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Su2022 Mutation Spectrum of TP53 Gene Predicts Clinicopathological Features and Survival of Gastric Cancer
AGA Abstracts
Su2022
shown to play a critical role in tumor response to treatment across numerous disease sites. We aimed to examine the relationship of various hematologic parameters during preoperative CRT to pathologic response in a population of rectal cancer patients. METHODS: We reviewed the records of all LARC patients treated at our institution between January 2010 and October 2014. All patients received neoadjuvant chemoradiation (50.4 Gy) with concurrent capecitabine followed by surgical resection. Clinical data including patient characteristics, tumor stage, and pathological response were determined for each patient. Hematologic and biochemical parameters were recorded at time of initial diagnosis and during week 2 of chemoradiation. Tumors were designated as having a good pathological response if pathological tumor stage (pT-stage) was less than pre-treatment T-stage and remaining viable tumor cells £5%. A poor pathological response was designated as no change in T-stage or >5% remaining viable tumor cells. Univariate analyses of clinical factors previously identified as significant predictors of pathologic complete response (tumor length > 5 cm, carcinoembryonic antigen (CEA) >2.5 ng/mL, distance from anal verge >5 cm, and circumferential extent of tumor >60%) as well as neutrophil/lymphocyte ratio (NLR) at week 2 were performed. These were also used to construct a multivariate logistic regression model to identify significant independent predictors of response. We used modified receiver-operating characteristics curves to determine the cut-off for the NLR ratio. RESULTS: 212 patients were included in the study. 91 patients (43%) were considered good responders and 121 patients (57%) were considered poor responders. Univariate analyses showed that pretreatment CEA level>2.5 ng/mL (p<0.01), tumor circumferential extent >60% (p=0.01), and NLR >3.4 at week 2 (p<0.01) were associated with poorer pathologic response to treatment. A multivariate logistic regression analysis revealed multiple significant independent predictors of poor pathologic response including CEA >2.5 ng/mL (OR 2.72; p<0.01), tumor circumferential extent >60% (OR 2.16; p=0.03), and NLR > 3.4 at week 2 (OR 2.72; p=0.01). CONCLUSIONS: Elevated NLR during chemoradiation treatment predicts for a poor pathologic response. This easily calculated ratio could be used to identify patients who may benefit from dose escalation or other risk-adapted strategies early on in the treatment course.
Mutation Spectrum of TP53 Gene Predicts Clinicopathological Features and Survival of Gastric Cancer Tomomitsu Tahara, Tomoyuki Shibata, Masaaki Okubo, Tomohiko Kawamura, Noriyuki Horiguchi, Takamitsu Ishizuka, Naoko Nakano, Mitsuo Nagasaka, Yoshihito Nakagawa, Naoki Ohmiya Background and aim: TP53 is the most frequently mutated gene in gastric cancer (GC) and may be possible candidate biomarker for GC. However, the relationship between TP53 mutation and clinicopathological features in GC is conflicting. Here, we screened TP53 mutation spectrum of 214 GC patients and investigated its association with clinicopathological features and prognosis. Methods: Matched endoscopic biopsies from GC and adjacent tissues from 214 patients were used for the experiment. All coding regions of TP53 gene (exon2 to exon11) were examined using Sanger sequencing. Results: TP53 nonsilent mutations were detected in 80 cases (37.4%), being frequently occurred as C:G to T:A single nucleotide transitions at 5'-CpG-3' sites. TP53 mutations occurred more frequently in differentiated histologic type than in undifferentiated type in the early stage (48.6% vs. 7%, P= 0.0006), while the mutations correlated with venous invasion among advanced stage (47.7% vs. 20.7%, P=0.04). Subset of GC with TP53 hot spot mutations (R175, G245, R248, R273, R282) presented significantly worse overall survival and recurrence free survival compared to others (both P=0.001). Conclusion: Our data suggest that GC with TP53 mutations seems to develop as differentiated histologic type and show aggressive biological behavior such as venous invasion. Moreover, our data emphasizes the importance of discriminating TP53 hot spot mutations (R175, G245, R248, R273, R282) to predict worse overall survival and recurrence free survival of GC patients.
Su2025 A1-Antitrypsin (SERPIN-A1) in Colon Cancer: Gene Expression and Clinical Relevance Dimitrios Kypraios, Athina Bakrakou, Apostolos Malachias, Nikolaos Saribegioglou, Loukas Theodoropoulos, Stavros Stavrinides, Dimitrios Xinopoulos, Maroulio Talieri INTRODUCTION: Colon cancer (CC) remains the third leading cause of worldwide cancerrelated death in men and women. Currently available prognostic and/or predictive markers for colon cancer lack specificity and sensitivity. Developing new biomarker for early detection, accurate diagnosis and therapeutic treatment for colon cancer is of great importance in improving the clinical outcome of the disease. Members of the serine protease inhibitor (Serpin) superfamily are found in all branches of life and play an important role in the regulation of enzymes involved in proteolytic cascades. The family includes alpha1-antitrypsin, alpha1-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin. Alpha1-antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. Kallikrein-related peptidases (KLKs) are involved in proteolytic cascades of different tissues. KLK14, acting via PAR-2 represents an autocrine/paracrine regulator of colon tumorigenesis and alpha1-antitrypsin is a natural inhibitor of KLK14. Therefore its role in regulating the proteolytic cascade in colon tumorigenesis is of great importance. AIM: The aim of this study was to analyze the expression of A1- antitrypsin in tissue samples at different stages in the process of colon cancer development. MATERIALS AND METHODS: In this study, we examined for first time, using quantitative real time PCR, the expression of alpha1antitrypsin in 101 colorectal carcinoma tissues for 70 of which normal paired mucosa were also available, as well as in 74 colorectal adenomas. We also clinically evaluated the impact of the results for those patients. RESULTS: Alpha1-antitrypsin expression was found to be significantly associated with TNM stage (p=0.028). Cox proportional hazard regression model using univariate analysis revealed that high status alpha1-antitrypsin expression is a significant factor for disease-free survival (DFS) (p=0.002) and overall survival (OS) (p=0.026) of patients. Kaplan-Meier survival curves demonstrated that alpha1-antitrypsin expression of low status is significantly associated with longer DFS (p=0.001) as well as OS (p=0.021) of patients. CONCLUSION: The present study suggests that A1-antitrypsin mRNA expression may represent a useful marker of unfavorable prognosis for CC.
Su2023 Changes of Immunoglobulin-Bound Glycans in Patients With Gastro-Intestinal Cancers Chihiro Dohi, Kazuhiro Nouso, Soichiro Ako, Yuuki Morimoto, Koji Miyahara, Hideaki Kinugasa, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada Background: Immunoglobulin G (IgG) is a glycosylated molecule of the immune system and is known to bear two glycans. The profiles of the glycans in IgG play an important role in the effector functions and the changes were reported in some immunological diseases such as rheumatoid arthritis and Crohn disease. The difference of the glycans were also reported in some cancers including gastric cancer. However, most of the reports were based on the examinations of a small number of patients or particular cancers. The aim of this study was to elucidate the changes of the serum N-glycan profile that were correlated with IgG comprehensively by examining a large number of various cancer patients using highthroughput system. Patients and Methods: We collected serum from 427 patients with various kinds of gastro-intestinal cancer (120 hepatocellular carcinoma, 104 pancreatic cancer, 83 colon cancer, 65 stomach cancer, 25 esophageal cancer, 16 gall bladder cancer and 14 bile duct cancer) and 526 healthy volunteers. Serum glycan profiles were examined by comprehensive, quantitative, high-throughput method developed by Nishimura et al. (Carbohydr Chem biochem 2011;65:219-71) and compared with clinical parameters focused on the glycans that bound to IgG. This study protocol conformed to the tenets of the Declaration of Helsinki and was approved by the ethics committee of the institute. Result: Among 69 glycans that we could detect by this method, 9 glycans were expressed only in IgG fraction in our previous study. In this study, we focused on these glycans and analyzed the expressions. Out of the 9 glycans, two glycans showed characteristic change in the patients with cancer. The expression of bi-antennary complexed glycan without galactose (m/z 1590) was higher in patients with cancer than in healthy volunteers (median= 18.12 and 8.36, respectively; p<0.0001), whereas the expression of bi-antennary complexed glycan with two terminal galactose residues (m/z 1914) was lower in patients with cancer than in healthy people (median= 11.20 and 14.58, respectively; p<0.0001). The ratio of these glycans (1590/1914) that represented the proportion of agalactosyl glycans was significantly higher in patients with cancer than in healthy volunteer (median= 1.61 and 0.59, respectively; p<0.0001, AUROC = 0.898). The ratio was quite similar regardless of the type of tumors except gall bladder cancer. Conclusion: Increased proportion of agalactosyl glycan in IgG seems to be a common features of gastro-intestinal cancers and might be useful for the diagnosis.
Su2026 Do Intra-Tumor Expression Levels of miR-200c, miR-21 and miR-92a Indicate High Risk of Metastases in Early Colorectal Cancer? Rikke K. Jepsen, Guy Novotny, Louise Klarskov, Ib J. Christensen, Estrid Høgdall, Lene Riis Introduction: Colorectal cancer (CRC) prognosis is highly linked to stage at diagnosis, and assessment of metastatic potential in early CRC lesions is of major importance for individualized treatment stratification. MicroRNAs (miRNAs) are involved in cancer development and progression through epigenetic modulation of carcinogenic pathways, and several specific miRNAs have been linked to metastatic disease. miR-21, miR-92a and miR-200c are regulators of pathways involved in migration, intravasation and metastasis, and their expression levels have also been associated with prognosis in CRC. We examine intra-tumor expression of the three miRNAs in early CRC tissue in order to determine intra-tumor heterogeneity, potential intra-tumor gradients and finally to clarify whether they could serve as markers for metastatic disease in early stage CRC. Material and methods: Two parallel studies on archived formalin fixed paraffin embedded (FFPE) CRC tissue. Intra-tumor heterogeneity was analyzed in 9 early metastatic CRCs in order to estimate intra- and inter-tumor variation by qRT PCR on isolated tissue samples from luminal, central and invasive border zones. Associations between miRNAs and early metastasizing tumors was investigated by measuring tumor miRNA expression levels in FFPE tissue from invasive and central tumor zones and normal colorectal mucosa from 47 early metastatic CRCs matched with 47 non-metastatic CRCs. Results: Mean intra tumor coefficient of variation in the heterogeneity cohort was 38.5% (range: 33.1-48.9%) only slightly less than variation between patients equal to 45.1% (range 37,0-49.5%). In the heterogeneity cohort target miRNAs showed a systematic gradient
Su2024 Neutrophil-Lymphocyte Ratio During Chemoradiation Predicts Pathologic Tumor Response for Rectal Cancer Patients Jillian R. Gunther, Awalpreet S. Chadha, Harpreet K. Arora, Sunil Krishnan INTRODUCTION: The current standard of care for locally advanced rectal cancer (LARC) includes preoperative chemoradiation (CRT) followed by surgical resection. There is much interest in predicting patient response to CRT early on to allow for risk-adapted strategies and/or possible avoidance of morbid treatments. Recently the immune system has been
AGA Abstracts
X : 10052$CH01 03-28-16 00:57:27 PDFd : 10052B : e
S-614
Page 614
Su2022
shown to play a critical role in tumor response to treatment across numerous disease sites. We aimed to examine the relationship of various hematologic parameters during preoperative CRT to pathologic response in a population of rectal cancer patients. METHODS: We reviewed the records of all LARC patients treated at our institution between January 2010 and October 2014. All patients received neoadjuvant chemoradiation (50.4 Gy) with concurrent capecitabine followed by surgical resection. Clinical data including patient characteristics, tumor stage, and pathological response were determined for each patient. Hematologic and biochemical parameters were recorded at time of initial diagnosis and during week 2 of chemoradiation. Tumors were designated as having a good pathological response if pathological tumor stage (pT-stage) was less than pre-treatment T-stage and remaining viable tumor cells £5%. A poor pathological response was designated as no change in T-stage or >5% remaining viable tumor cells. Univariate analyses of clinical factors previously identified as significant predictors of pathologic complete response (tumor length > 5 cm, carcinoembryonic antigen (CEA) >2.5 ng/mL, distance from anal verge >5 cm, and circumferential extent of tumor >60%) as well as neutrophil/lymphocyte ratio (NLR) at week 2 were performed. These were also used to construct a multivariate logistic regression model to identify significant independent predictors of response. We used modified receiver-operating characteristics curves to determine the cut-off for the NLR ratio. RESULTS: 212 patients were included in the study. 91 patients (43%) were considered good responders and 121 patients (57%) were considered poor responders. Univariate analyses showed that pretreatment CEA level>2.5 ng/mL (p<0.01), tumor circumferential extent >60% (p=0.01), and NLR >3.4 at week 2 (p<0.01) were associated with poorer pathologic response to treatment. A multivariate logistic regression analysis revealed multiple significant independent predictors of poor pathologic response including CEA >2.5 ng/mL (OR 2.72; p<0.01), tumor circumferential extent >60% (OR 2.16; p=0.03), and NLR > 3.4 at week 2 (OR 2.72; p=0.01). CONCLUSIONS: Elevated NLR during chemoradiation treatment predicts for a poor pathologic response. This easily calculated ratio could be used to identify patients who may benefit from dose escalation or other risk-adapted strategies early on in the treatment course.
Mutation Spectrum of TP53 Gene Predicts Clinicopathological Features and Survival of Gastric Cancer Tomomitsu Tahara, Tomoyuki Shibata, Masaaki Okubo, Tomohiko Kawamura, Noriyuki Horiguchi, Takamitsu Ishizuka, Naoko Nakano, Mitsuo Nagasaka, Yoshihito Nakagawa, Naoki Ohmiya Background and aim: TP53 is the most frequently mutated gene in gastric cancer (GC) and may be possible candidate biomarker for GC. However, the relationship between TP53 mutation and clinicopathological features in GC is conflicting. Here, we screened TP53 mutation spectrum of 214 GC patients and investigated its association with clinicopathological features and prognosis. Methods: Matched endoscopic biopsies from GC and adjacent tissues from 214 patients were used for the experiment. All coding regions of TP53 gene (exon2 to exon11) were examined using Sanger sequencing. Results: TP53 nonsilent mutations were detected in 80 cases (37.4%), being frequently occurred as C:G to T:A single nucleotide transitions at 5'-CpG-3' sites. TP53 mutations occurred more frequently in differentiated histologic type than in undifferentiated type in the early stage (48.6% vs. 7%, P= 0.0006), while the mutations correlated with venous invasion among advanced stage (47.7% vs. 20.7%, P=0.04). Subset of GC with TP53 hot spot mutations (R175, G245, R248, R273, R282) presented significantly worse overall survival and recurrence free survival compared to others (both P=0.001). Conclusion: Our data suggest that GC with TP53 mutations seems to develop as differentiated histologic type and show aggressive biological behavior such as venous invasion. Moreover, our data emphasizes the importance of discriminating TP53 hot spot mutations (R175, G245, R248, R273, R282) to predict worse overall survival and recurrence free survival of GC patients.
Su2025 A1-Antitrypsin (SERPIN-A1) in Colon Cancer: Gene Expression and Clinical Relevance Dimitrios Kypraios, Athina Bakrakou, Apostolos Malachias, Nikolaos Saribegioglou, Loukas Theodoropoulos, Stavros Stavrinides, Dimitrios Xinopoulos, Maroulio Talieri INTRODUCTION: Colon cancer (CC) remains the third leading cause of worldwide cancerrelated death in men and women. Currently available prognostic and/or predictive markers for colon cancer lack specificity and sensitivity. Developing new biomarker for early detection, accurate diagnosis and therapeutic treatment for colon cancer is of great importance in improving the clinical outcome of the disease. Members of the serine protease inhibitor (Serpin) superfamily are found in all branches of life and play an important role in the regulation of enzymes involved in proteolytic cascades. The family includes alpha1-antitrypsin, alpha1-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin. Alpha1-antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. Kallikrein-related peptidases (KLKs) are involved in proteolytic cascades of different tissues. KLK14, acting via PAR-2 represents an autocrine/paracrine regulator of colon tumorigenesis and alpha1-antitrypsin is a natural inhibitor of KLK14. Therefore its role in regulating the proteolytic cascade in colon tumorigenesis is of great importance. AIM: The aim of this study was to analyze the expression of A1- antitrypsin in tissue samples at different stages in the process of colon cancer development. MATERIALS AND METHODS: In this study, we examined for first time, using quantitative real time PCR, the expression of alpha1antitrypsin in 101 colorectal carcinoma tissues for 70 of which normal paired mucosa were also available, as well as in 74 colorectal adenomas. We also clinically evaluated the impact of the results for those patients. RESULTS: Alpha1-antitrypsin expression was found to be significantly associated with TNM stage (p=0.028). Cox proportional hazard regression model using univariate analysis revealed that high status alpha1-antitrypsin expression is a significant factor for disease-free survival (DFS) (p=0.002) and overall survival (OS) (p=0.026) of patients. Kaplan-Meier survival curves demonstrated that alpha1-antitrypsin expression of low status is significantly associated with longer DFS (p=0.001) as well as OS (p=0.021) of patients. CONCLUSION: The present study suggests that A1-antitrypsin mRNA expression may represent a useful marker of unfavorable prognosis for CC.
Su2023 Changes of Immunoglobulin-Bound Glycans in Patients With Gastro-Intestinal Cancers Chihiro Dohi, Kazuhiro Nouso, Soichiro Ako, Yuuki Morimoto, Koji Miyahara, Hideaki Kinugasa, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada Background: Immunoglobulin G (IgG) is a glycosylated molecule of the immune system and is known to bear two glycans. The profiles of the glycans in IgG play an important role in the effector functions and the changes were reported in some immunological diseases such as rheumatoid arthritis and Crohn disease. The difference of the glycans were also reported in some cancers including gastric cancer. However, most of the reports were based on the examinations of a small number of patients or particular cancers. The aim of this study was to elucidate the changes of the serum N-glycan profile that were correlated with IgG comprehensively by examining a large number of various cancer patients using highthroughput system. Patients and Methods: We collected serum from 427 patients with various kinds of gastro-intestinal cancer (120 hepatocellular carcinoma, 104 pancreatic cancer, 83 colon cancer, 65 stomach cancer, 25 esophageal cancer, 16 gall bladder cancer and 14 bile duct cancer) and 526 healthy volunteers. Serum glycan profiles were examined by comprehensive, quantitative, high-throughput method developed by Nishimura et al. (Carbohydr Chem biochem 2011;65:219-71) and compared with clinical parameters focused on the glycans that bound to IgG. This study protocol conformed to the tenets of the Declaration of Helsinki and was approved by the ethics committee of the institute. Result: Among 69 glycans that we could detect by this method, 9 glycans were expressed only in IgG fraction in our previous study. In this study, we focused on these glycans and analyzed the expressions. Out of the 9 glycans, two glycans showed characteristic change in the patients with cancer. The expression of bi-antennary complexed glycan without galactose (m/z 1590) was higher in patients with cancer than in healthy volunteers (median= 18.12 and 8.36, respectively; p<0.0001), whereas the expression of bi-antennary complexed glycan with two terminal galactose residues (m/z 1914) was lower in patients with cancer than in healthy people (median= 11.20 and 14.58, respectively; p<0.0001). The ratio of these glycans (1590/1914) that represented the proportion of agalactosyl glycans was significantly higher in patients with cancer than in healthy volunteer (median= 1.61 and 0.59, respectively; p<0.0001, AUROC = 0.898). The ratio was quite similar regardless of the type of tumors except gall bladder cancer. Conclusion: Increased proportion of agalactosyl glycan in IgG seems to be a common features of gastro-intestinal cancers and might be useful for the diagnosis.
Su2026 Do Intra-Tumor Expression Levels of miR-200c, miR-21 and miR-92a Indicate High Risk of Metastases in Early Colorectal Cancer? Rikke K. Jepsen, Guy Novotny, Louise Klarskov, Ib J. Christensen, Estrid Høgdall, Lene Riis Introduction: Colorectal cancer (CRC) prognosis is highly linked to stage at diagnosis, and assessment of metastatic potential in early CRC lesions is of major importance for individualized treatment stratification. MicroRNAs (miRNAs) are involved in cancer development and progression through epigenetic modulation of carcinogenic pathways, and several specific miRNAs have been linked to metastatic disease. miR-21, miR-92a and miR-200c are regulators of pathways involved in migration, intravasation and metastasis, and their expression levels have also been associated with prognosis in CRC. We examine intra-tumor expression of the three miRNAs in early CRC tissue in order to determine intra-tumor heterogeneity, potential intra-tumor gradients and finally to clarify whether they could serve as markers for metastatic disease in early stage CRC. Material and methods: Two parallel studies on archived formalin fixed paraffin embedded (FFPE) CRC tissue. Intra-tumor heterogeneity was analyzed in 9 early metastatic CRCs in order to estimate intra- and inter-tumor variation by qRT PCR on isolated tissue samples from luminal, central and invasive border zones. Associations between miRNAs and early metastasizing tumors was investigated by measuring tumor miRNA expression levels in FFPE tissue from invasive and central tumor zones and normal colorectal mucosa from 47 early metastatic CRCs matched with 47 non-metastatic CRCs. Results: Mean intra tumor coefficient of variation in the heterogeneity cohort was 38.5% (range: 33.1-48.9%) only slightly less than variation between patients equal to 45.1% (range 37,0-49.5%). In the heterogeneity cohort target miRNAs showed a systematic gradient
Su2024 Neutrophil-Lymphocyte Ratio During Chemoradiation Predicts Pathologic Tumor Response for Rectal Cancer Patients Jillian R. Gunther, Awalpreet S. Chadha, Harpreet K. Arora, Sunil Krishnan INTRODUCTION: The current standard of care for locally advanced rectal cancer (LARC) includes preoperative chemoradiation (CRT) followed by surgical resection. There is much interest in predicting patient response to CRT early on to allow for risk-adapted strategies and/or possible avoidance of morbid treatments. Recently the immune system has been
AGA Abstracts
X : 10052$CH01 03-28-16 00:57:27 PDFd : 10052B : e
S-614
Page 614