Ction between ampullary and pancreatic adenocarcinomas. More importantly, our gene expression and proteomic analysis identified two prognostically relevant subgroups of ampullary adenocarcinomas that can be histologically categorized as either intestinal-like or pancreaticobiliary-like ampullary subtypes. Univariate and multivariate analysis of an independent validation cohort demonstrated that histologic subtype is an independent prognostic factor in patients with ampullary adenocarcinoma. Patients with intestinal subtype of ampullary adenocarcinoma have better OS than those with pancreaticobiliary subtype, which is characterized by the activaGene Profiling of Periampullary CarcinomasTable 1. Patient and Tumor Characteristics of Ampullary Validation Dataset.Table 2. Univariate and Multivariate Analysis of Factors Associated with Overall Survival.Intestinal Pt. No. Histological subtype 24Pancreaticobiliary Pt. No. 32 63 (28?3) 11 34Mixed Pt. No. 24 AgeUnivariate HR 95 CIMultivariate P-value HR 95 CI 0.84 0.51 0.05 0.46 0.51 0.95 0.007 0.7 0.71 2.09 1.03?.27 0.04 1.94 0.66?.71 0.23 P-value1.00 0.98?.Poorly Differentiated 0.72 0.27?.9 T3/T4 2.74 0.99?.Median age, years (range) 66 (30?7) Female gender T Stage T1 T2 T3 T4 N Stage N0 N1 Differentiation Well Moderate Poor Margin Status R0 R1 Mucinous Ampullary adenoma Adjuvant Treatment Systemic Chemotherapy 5 Radiation Therapy CDX-2+ CK7+/CK202 5 14 8 21 21 58 33 24 0 0 17 100 0 0 71 5 13 6 21 54 25 19 5 79 21 10 14 0 0 42 58 0 0 1264 (37?7) 11Lymph Node Positive 1.28 0.67?.44 Positive Margins 1.63 0.38?.93 1.02 0.52?.99 2.47 1.28?.79 1.14 0.59?.21 1.14 0.58?.2 9 196 28 594 8 1117 33 46Adjuvant Treatment Pancreaticobiliary Subtype CDX-2 Positive CK7+/CK8251146doi:10.1371/journal.pone.0065144.t3 149 440 160 6728 4 288 13 623 1 196 4 419 17 959 53 2812 10 950 42 38doi:10.1371/journal.pone.0065144.ttion of several targetable pathways. Thus our findings support both the biological and clinical significance of classifying ampullary adenocarcinomas into two distinct subtypes, and suggest potential subtype-specific therapeutic strategies. In this study, the samples selected for gene expression and proteomic analysis were required to meet strict inclusion criteria to minimize any impact of cancer misclassification and dilution of 23148522 results through inclusion of non-carcinoma tissue. By classifying the ampullary carcinomas samples as unknowns and MedChemExpress SIS 3 comparing them to pathologically verified duodenal, biliary and pancreatic carcinoma samples, we have attempted to molecularly characterize the epithelium of origin of the histologically diverse ampullary adenocarcinomas. Our gene expression array data clearly show that ampullary adenocarcinomas have a different gene expression profile 79983-71-4 compared to pancreatic adenocarcinomas. Thus, our data suggests that ampullary adenocarcinomas do not arise from the ampullo-pancreatic ductal epithelial cells in the ampulla of Vater. Though our study was limited by the presence of only two extrahepatic biliary cases, these cases grouped with our ampullary samples that displayed a pancreaticobiliary morphology. As our ampullary and pancreatic adenocarcinomas were clearly distinct, we feel this group is 1676428 best classified as a biliary-like subgroup of ampullary adenocarcinoma.As post-translational modifications can lead to marked discordance between mRNA levels and protein function [29,30], we directly examined the expression of proteins and phospho-proteins in a number of kno.Ction between ampullary and pancreatic adenocarcinomas. More importantly, our gene expression and proteomic analysis identified two prognostically relevant subgroups of ampullary adenocarcinomas that can be histologically categorized as either intestinal-like or pancreaticobiliary-like ampullary subtypes. Univariate and multivariate analysis of an independent validation cohort demonstrated that histologic subtype is an independent prognostic factor in patients with ampullary adenocarcinoma. Patients with intestinal subtype of ampullary adenocarcinoma have better OS than those with pancreaticobiliary subtype, which is characterized by the activaGene Profiling of Periampullary CarcinomasTable 1. Patient and Tumor Characteristics of Ampullary Validation Dataset.Table 2. Univariate and Multivariate Analysis of Factors Associated with Overall Survival.Intestinal Pt. No. Histological subtype 24Pancreaticobiliary Pt. No. 32 63 (28?3) 11 34Mixed Pt. No. 24 AgeUnivariate HR 95 CIMultivariate P-value HR 95 CI 0.84 0.51 0.05 0.46 0.51 0.95 0.007 0.7 0.71 2.09 1.03?.27 0.04 1.94 0.66?.71 0.23 P-value1.00 0.98?.Poorly Differentiated 0.72 0.27?.9 T3/T4 2.74 0.99?.Median age, years (range) 66 (30?7) Female gender T Stage T1 T2 T3 T4 N Stage N0 N1 Differentiation Well Moderate Poor Margin Status R0 R1 Mucinous Ampullary adenoma Adjuvant Treatment Systemic Chemotherapy 5 Radiation Therapy CDX-2+ CK7+/CK202 5 14 8 21 21 58 33 24 0 0 17 100 0 0 71 5 13 6 21 54 25 19 5 79 21 10 14 0 0 42 58 0 0 1264 (37?7) 11Lymph Node Positive 1.28 0.67?.44 Positive Margins 1.63 0.38?.93 1.02 0.52?.99 2.47 1.28?.79 1.14 0.59?.21 1.14 0.58?.2 9 196 28 594 8 1117 33 46Adjuvant Treatment Pancreaticobiliary Subtype CDX-2 Positive CK7+/CK8251146doi:10.1371/journal.pone.0065144.t3 149 440 160 6728 4 288 13 623 1 196 4 419 17 959 53 2812 10 950 42 38doi:10.1371/journal.pone.0065144.ttion of several targetable pathways. Thus our findings support both the biological and clinical significance of classifying ampullary adenocarcinomas into two distinct subtypes, and suggest potential subtype-specific therapeutic strategies. In this study, the samples selected for gene expression and proteomic analysis were required to meet strict inclusion criteria to minimize any impact of cancer misclassification and dilution of 23148522 results through inclusion of non-carcinoma tissue. By classifying the ampullary carcinomas samples as unknowns and comparing them to pathologically verified duodenal, biliary and pancreatic carcinoma samples, we have attempted to molecularly characterize the epithelium of origin of the histologically diverse ampullary adenocarcinomas. Our gene expression array data clearly show that ampullary adenocarcinomas have a different gene expression profile compared to pancreatic adenocarcinomas. Thus, our data suggests that ampullary adenocarcinomas do not arise from the ampullo-pancreatic ductal epithelial cells in the ampulla of Vater. Though our study was limited by the presence of only two extrahepatic biliary cases, these cases grouped with our ampullary samples that displayed a pancreaticobiliary morphology. As our ampullary and pancreatic adenocarcinomas were clearly distinct, we feel this group is 1676428 best classified as a biliary-like subgroup of ampullary adenocarcinoma.As post-translational modifications can lead to marked discordance between mRNA levels and protein function [29,30], we directly examined the expression of proteins and phospho-proteins in a number of kno.
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