- Email: [email protected]
307 Novel Methylated DNA Markers for the Detection of Colorectal Neoplasia in Lynch Syndrome
of developing EAC. Analyses are underway on larger groups of patients to further improve the tool's accuracy.
accurate detection of LS-CRN (adenoma (AD) and adenocarcinoma (ACA)) and to determine if they are comparably discriminant for detection of sporadic CRN. Methods: For discovery, we evaluated 54 paraffin-embedded tissues from LS patients (18 normal mucosa, 18 AD >1cm, and 18 ACA). Differentially methylated regions were identified using an unbiased whole methylome method (reduced representation bisulfite sequencing (RRBS)) based on background methylation, fold change between CRN and normal mucosa, and area under the ROC curve (AUC). Top candidate MDMs from this RRBS on LS tissues and selected MDMs from a previous RRBS on sporadic tissues underwent subsequent biological validation. For validation, blinded methylation-specific PCR assays were performed on DNA extracted from 200 paraffin-embedded tissues (103 LS (26 normal mucosa, 46 AD, 31 ACA) and 115 sporadic (35 normal mucosa, 44 AD, 36 ACA)). AUC was calculated for each MDM by nominal logistic regression. Results: Discovery Phase: We selected 9 MDMs that met selection criteria from LS-RRBS and 12 MDMs from a prior discovery effort on sporadic CRN to carry forward to biological validation. Validation Phase: Median age in LS was 55 (range 19-94) and in sporadic patients 67 (32-93); 55% and 46%, respectively, were women (p=0.2). The 10 MDMs most discriminant for LS-CRN were selected, and their performance in LS was compared to that in sporadic tissues (Table). These MDMs were highly discriminant for sporadic AD, sporadic ACA, and LS-ACA, but many were less so for LS-AD. OPLAH was distinguished as the most discriminant MDM across all LS and sporadic CRNs with AUCs exceeding 0.97 for both AD and ACA in each group. Plots of OPLAH distributions from both LS and sporadic groups demonstrate this high degree of discrimination (Figure). At 100% specificity, sensitivity of OPLAH for AD was 85% in LS and 97% in sporadic patients (p=0.13) and for ACA was 96% and 97%, respectively (p=1.0). At 100% specificity, sensitivity of a MDM panel for AD was 95% (38/40) in LS and 97% (37/38) in sporadic groups (p= 1.0) and sensitivity for ACA was 100% (27/27) and 100% (36/36), respectively (p=1.0). Conclusion: Highly discriminant MDMs and MDM panels for LS-CRN were identified. Such markers applied to stool or other media have potential value in detection of LS-CRN. Performance Comparison of Top Discriminate Markers for the Detection of Lynch Associated CRN (AUC data shown)
AGA Abstracts
306 Circulating microRNA192 in Combination With CA19-9 in Serum Predicts Tumour Stage and Aggressiveness Prior to Surgery and Can Be Used As NonInvasive Prognostic Biomarker in Periampullary Carcinoma Murali M. Kuruva, Yesaswini Komaragiri Venkata Sri Raja Rajeswari, HVV Murthy, G. V. Rao, Pradeep Rebala, Nageshwar D. Reddy, Rupjyoti Talukdar, Mitnala Sasikala Background: Prognosis of pancreatobiliary subtype of periampullary carcinoma (PAC) is poor, although clinical presentation and treatment options for PAC subtypes are similar. Recent studies demonstrated clinical utility of circulating miRNAs as non-invasive biomarkers for early diagnosis/prognosis of human cancers. Specific objectives of this study were to a) evaluate the expression of circulating miRNA that were found to be differentially expressed in PAC tumor tissues b) test the importance of identified miRNAs independently or in combination with serum CA19-9 to identify a prognostic biomarker for PAC. Methods: Tumor tissue, adjacent normal tissue and whole blood from 109 PAC patients undergoing pancreaticoduodenectomy for resectable periampullary tumors and whole blood from 92 healthy volunteers were obtained after taking informed consent following the principles of declaration of Helsinki. The study followed Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) guidelines. Nine miRNAs (miR-31,375, 192, 196a, 215, 194, 203, 130b and 217) that were earlier reported to be differentially expressed in PAC tumors were evaluated in tissue and plasma by qRT-PCR. Post CBD stenting serum CA19-9 levels were estimated by electro chemiluminiscence method. Statistical analysis was performed using ROC, logistic regression, Kaplan -Meier survival curve and Cox proportional - hazard regression for individual miRNAs and in combination with CA19-9 to identify a better prognostic biomarker. Results: Among the nine miRNAs which showed differential expression in PAC tumors, five miRNAs (miR 375, 31, 192,196a and 194) showed differential expression in circulation.miRNA192 levels were significantly increased both in circulation and in tumor tissue (r=0.96, P<0.0001) in comparison to controls. Such an increase correlated with tumor stage and tumor aggressiveness (perineural invasion and lymphovascular embolization). Area under the curve (AUC) of circulating miRNA 192 + CA19-9 combination was 0.88(95% CI, 0.78 to 0.98) for tumor stage III and was 0.90 (95% CI, 0.77 to 1.00) for tumor aggressiveness. Higher circulating levels of miR192 (3.97±1.02 fold increase) and increased CA19-9 in serum (64.5 ± 33.7units/L);(Figure 1) correlated significantly with poor survival in stage III patients (median: 22 months, P=0.0008, log-rank test) in comparison to lower levels of circulating miRNA 192 (1.28±0.54 fold increase) and serum CA19-9 (24.8 ± 5.03units/L) in stage I &II PAC patients with 36 months median survival ( P=0.11, log-rank test).Cox-proportional regression analysis revealed the prognostic importance of determining circulating miR192 and CA19-9 in combination (HR=1.005, P=0.0001) for PAC (Figure 2). Conclusion: Circulating miRNA192 in combination with serum CA19-9 can be a better non invasive prognostic indicator of stage III PAC and survival
miRNA192 and CA19-9 levels in stage I,II,III of PAC patients
Marker distributions of methylated OPLAH in normal and neoplastic tissues from Lynch and sporadic patients (PCR product copies normalized to beta-actin)
Combination of miR192 and CA19-9 predicts survival in PAC patients
307 308 Novel Methylated DNA Markers for the Detection of Colorectal Neoplasia in Lynch Syndrome Veroushka Ballester, Bradley W. Anderson, Tracy C. Yab, William R. Taylor, Calise K. Berger, Patrick H. Foote, John B. Kisiel, Douglas W. Mahoney, Seth W. Slettedahl, Lisa A. Boardman, Thomas Smyrk, Graham P. Lidgard, David A. Ahlquist
The Impact of a Value-Based Health Care in Inflammatory Bowel Diseases on Health Care Utilization Welmoed K. van Deen, Martha Skup, Adriana Centeno, Natalie E. Duran, Precious Lacey, Darius Jatulis, Eric Esrailian, Martijn G. van Oijen, Daniel Hommes
Background: Molecular methods have potential application to detection of neoplasia in Lynch Syndrome (LS). Methylated DNA markers (MDMs) optimized for the detection of sporadic colorectal neoplasia (CRN) have generally been less discriminant for LS-CRN, especially for LS-adenomas, suggesting biological differences in neoplasm progression between groups. Better somatic markers for LS-CRN detection are needed. Specific discovery of MDMs for LS-CRN has not been reported. Aim: To identify and validate MDMs for
Background Value-based health care (VBHC) is thought to be the solution to solve the cost crisis. Care coordination in combination with continuous measurement of outcomes and costs are main components of VBHC. Despite the fact that many institutions have implemented key elements of VBHC, the scientific evidence for VBHC is still limited. In this study we evaluated the performance of a VBHC program specifically designed for inflammatory bowel diseases (IBD) management, in the first year after implementation. Care coordination, task differentiation, and remote patient monitoring were the key-components of this program.
AGA Abstracts
S-70
accurate detection of LS-CRN (adenoma (AD) and adenocarcinoma (ACA)) and to determine if they are comparably discriminant for detection of sporadic CRN. Methods: For discovery, we evaluated 54 paraffin-embedded tissues from LS patients (18 normal mucosa, 18 AD >1cm, and 18 ACA). Differentially methylated regions were identified using an unbiased whole methylome method (reduced representation bisulfite sequencing (RRBS)) based on background methylation, fold change between CRN and normal mucosa, and area under the ROC curve (AUC). Top candidate MDMs from this RRBS on LS tissues and selected MDMs from a previous RRBS on sporadic tissues underwent subsequent biological validation. For validation, blinded methylation-specific PCR assays were performed on DNA extracted from 200 paraffin-embedded tissues (103 LS (26 normal mucosa, 46 AD, 31 ACA) and 115 sporadic (35 normal mucosa, 44 AD, 36 ACA)). AUC was calculated for each MDM by nominal logistic regression. Results: Discovery Phase: We selected 9 MDMs that met selection criteria from LS-RRBS and 12 MDMs from a prior discovery effort on sporadic CRN to carry forward to biological validation. Validation Phase: Median age in LS was 55 (range 19-94) and in sporadic patients 67 (32-93); 55% and 46%, respectively, were women (p=0.2). The 10 MDMs most discriminant for LS-CRN were selected, and their performance in LS was compared to that in sporadic tissues (Table). These MDMs were highly discriminant for sporadic AD, sporadic ACA, and LS-ACA, but many were less so for LS-AD. OPLAH was distinguished as the most discriminant MDM across all LS and sporadic CRNs with AUCs exceeding 0.97 for both AD and ACA in each group. Plots of OPLAH distributions from both LS and sporadic groups demonstrate this high degree of discrimination (Figure). At 100% specificity, sensitivity of OPLAH for AD was 85% in LS and 97% in sporadic patients (p=0.13) and for ACA was 96% and 97%, respectively (p=1.0). At 100% specificity, sensitivity of a MDM panel for AD was 95% (38/40) in LS and 97% (37/38) in sporadic groups (p= 1.0) and sensitivity for ACA was 100% (27/27) and 100% (36/36), respectively (p=1.0). Conclusion: Highly discriminant MDMs and MDM panels for LS-CRN were identified. Such markers applied to stool or other media have potential value in detection of LS-CRN. Performance Comparison of Top Discriminate Markers for the Detection of Lynch Associated CRN (AUC data shown)
AGA Abstracts
306 Circulating microRNA192 in Combination With CA19-9 in Serum Predicts Tumour Stage and Aggressiveness Prior to Surgery and Can Be Used As NonInvasive Prognostic Biomarker in Periampullary Carcinoma Murali M. Kuruva, Yesaswini Komaragiri Venkata Sri Raja Rajeswari, HVV Murthy, G. V. Rao, Pradeep Rebala, Nageshwar D. Reddy, Rupjyoti Talukdar, Mitnala Sasikala Background: Prognosis of pancreatobiliary subtype of periampullary carcinoma (PAC) is poor, although clinical presentation and treatment options for PAC subtypes are similar. Recent studies demonstrated clinical utility of circulating miRNAs as non-invasive biomarkers for early diagnosis/prognosis of human cancers. Specific objectives of this study were to a) evaluate the expression of circulating miRNA that were found to be differentially expressed in PAC tumor tissues b) test the importance of identified miRNAs independently or in combination with serum CA19-9 to identify a prognostic biomarker for PAC. Methods: Tumor tissue, adjacent normal tissue and whole blood from 109 PAC patients undergoing pancreaticoduodenectomy for resectable periampullary tumors and whole blood from 92 healthy volunteers were obtained after taking informed consent following the principles of declaration of Helsinki. The study followed Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) guidelines. Nine miRNAs (miR-31,375, 192, 196a, 215, 194, 203, 130b and 217) that were earlier reported to be differentially expressed in PAC tumors were evaluated in tissue and plasma by qRT-PCR. Post CBD stenting serum CA19-9 levels were estimated by electro chemiluminiscence method. Statistical analysis was performed using ROC, logistic regression, Kaplan -Meier survival curve and Cox proportional - hazard regression for individual miRNAs and in combination with CA19-9 to identify a better prognostic biomarker. Results: Among the nine miRNAs which showed differential expression in PAC tumors, five miRNAs (miR 375, 31, 192,196a and 194) showed differential expression in circulation.miRNA192 levels were significantly increased both in circulation and in tumor tissue (r=0.96, P<0.0001) in comparison to controls. Such an increase correlated with tumor stage and tumor aggressiveness (perineural invasion and lymphovascular embolization). Area under the curve (AUC) of circulating miRNA 192 + CA19-9 combination was 0.88(95% CI, 0.78 to 0.98) for tumor stage III and was 0.90 (95% CI, 0.77 to 1.00) for tumor aggressiveness. Higher circulating levels of miR192 (3.97±1.02 fold increase) and increased CA19-9 in serum (64.5 ± 33.7units/L);(Figure 1) correlated significantly with poor survival in stage III patients (median: 22 months, P=0.0008, log-rank test) in comparison to lower levels of circulating miRNA 192 (1.28±0.54 fold increase) and serum CA19-9 (24.8 ± 5.03units/L) in stage I &II PAC patients with 36 months median survival ( P=0.11, log-rank test).Cox-proportional regression analysis revealed the prognostic importance of determining circulating miR192 and CA19-9 in combination (HR=1.005, P=0.0001) for PAC (Figure 2). Conclusion: Circulating miRNA192 in combination with serum CA19-9 can be a better non invasive prognostic indicator of stage III PAC and survival
miRNA192 and CA19-9 levels in stage I,II,III of PAC patients
Marker distributions of methylated OPLAH in normal and neoplastic tissues from Lynch and sporadic patients (PCR product copies normalized to beta-actin)
Combination of miR192 and CA19-9 predicts survival in PAC patients
307 308 Novel Methylated DNA Markers for the Detection of Colorectal Neoplasia in Lynch Syndrome Veroushka Ballester, Bradley W. Anderson, Tracy C. Yab, William R. Taylor, Calise K. Berger, Patrick H. Foote, John B. Kisiel, Douglas W. Mahoney, Seth W. Slettedahl, Lisa A. Boardman, Thomas Smyrk, Graham P. Lidgard, David A. Ahlquist
The Impact of a Value-Based Health Care in Inflammatory Bowel Diseases on Health Care Utilization Welmoed K. van Deen, Martha Skup, Adriana Centeno, Natalie E. Duran, Precious Lacey, Darius Jatulis, Eric Esrailian, Martijn G. van Oijen, Daniel Hommes
Background: Molecular methods have potential application to detection of neoplasia in Lynch Syndrome (LS). Methylated DNA markers (MDMs) optimized for the detection of sporadic colorectal neoplasia (CRN) have generally been less discriminant for LS-CRN, especially for LS-adenomas, suggesting biological differences in neoplasm progression between groups. Better somatic markers for LS-CRN detection are needed. Specific discovery of MDMs for LS-CRN has not been reported. Aim: To identify and validate MDMs for
Background Value-based health care (VBHC) is thought to be the solution to solve the cost crisis. Care coordination in combination with continuous measurement of outcomes and costs are main components of VBHC. Despite the fact that many institutions have implemented key elements of VBHC, the scientific evidence for VBHC is still limited. In this study we evaluated the performance of a VBHC program specifically designed for inflammatory bowel diseases (IBD) management, in the first year after implementation. Care coordination, task differentiation, and remote patient monitoring were the key-components of this program.
AGA Abstracts
S-70