Poor Tumor Cell Differentiation Research Articles

Dual epigenetic changes in diabetes mellitus-associated pancreatic ductal adenocarcinoma correlate with downregulation of E-cadherin and worsened prognosis.

Diabetes mellitus (DM) is a risk factor for pancreatic ductal adenocarcinoma (PDAC) that promotes the promoter methylation of CDH1. It is still unclear whether DM can exert other epigenetic effects, such as altering microRNA (miR) expression, in PDAC. The expression of miR-100-5p is known to be changed in DM patients and can suppress the expression of E-cadherin. In this study, the correlation between DM status and dual epigenetic changes was evaluated in PDAC specimens from patients who underwent radical surgical resection. A total of 132 consecutive patients with PDAC were clinicopathologically evaluated. E-cadherin and nuclear β-catenin expression was measured using immunohistochemistry. DNA and miRs were extracted from the main tumor site on formalin-fixed paraffin-embedded tissue sections. TaqMan miR assays were applied to assess miR-100-5p expression. Bisulfite modification was conducted on the extracted DNA, which was then subjected to methylation-specific polymerase chain reaction. Immunohistochemistry revealed that decreased E-cadherin expression and increased nuclear β-catenin expression were significantly associated with DM and poor tumor cell differentiation. The presence of long-duration DM (≥3 years) was a significant factor contributing to CDH1 promoter methylation (p < 0.01), while miR-100-5p expression was proportionally correlated with the preoperative HbA1c level (R = 0.34, p < 0.01), but not the duration of DM. The subjects with high miR-100-5p expression and CDH1 promoter methylation showed the highest level of vessel invasion and prevalence of tumor size ≥30 mm. PDAC subjects with dual epigenetic changes showed poorer overall survival (OS) than those with a single epigenetic change. miR-100-5p expression ≥4.13 and CDH1 promoter methylation independently predicted poor OS and disease-free survival (DFS) in the multivariate analysis. OS and DFS worsened in DM subjects with both HbA1c ≥ 6.5% and DM duration ≥3 years. Thus, DM is associated with two modes of epigenetic change by independent mechanisms and worsens prognosis.

A Differentiation-Related Gene Prognostic Index Contributes to Prognosis and Immunotherapy Evaluation in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common gastrointestinal tumor with a poor prognosis, which is associated with poor differentiation of tumor cells. However, the potential value of cell differentiation-related molecules in predicting the benefit and prognosis of immune checkpoint inhibitors (ICI) therapy remains unknown. Herein, to investigate the differentiation trajectory of HCC cells and their clinical significance, a differentiation-related gene prognostic index (DRGPI) based on HCC differentiation-related genes (HDRGs) was constructed to elucidate the immune characteristics and therapeutic benefits of ICI in the HCC subgroup defined by DRGPI. Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from four HCC samples were integrated for bioinformatics analysis. Then, PON1, ADH4, SQSTM1, HSP90AA1, and STMN1 were screened out to construct a DRGPI. More intriguingly, RT-qPCR validation of the expression of these genes yielded consistent results with the TCGA database. Next, the risk scoring (RS) constructed based on DRGPI suggested that the overall survival (OS) of the DRGPI-high patients was significantly worse than that of the DRGPI-low patients. A nomogram was constructed based on DRGPI-RS and clinical characteristics, which showed strong predictive performance and high accuracy. The comprehensive results indicated that a low DRGPI score was associated with low TP53 mutation rates, high CD8 T cell infiltration, and more benefit from ICI therapy. Homoplastically, the high DRGPI score reflected the opposite results. Taken together, our study highlights the significance of HCC cell differentiation in predicting prognosis, indicating immune characteristics, and understanding the therapeutic benefits of ICI, and suggests that DRGPI is a valuable prognostic biomarker for HCC.

Controlling nutritional status score as a prognostic marker to predict overall survival in resected biliary tract cancers.

BackgroundThe aim of our study was to explore the prognostic significance of the preoperative controlling nutritional status (CONUT) score and establish a nomogram to predict overall survival (OS) and to achieve a more accurate prognostic risk stratification.MethodsClinicopathological records of 371 patients who underwent surgical resection for biliary tract cancers (BTC) from December 2002 to December 2017 were reviewed retrospectively. The associations of the CONUT score with clinicopathological factors and OS were evaluated. Univariate and multivariable Cox regression analysis were used to screen out independent predictors. A nomogram was developed and validated to estimate OS.ResultsThe CONUT score was an independent predictor of OS [hazard ratio 1.478, 95% confidence interval (CI), 1.078–2.025, P=0.015]. And patients with a high CONUT score tended to have a poor prognosis with poor differentiation (P=0.011) of tumor cells and longer hospital stays (P=0.046). Besides the CONUT score, carbohydrate antigen 19-9, surgical method, and the American Joint Committee on Cancer (AJCC; 7th edition) TNM stage were contained in the final prognostic model. An OS nomogram was generated to visually predict 1-, 3-, and 5-year OS. The C-index was 0.714 (95% CI, 0.673–0.755) and 0.679 (95% CI, 0.616–0.742) in the development and validation cohort respectively. The nomogram provided superior discriminative power than the AJCC TNM staging system. The nomogram also demonstrated good risk stratification power in the entire cohort of BTC patients as well as for both BTC and surgical method subgroups.ConclusionsThe nomogram based on the CONUT score can predict OS in patients with BTCs, and it performed better than the AJCC TNM staging system.

Lymphoid enhancer-binding factor-1 promotes stemness and poor differentiation of hepatocellular carcinoma by directly activating the NOTCH pathway

The poorly differentiated hepatocellular carcinoma (HCC) cells are usually characterized by immature hepatic progenitor cell-like properties, such as enhanced self-renewal ability, resistance to chemotherapeutic drugs, and a loss of mature hepatocyte proteins. However, the molecular mechanisms governing this process still remain unclear. In this study, we found the lymphoid enhancer-binding factor-1 (LEF1), a transcriptional factor, was frequently overexpressed in HCCs, which was significantly associated with poor prognosis and tumor cell differentiation. Functional studies have found that LEF1 enhanced cell growth, foci formation, colony formation in soft agar, and tumor formation in nude mice. Different from its canonical roles in the WNT signaling pathway, we found that LEF1 could activate the critical members (e.g., NOTCH1 and NOTCH2) of the NOTCH signaling pathway through directly binding to their promoter regions. Further studies have found that LEF1 could enhance the self-renewal ability, drug resistance, dedifferentiation, and invasion of HCC cells. The oncogenic functions and the effects of LEF1 on cancer stemness could be effectively inhibited by NOTCH inhibitor. Further characterization of LEF1 may lead to the development of novel therapeutic strategies for HCC treatment.

Catecholamine-Synthesizing Enzymes in Pheochromocytoma and Extraadrenal Paraganglioma.

In chromaffin cells, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine β-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) are mainly involved in catecholamine synthesis. In this study, we evaluated the association between the status of catecholamine-synthesizing enzymes and histopathological features of pheochromocytoma and extraadrenal paraganglioma with special emphasis upon their postoperative clinical behavior. Immunohistochemical evaluation of TH, DBH, AADC, PNMT, Ki 67, and S-100 was performed in 29 pheochromocytoma and 10 extraadrenal paraganglioma and one lymph node harboring metastatic pheochromocytoma. Among these cases, metastasis was subsequently developed in three cases. Urinary normetanephrine (U-NM) levels were significantly higher in clinical metastatic cases than non-metastatic ones. Ki 67 labeling index was significantly higher in both clinical metastatic cases and the Adrenal Gland Scaled Score (PASS) score of ≧4 cases than PASS < 4 cases, although this score was originally used in pheochromocytoma. H-score of AADC and DBH were significantly lower in PASS ≧4 cases than those with < 4 cases, and in the cases associated with intratumoralnecrosis (n = 4), the presence of spindle shaped tumor cells (n = 4), and large nests of cells or diffuse growth (n = 5). Lower status of intratumoral AADC could be related to poor differentiation of tumor cells in both catecholamine production and morphology and could be related to aggressive biological behavior of both pheochromocytoma and extraadrenal paraganglioma.

Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study.

The programmed death-1-ligand 1 (PD-L1) has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In the study, we tried to reveal the clinical significance of PD-L1 in patients with non-small cell lung cancer (NSCLC), which is one of the most aggressive and intractable malignant tumors. PD-L1 expression in 120 NSCLC tissue specimens and 10 benign control samples embedded with wax were retrospectively detected by immunohistochemistry. No PD-L1 was detected in the 10 benign controls, whereas 57.5% of NSCLC tissue specimens showed PD-L1 expression. There was no relationship between PD-L1 expression and patient age, gender or histopathological type. However, PD-L1 expression was significantly correlated to the degree of tumor cell differentiation, stage of tumor node metastasis (TNM) and patient survival. Poor tumor cell differentiation and advanced TNM stage were related to higher PD-L1 expression. PD-L1-negative NSCLC patients had longer overall 5-year survival than PD-L1-positive patients ( P <0.0001). PD-L1 status was a significant independent prognostic factor of NSCLC (χ2 = 18.153, RR = 2.946, P <0.001). Up-regulated PD-L1 expression in NSCLC is related to the degree of tumor cell differentiation and TNM stage. PD-L1 status may be a new predictor of prognosis for patients with NSCLC.

MDMX is a prognostic factor for non-small cell lung cancer and regulates its sensitivity to cisplatin.

Chemoradiotherapy is the standard treatment modality for advanced non-small cell lung cancer (NSCLC). However, drug and radiation resistance remain major factors influencing its clinical outcome. The purpose of this study was to evaluate whether MDMX can affect the chemosensitivity and clinical outcome of NSCLC. Quantitative real-time PCR (qRT-PCR) was performed to assess MDMX mRNA expression levels in 105 primary NSCLC tissues, its corresponding non-cancerous tissues and two NSCLC-derived cell lines (A549 and SK-MES-1). In addition, immunohistochemistry was carried out to detect MDMX protein expression in the primary NSCLC tissues. The MDMX expression levels were correlated with clinicopathological and survival features. The effects of MDMX expression knockdown on NSCLC cell proliferation and chemosensitivity were evaluated using MTT, flow cytometry and soft agar colony assays. We found that the mRNA expression level of MDMX in NSCLC tissues was significantly higher than that in its corresponding non-tumorous tissues. High MDMX expression was found to be related to poor tumor cell differentiation, advanced TNM stages and the occurrence of lymph node metastases. Patients with a high MDMX expression level exhibited a lower overall survival rate than those with a low expression level. Multivariate analysis showed that a high MDMX protein expression level may serve as an independent prognostic factor for NSCLC patients. In addition, we found that MDMX expression knockdown combined with cisplatin treatment in vitro significantly increased apoptosis and decreased soft agar colony formation in NSCLC-derived cells. Our data indicate that MDMX expression may serve as an independent unfavorable prognostic factor for NSCLC patient outcome, which in turn may at least partly be due to the ability of the MDMX protein to regulate the proliferative capacity and chemosensitivity of NSCLC cells.

FBXW7 expression is associated with prognosis and chemotherapeutic outcome in Chinese patients with gastric adenocarcinoma

BackgroundFBXW7, a component of the Skp-Cullin1-F-box, mediates target protein recognition. It is a tumor suppressor gene that plays a role in the regulation of cell cycle exit and reentry via c-Myc, c-Jun and Notch degradation. There are few studies, particularly involving a large patient cohort, that have evaluated FBXW7 during gastric cancer progression.MethodsOur study aimed to evaluate the value of FBXW7 as a clinical marker in gastric adenocarcinoma (GC) patients including a subset treated with postoperative chemotherapy. Quantitative reverse transcription PCR (qRT-PCR) assay was used to measure FBXW7 transcript levels in tumors paired with normal gastric tissue in 24 gastric adenocarcinoma patients. Subsequently, 546 additional GC samples were evaluated from patients that underwent radical gastrectomy, including 118 early stage cases(Stage I) and 428 advanced stage cases (Stages II or III). Amongst the advanced stage patient cases evaluated, 347 received postoperative adjuvant chemotherapy. All 546 gastric adenocarcinoma cases were then evaluated by tissue microarray and immunohistochemistry (IHC) for FBXW7 expression. Clinicopathological features and diagnoses were confirmed by histopathologic evaluation and review of clinical data. Overall survival (OS) was then evaluated in the 546 gastric cancer patients.ResultsBy immunohistologic evaluation, low expression of FBXW7 in primary gastric cancer significantly correlated with poor differentiation of tumor cells. Moreover, low FBXW7 expression was associated with worse survival as well as worse adjuvant chemotherapy response.ConclusionOur findings suggest that FBXW7 may serve as an important predictor in chemotherapeutic responses.

ADAMTS14 Gene Polymorphism and Environmental Risk in the Development of Oral Cancer.

BackgroundOral cancer is a common malignancy that is shown to be causally associated with hereditary and acquired factors. ADAMTS14 is a member of the ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin motifs) metalloproteinase family that plays an important role in extracellular matrix (ECM) assembly and degradation. Elevation or deficiency of certain ADAMTS proteinases has been known to be implicated in a wide range of pathological processes including atherosclerosis, arthritis, and cancer. The present study aimed to explore the impact of ADAMTS14 gene polymorphisms, combined with environmental risks on the susceptibility to oral tumorigenesis.Methodology/Principal FindingsFour single-nucleotide polymorphisms (SNPs) of the ADAMTS14 gene, including rs10823607, rs12774070, rs4747096, and rs61573157 were evaluated from 1200 normal controls and 850 patients with oral cancer. We failed to detect a significant association of four individual SNPs with oral cancer between case and control group. However, while considering behavioral exposure of environmental carcinogens, the presence of four ADAMTS14 SNPs, combined with betel nut chewing and/or smoking, profoundly leveraged the risk of oral cancer. Moreover, we observed a significant association of rs12774070, which is predicted to alter the expression and function of ADAMTS14 by in silico and bioinformatics analyses, with poor tumor cell differentiation (AOR: 0.59; 95% CI: 0.38–0.92; p = 0.02) in patients who chewed betel nuts.ConclusionsThese results implicate the interaction between ADAMTS14 gene polymorphisms and environmental mutagens as a risk factor of oral tumorigenesis and suggest a correlation of rs12774070 with the degree of oral tumor cell differentiation.

A meta-analysis reveals prognostic role of programmed death ligand-1 in Asian patients with non-small cell lung cancer.

Accumulating studies explored the clinicopathologic and prognostic value of programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC), but the results were controversial. We therefore conducted a meta-analysis to evaluate the predictive role of PD-L1 in NSCLC patients. We systematically collected relevant studies from PubMed, Embase, Web of Science and China National Knowledge Infrastructure. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS), and odd ratios (ORs) with 95% CIs for clinicopathologic factors were calculated. A total of 15 studies involving 3605 patients were included in this meta-analysis. The results showed no prognostic role of PD-L1 in the whole patients (HR=1.60, 95% CI: 0.88-2.89, P=0.123). Subgroup analysis showed that PD-L1 was associated with decreased OS in Asian patients (HR=2.00, 95% CI: 1.55-2.57, P<0.001). Among all the clinicopathologic factors, PD-L1 overexpression was significantly in relevance with poor tumor cell differentiation (HR=1.84, 95% CI: 1.49-2.28, P<0.001), late stage (HR=1.21, 95% CI: 1.02-1.43, P=0.026) and anaplastic lymphoma kinase (ALK) translocation (HR=2.63, 95% CI: 1.08-6.40, P=0.034), but not with other factors. In conclusion, our meta-analysis demonstrated that PD-L1 has a prognostic role in Asian patients with NSCLC.

Cyclin D1 expression predicts postoperative distant metastasis and survival in resectable esophageal squamous cell carcinoma.

PurposeWe aim to identify esophageal squamous cell carcinoma patients with increased risk of postoperative metastases.ResultsA high level of cyclin D1 expression, together with poor tumor cell differentiation and advanced tumor stages, increased risk of postoperative metastasis and decreased distant metastasis-free survival in ESCC in both cohorts. A high level of cyclin D1 expression also decreased overall survival in the training cohort (p < 0.01) but not in the validation cohort (p = 0.415). However, when the two cohorts of patients were pooled to obtain a larger case number, a high level of cyclin D1 expression was again demonstrated as an independent predictor that decreased overall survival (p < 0.01).MethodsWe used data from two institutions to establish training (n = 319) and validation (n = 164) cohorts. Tissue microarrays were generated for immunohistochemical evaluation. The correlation among cyclin D1 expression, clinicopathologic variables, postoperative distant metastases, overall survival, and distant metastasis-free survival were analyzed. Multivariate analyses were used to test the independent factors impacting postoperative distant metastases and survival. The outcomes generated from the training cohort were then tested using the validation cohort and pooled dataset.ConclusionsHigh level of cyclin D1 expression increased distant metastasis, decreased overall survival and distant metastasis-free survival in resectable ESCC. Using a combination of cyclin D1 expression, tumor cell differentiation grade, and tumor stages, identifying patients with increased risk of postoperative metastases becomes possible.

Skewed Distribution of IL-7 Receptor-α-Expressing Effector Memory CD8+ T Cells with Distinct Functional Characteristics in Oral Squamous Cell Carcinoma

CD8+ T cells play important roles in anti-tumor immunity but distribution profile or functional characteristics of effector memory subsets during tumor progression are unclear. We found that, in oral squamous carcinoma patients, circulating CD8+ T cell pools skewed toward effector memory subsets with the distribution frequency of CCR7−CD45RA−CD8+ T cells and CCR7− CD45RA+CD8+ T cells negatively correlated with each other. A significantly higher frequency of CD127lo CCR7−CD45RA−CD8+ T cells or CCR7−CD45RA+CD8+ T cells among total CD8+ T cells was found in peripheral blood or tumor infiltrating lymphocytes, but not in regional lymph nodes. The CD127hi CCR7−CD45RA−CD8+ T cells or CCR7−CD45RA+CD8+ T cells maintained significantly higher IFN-γ, IL-2 productivity and ex vivo proliferative capacity, while the CD127lo CCR7−CD45RA−CD8+ T cells or CCR7−CD45RA+CD8+ T cells exhibited higher granzyme B productivity and susceptibility to activation induced cell death. A higher ratio of CCR7−CD45RA+CD8+ T cells to CCR7−CD45RA−CD8+ T cells was associated with advanced cancer staging and poor differentiation of tumor cells. Therefore, the CD127lo CCR7−CD45RA−CD8+ T cells and CCR7−CD45RA+CD8+ T cells are functionally similar CD8+ T cell subsets which exhibit late differentiated effector phenotypes and the shift of peripheral CD8+ effector memory balance toward CCR7−CD45RA+CD8+ T cells is associated with OSCC progression.

Clinical Significance of Programmed Death-1 Ligand-1 Expression in Patients with Non-Small Cell Lung Cancer: A 5-year-follow-up Study

The programmed death-1-ligand 1 (PD-L1) has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In the study, we tried to reveal the clinical significance of PD-L1 in patients with non-small cell lung cancer (NSCLC), which is one of the most aggressive and intractable malignant tumors. PD-L1 expression in 120 NSCLC tissue specimens and 10 benign control samples embedded with wax were retrospectively detected by immunohistochemistry. No PD-L1 was detected in the 10 benign controls, whereas 57.5% of NSCLC tissue specimens showed PD-L1 expression. There was no relationship between PD-L1 expression and patient age, gender or histopathological type. However, PD-L1 expression was significantly correlated to the degree of tumor cell differentiation, stage of tumor node metastasis (TNM) and patient survival. Poor tumor cell differentiation and advanced TNM stage were related to higher PD-L1 expression. PD-L1-negative NSCLC patients had longer overall 5-year survival than PD-L1-positive patients ( P <0.0001). PD-L1 status was a significant independent prognostic factor of NSCLC (χ2 = 18.153, RR = 2.946, P <0.001). Up-regulated PD-L1 expression in NSCLC is related to the degree of tumor cell differentiation and TNM stage. PD-L1 status may be a new predictor of prognosis for patients with NSCLC.

Podocalyxin-Like Protein 1 Expression and Correlation with Clinical Characteristics in Epithelial Serous and Mucinous Ovarian Carcinoma and Tumor-Like Lesions

Objective: Podocalyxin-like protein 1 (PCLP1) may be involved in the invasion and metastasis of tumors. However, to date the role of PCLP1 in the progression of epithelial ovarian carcinoma has not been investigated. Methods: PCLP1 expression was examined by immunohistochemistry in 471 cases with various degrees of ovarian epithelial lesions, including 46 cases of normal ovarian epithelial tissue, 105 benign serous tumors, 74 borderline serous tumors, 94 serous carcinomas, 58 benign mucinous tumors, 50 borderline mucinous tumors and 44 mucinous carcinomas. Associations between PCLP1 expression and various clinical characteristics were analyzed. Results: PCLP1 expression in mucinous carcinoma and borderline mucinous tumor tissues was found to be significantly lower than that observed in normal and benign mucinous tumor tissue. In addition, PCLP1 expression was significantly lower in mucinous carcinoma patients in advanced clinical stage and with poor differentiation of tumor cells. No positive results were observed in serous carcinomas. Conclusions: Our findings suggest that PCLP1 may be involved in the progression of ovarian mucinous lesions but not in serous lesions. Low PCLP1 expression may be a potential predictor of a poor prognosis in mucinous carcinomas.

Overexpression of Forkhead box M1 protein associates with aggressive tumor features and poor prognosis of hepatocellular carcinoma

The aim of this study was to detect the expression of the Forkhead box M1 (FOXM1) protein in human hepatocellular carcinoma (HCC) and to associate FOXM1 expression with clinicopathological features of the patients, and predict the prognosis of patients with FOXM1 expression. Surgical tissue specimens from 151 HCC patients were subjected to a tissue microarray construction and immunohistochemistry analysis of FOXM1 and the proliferation marker proliferating cell nuclear antigen (PCNA). The data showed that the FOXM1 protein was expressed in 59.3% of the HCC tissues, which was significantly higher compared to that of the surrounding non-tumorous tissues (23.8%; P<0.001). Moreover, FOXM1 expression was positively correlated with the labeling index of PCNA (P<0.001) in HCC and with aggressive tumor phenotypes, such as larger tumor size, multiple tumors, bilobar involvement, poor tumor cell differentiation, advanced stage and macrovascular invasion (P<0.05). In addition, HCC patients with FOXM1-positive tumors had a poorer recurrence-free and overall survival after hepatectomy than those with FOXM1-negative tumors. Multivariate Cox regression analysis demonstrated that FOXM1 expression was an independent predictor of unfavorable outcome (P<0.05). The data from the current study suggest that FOXM1 may play an important role in HCC progression and could be further evaluated as a prognostic biomarker and potential therapeutic target.

Prognostic Factors and Family History for Survival of Esophageal Squamous Cell Carcinoma Patients After Surgery

Surgical resection is the most effective treatment for patients with isolated esophageal cancer, but the 5-year survival rate is still very poor in spite of recent advances in early diagnosis and extended lymphadenectomy. To identify the high-risk group and the factors affecting postoperative course, we analyzed the prognostic factors including the family history of esophageal cancer in survival after esophagectomy. A total of 1,553 patients with esophageal squamous cell carcinoma after surgery were the subject of the present study. Thirty-one percent of all these patients have family history of esophageal cancer. The prognostic factors analyzed in this study included age, sex, tumor size, tumor location, lymphadenopathy, histologic type, grade of differentiation, stage of cancer, adjuvant treatments, and family history of esophageal cancer. The overall 3-year and 5-year postoperative survival rates were 43.7% and 26.2%, respectively, for all patients with esophagectomy. The five prognostic factors determined as significant by univariate p value were tumor size, lymphadenopathy, grade of differentiation, stage of cancer, and family history of esophageal cancer. Multivariate analysis showed that the independent prognostic factors were tumor size, grade of differentiation, stage of cancer, and family history of esophageal cancer. Our study also found that patients in groups with mid and upper segment esophageal squamous cell carcinoma, smaller tumor size, earlier stage of cancer, and poor differentiation of tumor cells had a significantly higher rate of positive family history than in the other groups, respectively. Tumor size, grade of differentiation, lymphadenopathy, stage of cancer, and family history of esophageal cancer were identified as prognostic factors after esophagectomy. Family history of esophageal cancer is an important prognostic factor that surgeons should take into consideration when selecting a treatment method.

Diverse Associations between ESR1 Polymorphism and Breast Cancer Development and Progression

To test the hypothesis that polymorphisms of ESR1, the gene encoding estrogen receptor alpha (ERalpha), are associated with susceptibility, clinical phenotype, and progression of breast cancer. A case-control study was done on 940 patients with incident breast cancer and 1,547 healthy female controls. Fifteen single-nucleotide polymorphisms (SNP) selected from chr6:152,170,379-152,466,100 (exons 1-8 of the ESR1 gene, excluding flanking sequences), reflecting major polymorphisms of this gene, were genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility and between cases with different clinical phenotypes to determine the role of ESR1 polymorphism in cancer progression. SNPs located in one cluster in intron 1 and one haplotype, based on these SNPs, showed a significant association with breast cancer susceptibility. The tumorigenic contribution of these intron 1 SNPs was more obvious in combination with reproductive risk factors (P for interaction <0.05). One of these intron 1 SNPs was also significantly associated with low ERalpha expression in tumors. Interestingly, the same intron 1 SNPs showed a correlation with worse clinical phenotypes, including poor differentiation of tumor cells and a late stage. These intron 1 SNPs also showed a significant association with the 5-year breast cancer-specific survival rate of patients, but had opposite effects in ERalpha-negative and ERalpha-positive early-stage patients. Our findings provide support for diverse roles of ESR1 polymorphism in determining susceptibility in different stages of breast cancer. The differences between the important ESR1 SNPs identified in Chinese women in this study and those identified in studies on Western women with breast cancer suggest different roles of ERalpha in these two populations.

Abstract 2837: Diverse associations between ESR1 polymorphisms and breast cancer development and progression

Abstract Purpose: To test the hypothesis that polymorphisms of ESR1, encoding estrogen receptor α (ERα), are associated with susceptibility, clinical phenotype, and progression of breast cancer. Patients and Methods: A case-control study was performed on 940 patients with incident breast cancer and 1547 healthy female controls. Fifteen single-nucleotide polymorphisms (SNPs) tagging all major polymorphisms of this gene were genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility, and between cases with different clinical phenotypes to determine the role of ESR1 polymorphism in cancer progression. Results. Three SNPs, located in one cluster in intron 1, were found to be important and the variant alleles showed a significant association with a decreased breast cancer risk and, coincidently, with low ERα expression in tumors. The tumorigenic contribution of these intron-1 SNPs was more obvious in combination with reproductive risk factors (p for interaction&amp;lt;0.05). Interestingly, the same SNPs showed a significant correlation with worse clinical phenotypes, including poor differentiation of tumor cells and a late stage. These intron 1 SNPs also showed a significant association with the five-year survival rate of all patients, but had opposite effects in ERα-negative and ERα-positive early-stage patients. Conclusions: Our findings provide support for diverse roles of ESR1 polymorphism in determining susceptibility in different stages of breast cancer. The differences between the important ESR1 SNPs identified in Chinese women in this study and those identified in studies on Western women with breast cancer suggest different roles of ERα in these two populations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2837.

Living donor liver transplantation for hepatocellular carcinoma: Increased recurrence but improved survival

In regions with a limited deceased donor pool, living donor adult liver transplantation (LDALT) has become an important treatment modality for patients with hepatocellular carcinoma (HCC) and cirrhosis. Studies have shown higher recurrence rates of HCC after LDALT in comparison with deceased donor liver transplantation (DDLT). The aim of our study was to examine the outcome results and recurrence rates for patients with HCC who underwent LDALT at our center. During an 8-year period, 139 patients underwent LDALT, of whom 28 (20.1%) had HCC in their explanted livers. The median follow-up was 40.8 months. The mean explant tumor size was 3.3 +/- 1.2, and the mean number of tumors was 1.5 +/- 0.8. Twenty-one patients (75%) had tumors within the Milan criteria, 5 patients had tumors outside the Milan criteria but within the University of California San Francisco (UCSF) criteria, and 2 patients were beyond the UCSF criteria. The overall 1- and 5-year patient and graft survival rates were 96% and 81%, respectively. Survival following LDALT was significantly better than survival following DDLT for HCC during the same time period (P = 0.02). Eight patients (28.6%) developed tumor recurrence. Poor differentiation of tumor cells was the most significant determinant of recurrence. Despite high recurrence rates of HCC following LDALT, overall 5-year survival appears to be excellent.

Decreased TIP30 Expression Promotes Tumor Metastasis in Lung Cancer

The HIV Tat-interacting protein (TIP30), also called CC3 or HTIP2, is encoded by Tip30, a putative tumor-suppressor gene located on human chromosome 11p15.1. In this study, we investigated the role of TIP30 in the progression and metastasis of lung cancer. TIP30 expression was analyzed in 206 paired lung cancers and adjacent non-tumor tissues, as well as in 70 matched lymph node metastases using a high-density tissue microarray. Results were compared with the clinicopathologic features of the patients from whom the tissues were taken. Low TIP30 expression levels were found in all 9 cases of small cell lung cancer and in 36.5% (72/197) of non-small cell lung cancer, which were correlated with lymph node metastasis in non-small cell lung cancer and with poor differentiation and advanced stage of tumor cells in squamous cell carcinoma. The immunostaining scores were significantly lower in the metastatic lesions than in the primary lesions. Down-regulation of TIP30 by a short hairpin RNA enhanced cell survival, migration, and invasion through Matrigel in vitro, and promoted lung metastasis and vascularization in nude mice. Further studies revealed that the down-regulation of TIP30 enhanced the expression of osteopontin, as well as matrix metalloproteinase-2 and vascular endothelial growth factor. Our results suggest that the down-regulation of TIP30 promotes metastatic progression of lung cancer, hence it could serve as a potential target for the development of lung cancer therapies.