Increased expression of α-methylacyl-coenzyme A racemase (AMACR; p504s) and p16 in distal hyperplastic polyps.

BACKGROUND: Hyperplastic polyps (HP) and sessile serrated adenomas (SSA) share morphological similarities. In this immunohistochemical study we chose a panel of potential relevant and promising biomarkers including α-methylacyl-coenzyme A racemase (AMACR; p504s), which is involved in the degradation of branched chained fatty acids derivates, and analysed a cohort of HPs and SSAs in order to identify different immunophenotypes in relation to lesion localisation. METHODS: 154 specimen were carefully selected and a micro tissue array (TMA) was constructed. Immunohistochemistry of p16Ink4a, Ki67, α-methylacyl-coenzyme A racemase (AMACR; p504s), BRAF, CK 20, MLH1 and ß-catenin was performed and and immunoexpression was compared among proximal and distal HPs as well as SSAs. RESULTS: None of the markers revealed a differential expression among HPs and SSAs. However, the study demonstrates a significant overexpression of AMACR (p = 0.004) and p16Ink4a (p = 0.028) in distal HPs compared to proximal HPs. In addition AMACR overexpression was associated with increased p16Ink4a immunoexpression (p < 0.001). CONCLUSIONS: In this study we describe differential AMACR and p16Ink4a in HPs in relation to their localisation. Distal HPs were characterized by AMACR and p16Ink4a overexpression in contrast to proximal HPs, although morphological identically. Thus AMACR overexpression points towards a pathobiological relevance of the protein in distal HPs. In context of recently published data this suggest distal HPs as potential precursor lesions of certain adenoma subtypes. However, at this point of time this finding remains speculative and needs to be confirmed by further studies. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1836116001066768.

AKR1B10 expression is associated with less aggressive hepatocellular carcinoma: a clinicopathological study of 168 cases.

BACKGROUND/AIMS: The detoxification enzyme AKR1B10, a member of the aldo-keto reductase superfamily, is discussed as a new biomarker candidate for hepatocellular carcinoma (HCC). Only rare clinicopathological data on AKRB1B10 in HCC exist. This retrospective study determines the diagnostic and prognostic relevance of AKR1B10 expression in HCC and its relationship to a series of clinicopathological parameters including underlying aetiological factors. METHODS: A series of 168 patients with HCCs treated either by surgical resection (n=92) or liver transplantation (n=76) were investigated after construction of a tissue micro-array. Immunohistochemically confirmed AKR1B10 expression was correlated with clinicopathologically relevant parameters as well as proliferative activity (indicated by Ki-67 immunostaining) and apoptosis (terminal deoxyribonucleotide transferase-mediated dUTP nick-end labelling). RESULTS: AKR1B10 overexpression is significantly associated with lower pT-classification (P=0.030) and highly statistically associated with an underlying viral hepatitis (P<0.001) and the presence of cirrhosis (P<0.001). In addition, loss of AKR1B10 expression correlates with increased proliferative activity (Ki-67, P=0.001). Kaplan-Meier survival analysis of the resection group reveals a poorer prognosis in patients with AKR1B10-negative HCCs compared with patients with strongly positive HCCs (P=0.046). CONCLUSIONS: This study confirms and expands data on the expression of AKR1B10 in HCC, suggesting that this enzyme is a valuable novel biomarker candidate for staging of HCC, especially in patients with underlying virus hepatitis or cirrhosis, and may present a new therapeutic target for multimodal therapy concepts. We confirm its prognostic value and conclude that high expression of AKR1B10 reflects a less aggressive tumour behaviour.

Regulatory BCL2 promoter polymorphism (-938C>A) is associated with adverse outcome in patients with prostate carcinoma.

Molecular markers predictive of prostate cancer prognosis are urgently needed. Overexpression of the antiapoptotic protein, Bcl-2, has repeatedly been shown to be associated with adverse outcome in this malignancy. We hypothesized that a regulatory BCL2 -938C>A promoter polymorphism, which significantly affects promoter activity and Bcl-2 expression in different malignancies, may influence survival. Reporter assays and electrophoretic mobility shift assays reveled that the -938C>A BCL2 promoter polymorphism significantly affects promoter activity and transcription factor binding in prostate cancer cells. Significantly higher BCL2 mRNA expression was observed in primary prostate carcinomas derived from patients with the AA, compared to CC, genotype. Survival analysis showed that the -938AA genotype was an independent, unfavorable prognostic factor for relapse-free survival in a primary cohort of 142 patients and in an independent replication cohort of 148 patients, with hazard ratios (HR) of 4.4 (95% CI, 1.3-15.1; p = 0.018) and 4.6 (95% CI, 1.5-14.2; p = 0.009). Furthermore, the -938AA genotype was independently associated with worse overall survival in the replication series, with a HR of 10.9 (95% CI, 1.2-99.3; p = 0.034). We conclude that the BCL2 -938C>A polymorphism is an independent predictor of relapse-free and overall survival in patients with prostate cancer. The BCL2 -938C>A polymorphism should be evaluated prospectively and may also have promise in assisting optimal patient choice for treatment with BCL2-targeted drugs already in evaluation for prostate cancer treatment.

Changes in staging for hepatocellular carcinoma after radiofrequency ablation prior to liver transplantation as found in the explanted liver.

BACKGROUND/AIMS: To analyze the efficacy of radiofrequency ablation (RFA) prior to liver transplantation (LT) in liver explants. METHODOLOGY: We reviewed pathological findings in the explanted livers of 13 patients with histologically proven HCC and liver cirrhosis who underwent RFA as bridging treatment prior to LT. Eight patients had solitary nodules with a median diameter of 4cm, whereas five patients had two tumors each with a median total diameter of 3.3cm prior to RFA. One session of RFA was performed by all patients. RESULTS: Tumor regression was proved in 3/13 patients whereas steady disease was observed in 5/13 patients (38%). Tumor regression was observed only in one of the five patients having two tumors prior to RFA. Pathology proved a multifocal tumor in four patients, including one patient with a radiological presumed solitary tumor. Tumor progression was observed in 5/13 patients (38%). CONCLUSIONS: Although the majority of our patients (8/13, 62%) had a solitary tumor at the beginning of treatment, tumor progression was observed in a large proportion (38%) among them. The underestimation of tumor lesions in radiology and partial necrosis of the tumor achieved in most patients limit the role of RFA as bridging treatment prior to LT.

Association of the GNAS1 T393C polymorphism with tumor stage and survival in gastric cancer.

AIM: To analyze the impact of the GNAS1 T393C polymorphism on prognosis and histopathology of gastric cancer. METHODS: Genomic DNA was extracted from paraffin-embedded tissues of 122 patients with primary gastric carcinoma and from the blood of 820 healthy white individuals. Allelic discrimination was performed by quantitative real-time polymerase chain reaction. Genotyping was correlated with histopathologic parameters and with overall survival according to the Kaplan-Meier approach and with multivariate analysis by multiple stepwise regression. RESULTS: Thirty-nine (32%) patients displayed a CC genotype, 57 (46.7%) a CT genotype and 26 (21.3%) a TT genotype. The frequency of the C allele (fC) in the patient group was 0.55, which was not significantly different from that of healthy blood donors. The distribution was compatible with the Hardy-Weinberg equilibrium. Analysis of clinicopathological parameters did not show any significant correlation of the T393C genotype with gender (P = 0.50), differentiation (P = 0.29), pT-category (P = 0.19), pN-category (P = 0.30), pM-category (P = 0.25), R-category (P = 0.95), the classifications according to WHO (P = 0.34), Laurén (P = 0.16), Goseki (P = 1.00) and Ming (P = 0.74). Dichotomization between C+ (CC+CT) and C-genotypes (TT), however, revealed significantly more advanced tumor stages (P = 0.023) and lower survival rates (P = 0.043) for C allele carriers. CONCLUSION: The present study provides strong evidence to suggest that the GNAS1 T393C allele carrier status influences tumor progression and survival in gastric cancer with higher tumor stages and a worse outcome for C allele carriers.

Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib.

Targeting the ubiquitin-proteasome pathway with the proteasome inhibitor bortezomib has emerged as a promising approach for the treatment of several malignancies. The cellular and molecular effects of this agent on colorectal cancer cells are poorly characterized. This study investigated the antiproliferative effect of bortezomib on colorectal cancer cell lines (Caco-2 and HRT-18). In order to define the proteins potentially involved in the mechanisms of action, proteome profiling was applied to detect the proteins altered by bortezomib. The in vitro efficacy of bortezomib as a single agent in colorectal cancer cell lines was confirmed. Proteome profiling with two-dimensional PAGE followed by mass spectrometry revealed the up-regulation of the major inducible isoform of heat shock protein 70 (hsp72) and lactate dehydrogenase B in both cell lines, as well as the induction of aldo-keto reductase family 1 member B10 (AKR1B10) in HRT-18 cells. Both AKR1B10 and hsp72 exert cell-protective functions. This study shows for the first time a bortezomib-induced up-regulation of AKR1B10. Small interfering RNA-mediated inhibition of this enzyme with known intracellular detoxification function sensitized HRT-18 cells to therapy with the proteasome inhibitor. To further characterize the relevance of AKR1B10 for colorectal tumors, immunohistochemical expression was shown in 23.2% of 125 tumor specimens. These findings indicate that AKR1B10 might be a target for combination therapy with bortezomib.

Association of GNB4 intron-1 haplotypes with survival in patients with UICC stage III and IV colorectal carcinoma.

BACKGROUND: Polymorphisms in genes encoding subunits of heterotrimeric G proteins have been repeatedly associated with the course of cancer. As previously shown, intron 1 of GNB4 harbours distinct haplotype blocks and block 1 is associated with survival and disease progression in urothelial bladder cancer. This study investigated whether haplotype block 2 is associated with survival in colorectal cancer patients. PATIENTS AND METHODS: The haplotype tagging polymorphism of GNB4 haplotype block 2 was genotyped in 136 colorectal cancer patients and associated with demographic and clinical data and survival. RESULTS: Haplotype block 2 is associated with survival in colorectal cancer patients. Patients with advanced tumour stages carrying the 2*1 haplotype revealed decreased survival (HR 2.04, 95% CI 0.91-3.69). In multivariate analysis, the diplotypes were independent prognostic factors. CONCLUSION: Intron-1 haplotypes of GNB4 might be predictive markers for survival of patients with advanced colorectal cancer, thus influencing the clinical management of these patients.

Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a rare primary liver malignancy. Until now, outcomes and prognostic factors after liver resection for these tumors have not been well-documented. STUDY DESIGN: Between April 1998 and December 2006, a total of 158 patients underwent surgical exploration in our institution for intended liver resection of ICC. Prospectively collected data of patients undergoing liver resection (n = 83) were analyzed with regard to preoperative findings, operative details, perioperative morbidity and mortality, pathologic findings, outcomes measured by tumor recurrence and survival, and prognostic factors for outcomes. RESULTS: Tumors were solitary in 47 patients. R0 resections were achieved in 53 patients. Vascular infiltration and lymph node metastasis were detected in 41% and 34%, respectively. After resection, the calculated 1-, 3-, and 5-year-survival rates were 71%, 38%, and 21%, respectively, with corresponding rates of 83%, 50%, and 30% in R0 resections. For 14 variables evaluated, only gender (p = 0.008), Union Internationale Contre le Cancer stage (p = 0.014), and R classification (p = 0.001) showed predictive value in the multivariate Cox proportional hazard regression. CONCLUSIONS: Results presented outline that an R0 resection leads to substantially prolonged survival in ICC and represents the considerable input of the surgeon to the outcomes of these patients. Union Internationale Contre le Cancer stage remains an important factor.

Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin-resected hepatocellular carcinoma.

BACKGROUND/AIMS: The mammalian target of rapamycin (mTOR) inhibitors play a key role in regulating signal transduction by blocking the mTOR pathway and combining anticancer and immunosuppressive properties. This study was undertaken to determine the prevalence and clinicopathological relevance of phospho-p70S6 (p-p70S6) kinase in hepatocellular carcinoma (HCC) and to investigate the effects of rapamycin on HCC in vitro. METHODS: A total of 196 patients with HCCs were treated either with surgical resection (n=106) or liver transplantation (n=90). Tumour tissue was investigated for p-p70S6, phospho-AKT, Ki-67, Cyclin-D1 and apoptosis, and staining results were correlated with clinicopathologically relevant parameters. RESULTS: Overall, p-p70S6 was detected in 24.5% (48/196) of HCCs. In the resection group, 26.4% (28/106) of HCC were positive and 22.2% (20/90) in the transplant group. p-p70S6 was significantly associated with elevated Cyclin-D1 immunoexpression and was correlated with decreased overall survival (P=0.011) in patients resected with a clear margin. In multivariate COX regression analysis, p-p70S6 was identified as an independent prognostic parameter in patients resected with a clear margin. Rapamycin induced apoptosis and growth inhibition by G0/G1 cell cycle arrest in vitro. However, in HCC patients p-p70S6 kinase was not associated with proliferation or apoptosis. CONCLUSIONS: Activation of p70S6 kinase indicates aggressive tumour behaviour in patients with clear margin-resected HCC. Identification of p-p70S6 kinase in HCC selects high-risk patients who may benefit from drugs targeting the mTOR pathway.

Survivin is upregulated during liver regeneration in rats and humans and is associated with hepatocyte proliferation.

BACKGROUND: Survivin regulates cell division and inhibits apoptosis. Liver regeneration is a complex process involving both proliferation and apoptosis. The role of survivin is not well elucidated and no data exist in humans. METHODS: Seventy per cent liver resection was used to investigate liver regeneration in rats. Survivin was identified by means of reverse transcriptase polymerase chain reaction, Western blotting and immunohistochemistry. Proliferation and apoptosis were quantified. Liver biopsies from 33 patients who underwent living donor liver transplantation were used to study survivin immuno-expression, proliferation and apoptosis within the first 17 days after transplantation. Seven healthy donors served as controls. RESULTS: Survivin transcript and protein were significantly upregulated in rat hepatocytes after 24-72 h during regeneration and showed a significant correlation with proliferation but not with apoptosis. In humans, survivin was nearly absent in donor and reperfused liver tissue but increased significantly 5-7 days after transplantation and correlated with proliferation but not with apoptosis. CONCLUSIONS: Survivin is upregulated in human and rodent liver regeneration and correlates with proliferation, suggesting an association of survivin and cell division.

Liver transplantation for hepatocellular carcinoma and cirrhosis in candidates with undetectable or very low alpha-fetoprotein levels: is an expansion of the listing criteria justified?

BACKGROUND: Liver transplantation (LT) is the optimal therapy for hepatocellular carcinoma (HCC) in the setting of cirrhosis. The purpose of this study was to evaluate the results after LT for HCC patients with very low alpha fetoprotein (AFP) values both in our series and in literature reports. METHODOLOGY: Data obtained prospectively on 51 transplanted patients with HCC having AFP values < 30 ng/mL preoperatively were analyzed. RESULTS: Four-year overall and recurrence-free survival was 81% and 79%, respectively (median follow up of 35 months). Twenty nine patients (57%) were within the Milan criteria. Thirteen patients (25%) demonstrated advanced tumor stages. Ablative bridging treatments were attempted in 27 instances, and were associated with significantly worse overall and recurrence-free survivals (p=0.0209 and p=0.0111, respectively). Patients with AFP values < 30 ng/mL and no bridging treatments experienced 4-year overall and recurrence-free survivals of 96% and 95%, respectively. CONCLUSIONS: HCC patients with AFP values < 30 ng/mL who undergo LT with no bridging treatments experience excellent overall and recurrence-free survival rates, even with advanced tumor stages, independent of the Milan listing criteria.

Pulmonary nodules at risk in patients undergoing liver transplantation for hepatocellular carcinoma.

The aim of this study was to evaluate the accuracy of pretransplant imaging in patients with hepatocellular carcinoma (HCC) considering small pulmonary nodules, and to determine whether preoperatively diagnosed small pulmonary nodules should be considered 'nodules at risk'. We evaluated 10 consecutive liver transplant patients with a diagnosis of HCC and pulmonary nodules detected by preoperative computerized tomography (CT) scanning. Pretransplant CT evaluation of pulmonary nodules showed a 90% accuracy rate. There was only one incorrect reading in the case of a patient, where a metastasis was misdiagnosed as a pulmonary fibroma. Two patients died from multifocal tumor recurrence with pulmonary metastases 17 and 19 months post-transplant. One more patient died 29 months post-transplantation on account of diffuse metastatic prostate carcinoma. Seven patients are currently alive with no evidence of tumor after a median follow-up period of 48 months post-transplantation. Small pulmonary nodules in high-risk HCC patients (low tumor grading, exceeding Milan criteria) may be characterized as nodules at risk, and evaluated very closely prior to listing and during the pre- and post-transplant periods.

Overall and relapse-free survival in oropharyngeal and hypopharyngeal squamous cell carcinoma are associated with genotypes of T393C polymorphism of the GNAS1 gene.

PURPOSE: In previous studies, we have shown that the T allele of a specific single-nucleotide polymorphism (SNP) in the Galphas gene (T393C) correlates with increased Galphas expression and hence apoptosis. The T allele was associated with a favorable outcome in a variety of human cancers, e.g., carcinoma of the urinary bladder, kidney, and colorectum. EXPERIMENTAL DESIGN: The prognostic value of the T393C SNP was evaluated in an unselected series of patients treated with curative intent for oropharyngeal and hypopharyngeal squamous cell carcinomas, including all tumor stages with different therapeutic regimens. Genotype analysis was done using DNA from paraffin-embedded tissue samples from 202 patients (162 men, 40 women) with a median follow-up of 38 months (1-133 months). The various genotypes were correlated with relapse-free and overall survival. RESULTS: GNAS1 393C homozygous patients displayed a higher risk for disease progression than T393 homozygous patients (hazard ratio CC versus TT, 1.9; 95% confidence interval, 1.1-3.2; P = 0.019). The same genotype effect was observed for overall survival with CC genotypes at higher risk for death compared with TT genotypes (hazard ratio, 1.7; 95% confidence interval, 1.1-2.9; P = 0.015). Multivariate analysis showed that, besides American Joint Committee on Cancer stage, tumor localization, and gender, the T393C polymorphism was an independent prognostic factor for disease progression and death. CONCLUSION: The T393C SNP could be considered as a genetic marker to predict the clinical course of patients suffering from oropharyngeal and hypopharyngeal cancer.

Liver transplantation in the setting of hepatocellular carcinoma and portal vein thrombosis: a challenging dilemma?

BACKGROUND: Portal vein thrombosis (PVT) represents a potentially unfavorable prognostic factor in liver transplantation (LT) for hepatocellular carcinoma (HCC). However, it is frequently difficult to establish preoperatively whether the thrombus is associated with tumor invasion or with stagnant flow. The purpose of this study was to further address this controversial issue. PATIENTS AND METHODS: We evaluated 12 consecutive patients who underwent liver transplantation for HCC in the setting of PVT. RESULTS: The origin of PVT in HCC patients could be accurately evaluated in 58% of the patients. Forty-two percent of patients had no evident portal vein invasion and only 17% of cases had tumor thrombi. One-third of patients experienced tumor recurrence within the first posttransplant year, and one-third of patients became long-term survivors (median survival of 36 months) with no evidence of tumor recurrence. One-year survival was 92%. Nine patients are currently alive after a median follow-up period of 25 months. CONCLUSIONS: PVT in the setting of HCC is characterized by poor patient outcome. However, a respectable number of instances are not accurately evaluated preoperatively, making the decision to exclude these patients from LT sometimes a challenging dilemma.

GNAS1 T393C polymorphism is associated with clinical course in patients with intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: The GNAS1 locus encodes the Galphas protein, which stimulates the formation of cyclo-adenosinemonophosphate (cAMP). The cAMP pathway mediates pleiotropic effects, including the regulation of apoptosis and proliferation. We have recently shown that TT genotypes of the single-nucleotide polymorphism T393C in the gene GNAS1 predict the clinical outcome of patients with various carcinomas. METHODS: Eighty-seven patients with intrahepatic cholangiocarcinoma (ICC) were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome. RESULTS: ICCs of patients with homozygous TT genotypes revealed a higher proliferation rate and a lower apoptotic rate. Homozygous TT patients were at highest risk for cancer-related deaths (hazard ratio = 2.74; 95% confidence interval = 1.03-7.28) compared with C-allele carriers. Kaplan-Meier curves for disease-specific overall and local recurrence-free survival in a subgroup with R(0)-resected ICC showed a significant association of T393 homozygosity with outcome, which was confirmed in multivariate Cox regression analysis. CONCLUSIONS: GNAS1 T393C is a novel independent host factor for disease progression in patients with ICC. Our finding that TT homozygosity (and not CC homozygosity) was associated with unfavorable clinical outcome points to the complex and differing functional effects induced by GNAS1 T393C polymorphism in various human carcinomas.

The T393C polymorphism in the gene GNAS1 of G protein is associated with survival of patients with invasive breast carcinoma.

The GNAS1 locus encodes the G(alpha)s protein which stimulates the formation of cyclic AMP (cAMP). Subsequently the cAMP pathway mediates various pleiotropic effects including regulation of apoptosis and proliferation. We have recently shown that genotypes of the single nucleotide polymorphism (SNP) T393C in the gene GNAS1 are associated with survival of patients suffering from bladder, renal cell and colorectal carcinoma. In the present study, the genotypes of the T393C SNP were determined in 279 patients with invasive breast carcinoma. Comparing the genotypes with the overall survival as well as important clinico-pathological parameters showed that carriers of the T allele had a significantly less favourable course of the disease when compared to carriers of the homozygous CC genotype. In multivariate analysis the homozygous TT genotype was independently associated with a decreased overall survival. Our results suggest that the GNAS1 T393C SNP is a novel genetic host factor for disease progression in patients with invasive breast carcinoma.

No association of the NFKB1 insertion/deletion promoter polymorphism with survival in colorectal and renal cell carcinoma as well as disease progression in B-cell chronic lymphocytic leukemia.

PURPOSE: Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor that plays a major role in the regulation of genes involved in immune and inflammatory response. Activation of NF-kappaB has also been associated with apoptosis and proliferation, thereby potentially also controlling oncogenesis. A functional insertion/deletion polymorphism has been identified in the promoter region of NFKB1, which apparently controls the transcription of NF-kappaB. The purpose of this study was, therefore, to investigate associations of the -94ins/delATTG polymorphism with susceptibility and survival of patients with different types of cancer. EXPERIMENTAL DESIGN: Genotype distributions in patients with colorectal carcinoma (n=139), B-cell chronic lymphocytic leukemia (n=72) and clear cell renal cell carcinoma (n=140), and in controls (n=307) were analyzed by pyrosequencing and compared with each other as well as associated with clinico-pathological parameters and demographic data. RESULTS: No statistically significant differences in both allele and genotype frequencies were observed between patients and healthy controls. Likewise, no association between -94ins/delATTG alleles and survival or disease progression was noticed. CONCLUSION: These results suggest that the NFKB1 promoter polymorphism has no effect on risk and course of disease in the three cancer entities that were analyzed.

Increased frequencies of CD8+ T lymphocytes recognizing wild-type p53-derived epitopes in peripheral blood correlate with presence of epitope loss tumor variants in patients with hepatocellular carcinoma.

Wild-type (WT) sequence p53 peptides are attractive candidates for broadly applicable cancer vaccines. The aim of this study was to evaluate the potential of a WT p53-based immunotherapeutic approach for patients with hepatocellular carcinoma (HCC). Circulating CD8+ T cells specific for WT p53(149-157) and WT p53(264-272) HLA-A*0201 restricted epitopes were directly identified in the peripheral blood by the use of peptide/HLA-A2.1 tetramers in 24 HCC patients. Cytotoxic T lymphocyte (CTL) activity after WT p53 peptide-specific stimulation was assessed by analysis of granzyme B and interferon-gamma mRNA transcription, using a quantitative real-time polymerase chain reaction assay. Tumor immunophenotyping was performed to evaluate the p53 status, the expression of major histocompatibility complex (MHC) and costimulatory molecules in freshly isolated tumor cells. HCC patients exhibited significantly higher frequencies of WT p53-specific memory CD8+ T cells and stronger WT p53-specific CTL activity, when compared with healthy controls. Increased frequencies of p53-specific CD8+ T cells and their activity correlated with selective HLA-A2 allele loss and reduced costimulatory molecule expression of tumor cells. Moreover, augmented numbers of p53-specific T cells coincided with high MHC class II expression in tumor cells but were inversely related to the T status of the tumor node metastasis staging system. Our results indicate the existence of natural immunosurveillance and tumor immune evasion, involving a T cell response against WT p53 tumor antigen in patients with HCC. These findings may have important implications for the future development of cancer vaccines.