the 15 genes as an internal reference control, we observed that low expression of beta(2)microglobulin (B2M) was a strong prognostic indicator of lymph node metastases (area under the curve (AUC)=0.85; 95% confidence interval (CI)=0.69-0.94). We also observed that the expression ratio of B2M/Spint2 had the highest prognostic accuracy (AUC=0.87; 95% CI=0.71-0.96) of all potential two-gene combinations. expression values of Spint2 correlated with the mean of the entire gene set at an R(2) value of 0.97, providing evidence that Spint2 serves not as an independent prognostic gene, but rather as a reliable reference control gene. These studies are the first to demonstrate a prognostic role of B2M at the mRNA level and suggest that low B2M expression levels might be useful for identifying patients with lymph node metastasis and/or poor survival.

BACKGROUND: beta-2-microglobulin (B2M) is essential for antigen presentation, yet may also possess proto-oncogenic properties. AIM: To determine the prognostic impact of B2M in patients with mismatch repair (MMR) proficient and deficient colorectal cancer (CRC) and to investigate whether this effect on outcome is dependent on the local immune response. METHODS: B2M protein expression and tumour-infiltrating immune cells (CD3, CD16, CD163, CD20, CD4, CD45RO, CD56, CD68, CD8, FoxP3, GranzymeB, iNOS, mast cell tryptase, MUM1, PD1, TIA-1) were evaluated in a well characterised tissue microarray of 408 CRCs. The predictive value for clinicopathological features and the prognostic significance of B2M expression were analysed, stratified by MMR status and the immunohistological characteristics of immune cell infiltrates. RESULTS: Interobserver agreement for B2M staining was high (intra-class correlation coefficient=0.91). Complete B2M loss was more frequent in MMR-deficient (19.4%) compared to MMR-proficient (7.1%) tumours (p<0.001). In MMR-deficient cases, B2M loss predicted rare local recurrence (p=0.034), infrequent nodal-positivity (p=0.035), absence of distant metastasis (p=0.048; sensitivity=100%) and a trend towards favourable survival (p=0.124) independent of immune infiltrates. No associations between B2M and clinicopathological features were observed in MMR-proficient cases. CONCLUSIONS: Our data show for the first time that absence of B2M protein expression identifies MMR-deficient cancers with a favourable clinical course and absence of metastatic disease. Validation of B2M protein expression for sub-classification of MMR-deficient CRC is recommended for future clinical trials.

AIM: To study the relation between the level of tissue polypeptide specific antigen (TPS), neuron-specific enolase (NSE), carcinoembryonic antigen (CEA) and beta(2)-microglobulin (beta(2)-mG) in serum and the biological behavior of lung cancer for the more scientific diagnosis of lung cancer. METHODS: To detect the level of TPS, NSE, CEA and beta(2)-mG in the serum of 94 patients with small cell lung cancer (SCLC), 86 patients with benign pulmonary diseases (BPD) and 89 patients in normal control group, the level of serum were examined by ELISA and immunoradiometric assay. RESULTS: The level of TPS and NSE in the serum of SCLC group [(437.8+/-516.6) U/L, (76.8+/-91.4) microg/L] were much higher than those in BPD group [(143.6+/-78.7) U/L, (13.3+/-10.8) microg/L] and normal group [(98.4+/-58.9) U/L, (10.1+/-5.7) microg/L, P<0.01)], and the level of CEA and beta(2)-mG in the serum of SCLC group were also obviously higher than those in normal group and BPD group (P<0.01). The sensitivity, specificity and accuracy of SCLC'S diagnosis by an indicator of TPS and NSE were 84.4%, 87.8%, 83.6% and 79.3%, 93.7%, 88.3%, respectively, and were much higher than CEA and beta(2)-Mg. In addition, the level of TPS and NSE in the patients' serum with metastatic SCLC were markedly higher than those in the patients with SCLC without metastasis, increased with the number of metastatic focuses. In clinical practice, the possibility of smokers suffering from lung cancer disease is 8 to 10 times higher than that of no-smokers, and 10 to 24 times higher of the people who smoked 30 to 40 cigarettes per day. From this comparison, the amount of smoking was closely related to the occurrence of lung cancer. CONCLUSION: TPS, NSE, CEA and beta(2)-mG in serum are useful for early diagnosis of lung cancer. There is complementarity in the combined detection of the level of TPS, NSE, CEA and beta(2)-MG. Their levels have close correlation with lung cancer, histological grades and lymphoid nodule metastasis.

beta2-Microglobulin (beta2M), a component of MHC class I molecules, is believed to be associated with tumour status in various cancers. In this study, we examined the expression of beta2M at different malignant stages of oral cavity squamous cell carcinoma (OCSCC). To determine the possible correlation between beta2M expression and various clinical characteristics, 256 samples from patients with OCSCC were evaluated by immunohistochemical staining. Strong beta2M expression was significantly correlated with a relatively advanced tumour stage (P<0.001), positive nodal status (P<0.001), and TNM stage (P<0.001). The cumulative 5-year survival rate was significantly correlated with a relatively advanced tumour stage (P<0.001), positive nodal status (P<0.001), TNM stage (P<0.001), and strong expression of beta2M (P<0.001). Thus, elevated beta2M expression is an indicator of poor survival (P<0.001). In addition, we extended our analysis of beta2M expression to the FaDu and SCC25 oral cancer cell lines. beta2-Microglobulin expression was positively correlated with cell migration and invasion in beta2M-overexpressing transfectants in Transwell chambers. The suppression of beta2M expression using small interfering RNA (siRNA) was sufficient to decrease cell migration and invasion in vitro. Taken together, our results suggest that beta2M expression in the tissues is associated with survival and may be involved in tumour progression and metastasis in OCSCC.

The aim of the present study was to investigate beta2-microglobulin (beta2-M) expression in normal oral mucosa and progressive oral squamous cell carcinoma (OSCC) and to assess the clinical significance of beta2-microglobulin expression. The study included 10 cases of normal oral mucosa epithelium specimens, 55 cases of primary OSCC specimens, and 25 cases of OSCC metastasis specimens. Immunohistochemistry was used to determine beta2-M expression, and its correlation with clinicopathological factors in progressive OSCC was evaluated. Immunohistochemistry showed that strong beta2-M expression was significantly asscociated with tumor size (T3, T4 vs. T1, T2; P=0.001), positive node status (N positive vs. N negative; P=0.000) and advanced clinical stage (, vs. , , P=0.000) in primary OSCC lesions. Compared to primary OSCC lesions, the frequency of beta2-M expression was significantly increased in metastatic OSCC lesions (P=0.02). In addition, in vitro results from Western blotting showed increased beta2-M expression in the two OSCC lines studied. Therefore, we speculate that the up-regulation of beta2-M expression may contribute to the oncogenesis of human oral mucosa, tumor invasion and metastasis.

CA 15-3, CA 125 and beta-2 microglobulin are three common tumor markers currently used for diagnosis, prognosis, assessment of therapeutic response, and/or to evaluate recurrence in breast and ovarian cancer and malignant lymphoproliferative disorders, respectively. In the present prospective study we assessed the role of these three serum proteins as biomarkers for renal cell carcinoma (RCC), as well as any association between tumor marker levels and clinical-pathological parameters. CA 15-3, CA 125, and beta-2 microglobulin were preoperatively measured in 332 patients who underwent nephrectomy for RCC. Estimates of cancer-specific survival (CSS) was calculated according to the Kaplan-Meier method. Multivariate analysis was performed to identify the most significant variables for predicting CSS. Preoperatively, 35.2% (n = 117), 9.6% (n = 32) and 30.4% (n = 101) of the patients had abnormal levels of CA 15-3, CA 125 and beta-2 microglobulin, respectively. Statistically significant differences resulted between CA 15-3, CA 125 and beta-2 microglobulin values and tumor size, Fuhrman grade, presence of lymph node, and visceral metastases. CSS was significantly decreased for patients with high levels of CA 15-3, CA 125, and beta-2 microglobulin (P < 0.0001, P < 0.0001, and P = 0.001, resp.). At multivariate analysis only age, the presence of visceral metastases, and high levels of CA 15-3 were independent adverse prognostic factors for CSS.