Impact of Tumor Localization and Molecular Subtypes on the Prognostic and Predictive Significance of p53 Expression in Gastric Cancer

We investigated the prognostic and predictive impact of p53 expression for gastric cancer (GC) patients treated without or with preoperative chemotherapy (CTx) and its relationship with specific molecular GC subtypes. Specimens from 694 GC patients (562 surgical resection specimens without or after CTx, 132 biopsies before CTx) were analyzed by p53 immunohistochemistry. High (H) and low (L) microsatellite instability (MSI) and Epstein–Barr virus positivity were determined previously. Our results show that aberrant p53 expression was a negative prognostic factor in uni- and multivariable analysis in the resection specimens cohort (each p < 0.01). Subgroup analysis showed the strongest prognostic effect for patients with distally located tumors or no CTx treatment. In the biopsy cohort before CTx, p53 did not predict response or survival. p53 expression was significantly different among the molecular subtypes in surgical resection and bioptic specimens with strong association of altered p53 with MSI-L. Patients with MSI-H and aberrant p53 showed the worst survival in the biopsy cohort. In conclusion, the prognostic impact of p53 in GC differs according to tumor localization and CTx. Altered p53 is characteristic for MSI-L, and the p53 status in biopsies before CTx delineates MSI-H subtypes with inverse prognostic impact.

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The prognostic impact of hypoxia-inducible factor-1α and VEGF, IGF-2, p21, p53 expression in gastric adenocarcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4571 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4571-4571

Author(s):

Y. Kakeji ◽

K. Mizokami ◽

Y. Sumiyoshi ◽

K. Yoshinaga ◽

H. Saeki ◽

...

Keyword(s):

Gastric Cancer ◽

Growth Factor ◽

Cox Regression ◽

Hypoxia Inducible Factor ◽

Depth Of Invasion ◽

Human Gastric Cancer ◽

Prognostic Impact ◽

P53 Expression ◽

Cox Regression Analysis ◽

Dismal Prognosis

4571 Background: Hypoxia caused by either radiation or chemotherapy induces various intracellular adaptive responses, which contribute to tumor progression. The clinicopathological characteristics of human gastric cancer and the clinical outcomes were analyzed to investigate the effects of the expression of hypoxia-inducible factor1α (HIF-1α) and some related proteins, such as, vascular endothelial growth factor (VEGF), insulin-like growth factor-2 (IGF-2), p21, and p53 on the prognosis of human gastric cancer. Methods: The expressions of HIF-1α, VEGF, IGF-2, p21, and p53 proteins were determined by immunohistochemistry in 216 specimens of primary gastric cancer. Results: Of all 216 patients, 85 (39.4%) showed a positive expression of HIF-1α. In addition, the HIF-1α expression positively correlated with the tumor size and depth of invasion, while it was also more frequent in tumors with lymphatic invasion and undifferentiated adenocarcinomas. Though the VEGF expression significantly correlated with the HIF-1α expression, the expressions of IGF-2, p21 and p53 did not show any correlation. HIF-1α-positive/p21-negative tumors had a lower apoptotic index, and the patients with such tumors also had a significantly poorer prognosis. Similarly, HIF-1α-positive/p53-positive tumors had a significantly poorer prognosis. A multivariate Cox regression analysis showed the depth of invasion, lymph node metastasis, and HIF-1α positivity to all be independent prognostic factors in patients with gastric cancer. Conclusions: Based on the above findings, HIF-1α is therefore considered to be a useful independent prognostic factor in gastric cancer, and the combination of a HIF-1α protein overexpression with the loss of p21 expression or nonfunctional p53 thus tends to indicate a dismal prognosis. Controlling hypoxia, especially in the HIF-1α pathways, may therefore hold the key to a greater individualization of therapy and also lead to the development of new treatments for patients with gastric cancer. No significant financial relationships to disclose.

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Differential Prognostic Effect of IDH1 Versus IDH2 Mutations in Myelodysplastic Syndromes: A Mayo Clinic Study of 277 Patients

Blood ◽

10.1182/blood.v118.21.971.971 ◽

2011 ◽

Vol 118 (21) ◽

pp. 971-971

Author(s):

Mrinal M. Patnaik ◽

Curtis A. Hanson ◽

Janice M Hodnefield ◽

Terra L Lasho ◽

Christy Finke ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Conflicts Of Interest ◽

Multivariable Analysis ◽

Refractory Anemia ◽

International Prognostic Scoring System ◽

Risk Category ◽

Prognostic Impact ◽

Prognostic Effect ◽

Idh Mutations ◽

Mutant Idh1

Abstract Abstract 971 Unlike the case in acute myeloid leukemia, there is limited information on the prognostic impact of IDH mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (six R132S and two R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts (RARS), 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1, and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (p=0.0004; HR 4.0, 95% CI 1.9–8.8), revised International Prognostic Scoring System (IPSS-R) risk category (p<0.0001), and red cell transfusion need (p=0.002) as independent predictors of inferior survival (Figure 1). In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (p=0.001; HR 7.0, 95% CI 2.3–20.8). The presence of IDH2 R140Q did not affect overall (p=0.54) or leukemia-free (p=0.81) survival (Figure 2). The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS. Disclosures: No relevant conflicts of interest to declare.

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Differences in immune contextures among different molecular subtypes of gastric cancer and their prognostic impact

Gastric Cancer ◽

10.1007/s10120-019-00974-4 ◽

2019 ◽

Vol 22 (6) ◽

pp. 1164-1175 ◽

Cited By ~ 4

Author(s):

Joo Yeon Kim ◽

Woo Gyeong Kim ◽

Chae Hwa Kwon ◽

Do Youn Park

Keyword(s):

Gastric Cancer ◽

Molecular Subtypes ◽

Prognostic Impact

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Prognostic Impact of Sarcopenia and Radiotherapy in Patients With Advanced Gastric Cancer Treated With Anti-PD-1 Antibody

Frontiers in Immunology ◽

10.3389/fimmu.2021.701668 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nalee Kim ◽

Jeong Il Yu ◽

Do Hoon Lim ◽

Jeeyun Lee ◽

Seung Tae Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Negative Impact ◽

Multivariable Analysis ◽

Immune Checkpoint Blockade ◽

Prognostic Impact ◽

Skeletal Muscle Index ◽

Entire Cohort ◽

Significant Difference ◽

History Of

BackgroundWe explored the combined effects of sarcopenia (SAR) and radiotherapy (RT) on outcomes in patients with advanced gastric cancer (AGC) treated with immune-checkpoint blockade (ICB).MethodsAmong 185 patients with AGC treated with ICB, we defined SAR as skeletal muscle index <49 cm2/m2 for men and <31 cm2/m2 for women; 93 patients met criteria. We defined high neutrophil-to-lymphocyte ratio (hNLR) as NLR≥3. Palliative RT was performed in 37 patients (20%) before ICB.ResultsWe frequently observed hNLR in patients with SAR (53% vs. 35%, p = 0.02). The median overall survival (OS) for the entire cohort was 5 months. Stratification by risk factors of SAR or hNLR revealed a significant difference in median OS (0 [N = 60] vs. 1 [N = 76] vs. 2 [N = 49]: 7.6 vs. 6.4 vs. 2.2 months, p < 0.001). Patients with microsatellite instability-high (MSI-H, N = 19) or Epstein-Barr virus (EBV)-positive tumors (N = 13) showed favorable outcomes compared to those with microsatellite stable (MSS, N = 142) tumors (median OS, not reached vs. 16.8 vs. 3.8 months, respectively). The benefit of RT was evident in patients with both SAR and hNLR (median OS, 3.1 vs. 1.3 months, p = 0.02) and MSS/EBV-negative tumor (median OS, 6.5 vs. 3.5 months, p = 0.03), but outcomes after RT in MSI-H tumor were not significantly different. In multivariable analysis, SAR/hNLR, molecular subtypes, and a history of RT were associated with OS (all p < 0.05).ConclusionsWe demonstrated the negative predictive value of SAR/hNLR on outcomes after ICB for AGC, and the history of RT could overcome the negative impact of SAR/hNLR and the MSS/EBV-negative subtype.

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Specific epigenetic age acceleration patterns among four molecular subtypes of gastric cancer and their prognostic value

Epigenomics ◽

10.2217/epi-2020-0290 ◽

2021 ◽

Author(s):

Yu-Jie Zhou ◽

Xiao-Fan Lu ◽

Jia-Lin Meng ◽

Qi-Wen Wang ◽

Jin-Nan Chen ◽

...

Keyword(s):

Gastric Cancer ◽

Prognostic Value ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Embryonic Stem ◽

Accelerated Aging ◽

Bmp Signaling ◽

Molecular Characteristics ◽

Epigenetic Clock ◽

Barr Virus

Aims: To determine the association of the methylation age (Horvath epigenetic clock) of gastric cancer (GC) tissues with molecular subtypes and patient survival. Materials & methods: Multivariate regression models were used to determine the association of methylation age acceleration (AA) with the clinical and molecular characteristics of 333 GC patients. Results: Relative to the chromosomal instability (CIN) subtype, the epigenetic AA was 49.8 (95% CI: 42.7–56.9) years for Epstein–Barr virus, 16.1 (10.6–21.6) years for microsatellite instability (MSI), and 6.05 (0.1–11.1) years for genomic stability (GS) subtype. GC patients with accelerated aging of tumor tissues had better outcomes (adjusted hazard ratio: 3.13; p = 0.03). Differentially methylated probes in patients with accelerated and decelerated methylation aging enriched in pathways including BMP signaling, HMGB1 signaling, STAT3 signaling and human embryonic stem cell pluripotency. Conclusions: Our results highlight the prognostic value of epigenetic AA in GC and suggest that epigenetic AA is also an indicator of molecular subtype in GC.

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Analysis of Molecular Pretreated Tumor Profiles as Predictive Biomarkers of Therapeutic Response and Survival Outcomes after Neoadjuvant Therapy for Rectal Cancer in Moroccan Population

Disease Markers ◽

10.1155/2020/8459303 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Ihsane El Otmani ◽

Fatima El Agy ◽

Sanae El Baradai ◽

Laila Bouguenouch ◽

Nada Lahmidani ◽

...

Keyword(s):

Rectal Cancer ◽

Surgical Resection ◽

Distant Metastasis ◽

Therapeutic Response ◽

High Expression ◽

Prognostic Impact ◽

P53 Expression ◽

Incomplete Response ◽

Pathologic Features ◽

Her 2

Pathologic features depending on tumor response to preoperative chemoradiotherapy are important to determine the outcomes in patients with rectal cancer. Evaluating the potential predictive roles of biomarker expression and their prognostic impact is a promising challenge. We reported here the immunohistochemical staining of a panel marker of mismatch repair protein (MMR), Ki67, HER-2, and p53. Additionally, identification of somatic mutations of KRAS, NRAS, and BRAF genes were performed by direct sequencing and pyrosequencing in pretreated biopsy tissues from 57 patients diagnosed for rectal cancer. Clinical features and pathological criteria for postneoadjuvant treatment surgical resection specimen’s data were collected. Immunohistochemical expression and mutational status were correlated with therapeutic response, overall survival, and disease progression. The mean age of patients was 56 years. Seven (12.3%) out of 57 patients had a complete therapeutic response. Our analysis showed that when using complete therapeutic response (Dworak 4) and incomplete therapeutic response (Dworak 3, 2, and 1) as grouping factor, high p53 expression at the pretreatment biopsy was significantly associated to an incomplete response (p=0.002). For 20 and 2 out of 57, KRAS and NRAS mutations were detected, respectively. The majority of these mutations affected codon 12. KRAS mutations detected at codon 146 (A146T, A146V) was associated with the appearance of recurrence and distant metastasis (p=0.019). A high expression of HER-2 corresponding to score 3+ was observed in 3 pretreatment biopsy specimens. This class was significantly associated with a short relapse-free survival (p=0.002). Furthermore, the high expression of Ki67 was moderately correlated with an older age (p=0.016, r=0.319). In addition, this shows that high p53 expression in the pretreatment biopsy was associated with an incomplete response in surgical resection specimens after neoadjuvant treatment, and a HER-2 score 3+ can be a predictive factor of distant metastasis and local recurrence. Larger, prospective, and more studies are needed.

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ASXL1 exon 12 Mutations Are Frequent in AML with Intermediate Risk Karyotype and Are Independently Associated with An Extremely Poor Outcome

Blood ◽

10.1182/blood.v118.21.416.416 ◽

2011 ◽

Vol 118 (21) ◽

pp. 416-416

Author(s):

Susanne Schnittger ◽

Christiane Eder ◽

Tamara Alpermann ◽

Annette Fasan ◽

Vera Grossmann ◽

...

Keyword(s):

De Novo ◽

Strong Association ◽

Multivariable Analysis ◽

Adverse Impact ◽

Prognostic Impact ◽

Intermediate Risk ◽

Employment Equity ◽

Mutational Status ◽

Equity Ownership ◽

The Impact

Abstract Abstract 416 Introduction: ASXL1 mutations have recently been described in a number of different myeloid malignancies. Data on frequency, association with other markers and outcome in AML are rare. Aim: The aim of this study was to evaluate ASXL1 mutations (ASXL1mut) in AML with intermediate risk karyotype for frequency, association with other mutations and impact on outcome. Methods: We analyzed 476 cases with intermediate risk de novo AML for ASXL1 mutations by direct Sanger sequencing of exon 12. Other mutations were analyzed as described previously and were available in part of the patients (NPM1: n=474, FLT3-ITD: n=473, FLT3-TKD: n=407, MLL-PTD: n=474, CEBPA: n=447, RUNX1: n=150, WT1: n=384, IDH1: n=464 and IDH2: n=444, TET2: n=109, NRAS: n=191; KRAS: n=110, DNMT3A: n=83). 397 cases had a normal karyotype (NK) and 79 had intermediate risk aberrant cytogenetics (according to MRC). Female/male ratio was 221/255 and age ranged from 18.5–100.4 y (median: 66.4). Results: Overall, in 70/476 patients (14.7%) ASXL1mut were detected. In detail, the most frequent mutation was p.G646WfsX12 (n=36) followed by p.E635RfsX15 (n=9), and p.Y591X (n=2). The remaining 21 mutations were non-recurrent consisting of 2 frameshift, 13 nonsense and 6 missense mutations. All mutations were detected with a mutation/wildtype load of 40–50% and none of the cases had more than one ASXL1mut. ASXL1mut were more frequent in males than in females (56/255, 22.0% vs 14/221, 6.3%, p=0.001) and were associated with higher median age (72.4 yrs vs 64.1 yrs, p<0.001). In detail, in the cohort > 65 yrs 21.7% (n=55/254) and in those <65 yrs only 6.8% (n=15/222) were ASXL1mut (p<0.001). With respect to morphology ASXL1mut were more frequent in AML without maturation than in all others (37.5% vs 14.3%, p=0.022). In 242 cases immunophenotyping data was available and cases with ASXL1mut (n=34) had a higher expression of CD13 (mean±SD, 55±23% vs. 43±25%, p=0.012), CD34 (46±32% vs. 24±26%, p<0.001), CD133 (29±27% vs. 16±23%, p=0.006) and HLA-DR (42±25% vs. 30±24%, p=0.009) as well as a lower expression of CD33 (66±21% vs. 77±21%, p=0.005) and thus had a more immature immunophenotype as compared to ASXL1wt. There was no association with leukocyte or platelet counts. With regard to cytogenetics ASXL1mut were more frequent in those with aberrant karyotype than in NK (20/79, 25.3% vs 50/397, 12.6%, p=0.008). Generally, ASXL1mut were observed together with all other molecular mutations but there was a strong correlation to RUNX1mut (n=18/43, 41.9% vs 19/107, 17.8% in RUNX1wt, p=0.003) and a negative correlation with NPM1mut (n=9/274; 3.3% vs. n=61/200, 30.5% in NPM1wt, p<0.001) and DNMT3Amut (1/26, 3.8% vs. 19/55 in DNMT3A, 34.5%, p=0.002). Patients with ASXL1mut had a shorter overall survival (OS) (median: 11.2 vs 38.8 months, p<0.001) and event free survival (EFS) (median: 9.0 vs 23.9 months, p<0.001). In detail, this adverse impact could be shown for both NK (OS: median: 10.9 vs 38.3 months, p<0.001; EFS: 9.8 vs. 26.5 months, p<0.001) and intermediate risk aberrant cytogenetics (OS: median: 8.6 vs 38.8 months, p<0.001; EFS: 5.3 vs 21.5 months, p=0.011), separately. Although the ASXL1mut were much more frequent in the elderly and compared to the ASXL1wt had a shorter OS (median: 7.0 vs 16.3 months, p=0.002) an adverse effect on survival could also be shown in the cohort <65 yrs (median OS: 11.6 vs 47.3 months, p<0.001 and median EFS: 9.3 vs 34.5 months, p<0.001). Because of the high coincidence of the two mutations the impact of ASXL1mut in dependence of RUNX1 status was analyzed. In the RUNX1mut (n=43) the ASXL1mut (n=18) still had an adverse impact on EFS (median: 5.3 vs 15.6 months, p=0.010) and a trend for shorter OS (10.7 vs. 20.5 months, p=0.079). In a multivariable analysis ASXL1 is an unfavourable factor for OS independent of age and RUNX1 mutational status (p=0.026, RR: 2.0). Conclusions:ASXL1 mutations belong to the most frequent mutations in intermediate risk AML. There is a strong association with male sex, high age, immature phenotype and RUNX1mut. Still, ASXL1mut retained its independent very poor prognostic impact. Although the number of known molecular markers in AML is continuously increasing and selection of the most import markers for diagnostic work-up seems challenging this data indicates that ASXL1 is one of the most prominent candidates. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Eder:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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Prognostic Potential of MAGEH1 and Its Correlation with Immune infiltrates in Gastric Cancer

10.21203/rs.3.rs-263136/v1 ◽

2021 ◽

Author(s):

Zitong Li ◽

Haoran Ke ◽

Wenlin Deng ◽

Fang Li ◽

Siqi Wang ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Cell Function ◽

Prognostic Impact ◽

Gene Markers ◽

Prognostic Effect ◽

Interactive Analysis ◽

Kaplan Meier ◽

Human Protein Atlas ◽

Stomach Adenocarcinoma

Abstract Background: MAGEH1 is a critical gene for regulatory T cell function. However, correlations of MAGEH1 to prognosis and tumor-infiltrating cells in different cancers remain unclear. This study was to determine the prognostic impact of MAGEH1 as well as evaluate MAGEH1 expression and immune infiltrate relevance in gastric cancer.Methods: Oncomine, TIMER2.0, Kaplan-Meier Potter, PrognoScan, Gene Expression Profiling Interactive Analysis (GEPIA), and the Human Protein Atlas database were utilized to analyze the differential MAGEH1 expression and its prognostic value. The relationship between MAGEH1 and gene markers of immune infiltration was confirmed by TIMER2.0 and GEPIA.Results: The prognostic effect of MAGEH1 varied across cancers. Particularly in gastric cancer, highly expressed MAGEH1 showed a significant association with poor prognosis in multiple databases whereas was linked to a better prognosis in patients with adjuvant 5-fluorouracil therapy. MAGEH1 expression positively correlated with infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, neutrophils, macrophages, and dendritic cells in stomach adenocarcinoma (STAD). Furthermore, MAGEH1 expression showed a strong link with markers for monocytes, macrophages, neutrophils and Tregs in STAD tissues.Conclusions: MAGEH1 can serve as a prognostic biomarker in gastric cancer and is related to immune infiltrates.

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Microsatellite instability and Epstein-Barr virus combined with PD-L1 could serve as a potential strategy for predicting the prognosis and efficacy of postoperative chemotherapy in gastric cancer

PeerJ ◽

10.7717/peerj.11481 ◽

2021 ◽

Vol 9 ◽

pp. e11481

Author(s):

Na Yang ◽

Yanhua Wu ◽

Meishan Jin ◽

Zhifang Jia ◽

Yueqi Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Microsatellite Instability ◽

Epstein Barr Virus ◽

Molecular Subtypes ◽

Postoperative Chemotherapy ◽

Rank Test ◽

Molecular Subtyping ◽

Barr Virus ◽

Epstein Barr ◽

Potential Strategy

Background Microsatellite instability (MSI) and Epstein-Barr virus (EBV)-positive molecular subtypes exhibit complex immune responses in gastric cancer (GC), and PD-L1 has emerged as a prognostic biomarker associated with the cancer immune microenvironment. This study aimed to determine the prognostic value of molecular subtypes and whether the addition of PD-L1 would accurately predict the prognosis and guide postoperative chemotherapy for GC patients. Methods We performed molecular subtyping of tissue microarray slides from 226 GC patients who were treated with radical gastrectomy. The MSI status and PD-L1 expression were evaluated through immunohistochemistry (IHC) and EBV status through situ hybridization. Multiplex polymerase chain reaction (PCR) was also performed on 50 cases to validate the accuracy of IHC in defining MSI status. Differences in overall survival (OS) were assessed using the Kaplan-Meier method, log-rank test and Cox proportional hazards regression model. Results Among the 226 GC patients, 52 (23.2%) patients were classified as the MSI subtype, 11 (4.9%) were EBV+ subtype, and 161 (71.9%) were MSS (Microsatellite stable) /EBV− subtype according to TCGA analysis. Two patients were both positive for MSI and EBV infection. EBV+ cases showed higher PD-L1 positivity than MSI cases and MSS/EBV− cases (81.8% vs. 50.0% vs. 35.4%, P = 0.003). Compared with the non-MSS/EBV− (MSI or EBV+ cases) subgroup, GC patients with MSS/EBV− were associated with the worst outcomes (HR = 1.610, 95% CI [1.046–2.479], P = 0.031). MSS/EBV− GCs alone could benefit from postoperative chemotherapy (HR = 0.452, 95% CI [0.299–0.682], P < 0.001), and PD-L1-positive expression could also predict a better prognosis (HR = 0.612, 95% CI [0.389–0.962], P = 0.033) in this subgroup. Considering both chemotherapy efficacy and PD-L1 expression in the MSS/EBV− subgroup, chemotherapy could improve the prognosis for PD-L1-negative MSS/EBV− GCs (HR = 0.357, 95% CI [0.217–0.587], P < 0.001) but not PD-L1-positive MSS/EBV− GCs. Conclusions Molecular subtyping combined with PD-L1 expression could serve as a potential strategy to better predict prognosis and guide postoperative chemotherapy of GC patients.

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Clinical significance of p53 protein, beta-catenin, and HER2 in patients with Epstein-Barr virus-associated gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.22 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 22-22

Author(s):

Dong Won Baek ◽

In Hee Lee ◽

Soo Jung Lee ◽

Byung Woog Kang ◽

Yee Soo Chae ◽

...

Keyword(s):

Gastric Cancer ◽

Epstein Barr Virus ◽

P53 Protein ◽

Host Cells ◽

Beta Catenin ◽

Altered Expression ◽

P53 Expression ◽

Barr Virus ◽

Nuclear Expression ◽

Epstein Barr

22 Background: Epstein-Barr virus (EBV) infection can cause cancer tumorigenesis and malignant transformation of host cells through the activation of oncogenic pathways. Therefore, we assessed the expression of p53 protein, beta-catenin, and HER2 and their prognostic implication in patients with EBV-associated gastric cancer (EBVaGC). Methods: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 117 patients were identified as EBV-positive using EBV-encoded RNA in-situ hybridization. The results of immunohistochemistry were interpreted as follows: strong p53 nuclear expression in at least 50% of tumor nuclei was interpreted as a positive result; strong positive cytoplasmic-nuclear expression patterns for β-catenin ( ≥ 10%) were considered altered expression; moderate or strong complete or basolateral membrane staining in 10% of tumor cells for HER2 was reported as a positive results. Results: The median age of the patients was 62 years (32-80) and 93 (79.5%) were male. The pathologic stages were as follows : stage I (n = 74), stage II (n = 25), and stage III (n = 18). Among the 117 patients, immunohistochemical staining for p53 was performed in 105 patients and 25 patients (23.8%) were positive. Beta-catenin was positive in 10 patients (17.5%) and HER2 was positive in 8 patients (6.8%), respectively. The positive expression of p53 was significantly associated with a high T stage (p = 0.006). Conversely, more patients without lymph node metastasis were p53 positive (p = 0.013). In the univariate analysis, the patients with p53 positive tumors showed a significantly improved disease-free survival (DFS) compared to the patient with negative tumors (p = 0.022), although the p53 status was marginally associated with overall survival (OS)(p = 0.080). However, p53 expression showed no prognostic significance on DFS in the multivariate analysis. Meanwhile, beta-catenin and HER2 was not found to be associated with DFS and OS in the survival analysis. Conclusions: The current study found a significant correlation between p53 expression and tumor progression in patients with EBVaGC.

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