167 results on '"Marsha L. Frazier"'
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2. Video 3 from DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF-β–Driven Epithelial–Mesenchymal Transition
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Ann McNeill Killary, Steven T. Lott, Subrata Sen, Ignacio I. Wistuba, Aysegul A. Sahin, Marsha L. Frazier, Jinyun Chen, Erica Lokken, Yu Cao, Guillermina Lozano, Jaime Rodriguez, Asif Rashid, Lynne V. Abruzzo, Dawn S. Chandler, Ying Wang, Aileen Frayna, Jacquelyn Reuther, Seetharaman Balasenthil, and Nanyue Chen
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Video 3 - MP4 file 3352K, DEAR1-shRNA clone without TGF-beta
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- 2023
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3. Data from DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF-β–Driven Epithelial–Mesenchymal Transition
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Ann McNeill Killary, Steven T. Lott, Subrata Sen, Ignacio I. Wistuba, Aysegul A. Sahin, Marsha L. Frazier, Jinyun Chen, Erica Lokken, Yu Cao, Guillermina Lozano, Jaime Rodriguez, Asif Rashid, Lynne V. Abruzzo, Dawn S. Chandler, Ying Wang, Aileen Frayna, Jacquelyn Reuther, Seetharaman Balasenthil, and Nanyue Chen
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Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation, and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum, with both Dear1−/− and Dear1+/− mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice. DEAR1 loss of function in the presence of TGF-β results in failure of acinar morphogenesis, upregulation of epithelial–mesenchymal transition (EMT) markers, anoikis resistance, migration, and invasion. Furthermore, DEAR1 blocks TGF-β–SMAD3 signaling, resulting in decreased nuclear phosphorylated SMAD3 by binding to and promoting the ubiquitination of SMAD3, the major effector of TGF-β–induced EMT. Moreover, DEAR1 loss increases levels of SMAD3 downstream effectors SNAIL1 and SNAIL2, with genetic alteration of DEAR1/SNAIL2 serving as prognostic markers of overall poor survival in a cohort of 889 cases of invasive breast cancer.Significance: Cumulative results provide compelling evidence that DEAR1 is a critical tumor suppressor involved in multiple human cancers and provide a novel paradigm for regulation of TGF-β–induced EMT through DEAR1′s regulation of SMAD3 protein levels. DEAR1 loss of function has important therapeutic implications for targeted therapies aimed at the TGF-β–SMAD3 pathway. Cancer Discov; 3(10); 1172–89. ©2013 AACR.This article is highlighted in the In This Issue feature, p. 1083
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- 2023
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4. Supplementary Figure 1 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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Ann McNeill Killary, Subrata Sen, Marsha L. Frazier, William E. Grizzle, Jennifer Carter, Jinyun Chen, Steven T. Lott, Nanyue Chen, and Seetharaman Balasenthil
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Supplementary Figure 1 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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- 2023
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5. Video 1 from DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF-β–Driven Epithelial–Mesenchymal Transition
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Ann McNeill Killary, Steven T. Lott, Subrata Sen, Ignacio I. Wistuba, Aysegul A. Sahin, Marsha L. Frazier, Jinyun Chen, Erica Lokken, Yu Cao, Guillermina Lozano, Jaime Rodriguez, Asif Rashid, Lynne V. Abruzzo, Dawn S. Chandler, Ying Wang, Aileen Frayna, Jacquelyn Reuther, Seetharaman Balasenthil, and Nanyue Chen
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Video 1 - MP4 file 3450K, Control shRNA clone without TGF-beta
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- 2023
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6. Supplementary Table 1 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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Ann McNeill Killary, Subrata Sen, Marsha L. Frazier, William E. Grizzle, Jennifer Carter, Jinyun Chen, Steven T. Lott, Nanyue Chen, and Seetharaman Balasenthil
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Supplementary Table 1 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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- 2023
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7. Supplementary Table 2 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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Ann McNeill Killary, Subrata Sen, Marsha L. Frazier, William E. Grizzle, Jennifer Carter, Jinyun Chen, Steven T. Lott, Nanyue Chen, and Seetharaman Balasenthil
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Supplementary Table 2 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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- 2023
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8. Supplementary Materials from DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF-β–Driven Epithelial–Mesenchymal Transition
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Ann McNeill Killary, Steven T. Lott, Subrata Sen, Ignacio I. Wistuba, Aysegul A. Sahin, Marsha L. Frazier, Jinyun Chen, Erica Lokken, Yu Cao, Guillermina Lozano, Jaime Rodriguez, Asif Rashid, Lynne V. Abruzzo, Dawn S. Chandler, Ying Wang, Aileen Frayna, Jacquelyn Reuther, Seetharaman Balasenthil, and Nanyue Chen
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Supplementary Materials - PDF file 3317K, Including supplementary methods, supplementary figures and legends, and supplementary tables
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- 2023
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9. Supplementary Figure 2 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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Ann McNeill Killary, Subrata Sen, Marsha L. Frazier, William E. Grizzle, Jennifer Carter, Jinyun Chen, Steven T. Lott, Nanyue Chen, and Seetharaman Balasenthil
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Supplementary Figure 2 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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- 2023
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10. Supplementary Table 3 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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Ann McNeill Killary, Subrata Sen, Marsha L. Frazier, William E. Grizzle, Jennifer Carter, Jinyun Chen, Steven T. Lott, Nanyue Chen, and Seetharaman Balasenthil
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Supplementary Table 3 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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- 2023
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11. Supplementary Figure Legends 1-4 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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Ann McNeill Killary, Subrata Sen, Marsha L. Frazier, William E. Grizzle, Jennifer Carter, Jinyun Chen, Steven T. Lott, Nanyue Chen, and Seetharaman Balasenthil
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Supplementary Figure Legends 1-4 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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- 2023
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12. Video 2 from DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF-β–Driven Epithelial–Mesenchymal Transition
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Ann McNeill Killary, Steven T. Lott, Subrata Sen, Ignacio I. Wistuba, Aysegul A. Sahin, Marsha L. Frazier, Jinyun Chen, Erica Lokken, Yu Cao, Guillermina Lozano, Jaime Rodriguez, Asif Rashid, Lynne V. Abruzzo, Dawn S. Chandler, Ying Wang, Aileen Frayna, Jacquelyn Reuther, Seetharaman Balasenthil, and Nanyue Chen
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Video 2 - MP4 file 3383K, Control shRNA clone with 2ng/ml TGF-beta
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- 2023
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13. Supplementary Figure 3 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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Ann McNeill Killary, Subrata Sen, Marsha L. Frazier, William E. Grizzle, Jennifer Carter, Jinyun Chen, Steven T. Lott, Nanyue Chen, and Seetharaman Balasenthil
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Supplementary Figure 3 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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- 2023
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14. Supplementary Table 4 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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Ann McNeill Killary, Subrata Sen, Marsha L. Frazier, William E. Grizzle, Jennifer Carter, Jinyun Chen, Steven T. Lott, Nanyue Chen, and Seetharaman Balasenthil
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Supplementary Table 4 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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- 2023
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15. Supplementary Figure 4 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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Ann McNeill Killary, Subrata Sen, Marsha L. Frazier, William E. Grizzle, Jennifer Carter, Jinyun Chen, Steven T. Lott, Nanyue Chen, and Seetharaman Balasenthil
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Supplementary Figure 4 from A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma
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- 2023
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16. Supplementary Figure 1 from Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
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Christopher I. Amos, John K. Wiencke, Ann G. Schwartz, Margaret R. Wrensch, Paige M. Bracci, Laura J. Bierut, Michael F. Seldin, Marsha L. Frazier, Wei Chen, Stacy M. Lloyd, Chongjuan Wei, Jennette D. Sison, Angela S. Wenzlaff, Emily Y. Lu, Huifeng Zhang, Margaret R. Spitz, Xifeng Wu, Helen M. Hansen, Ivan P. Gorlov, and Kyle M. Walsh
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PDF file - 926K, Triangle plot showing estimated admixture in the African-American case-control population. Estimates were performed using 102 AIMs and data from the International HapMap Project on 167 Yoruban African (Green dots), 165 European (Red dots), 84 Chinese (Yellow dots) and 86 Japanese (Dark Blue dots) founders. The figure depicts ancestry in 1308 African-American lung cancer cases (Pink dots) and 1241 controls (Light Blue dots).
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- 2023
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17. Supplementary Table 1 from Circulation of Progenitor Cells in Obese and Lean Colorectal Cancer Patients
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Mikhail G. Kolonin, Marsha L. Frazier, Jinyun Chen, Yan Zhang, and Charles F. Bellows
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PDF file - 53K
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- 2023
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18. Supplementary Figure 2 from Circulation of Progenitor Cells in Obese and Lean Colorectal Cancer Patients
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Mikhail G. Kolonin, Marsha L. Frazier, Jinyun Chen, Yan Zhang, and Charles F. Bellows
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PDF file - 102K
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- 2023
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19. Supplementary Table 1 from Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
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Christopher I. Amos, John K. Wiencke, Ann G. Schwartz, Margaret R. Wrensch, Paige M. Bracci, Laura J. Bierut, Michael F. Seldin, Marsha L. Frazier, Wei Chen, Stacy M. Lloyd, Chongjuan Wei, Jennette D. Sison, Angela S. Wenzlaff, Emily Y. Lu, Huifeng Zhang, Margaret R. Spitz, Xifeng Wu, Helen M. Hansen, Ivan P. Gorlov, and Kyle M. Walsh
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PDF file - 67K, Imputed SNP associations from the case-control analysis of lung cancer (by histology) in African-Americans (P
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- 2023
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20. Supplementary Figure 2 from Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
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Christopher I. Amos, John K. Wiencke, Ann G. Schwartz, Margaret R. Wrensch, Paige M. Bracci, Laura J. Bierut, Michael F. Seldin, Marsha L. Frazier, Wei Chen, Stacy M. Lloyd, Chongjuan Wei, Jennette D. Sison, Angela S. Wenzlaff, Emily Y. Lu, Huifeng Zhang, Margaret R. Spitz, Xifeng Wu, Helen M. Hansen, Ivan P. Gorlov, and Kyle M. Walsh
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PDF file - 561K, Association of SNPs on chromosome 15q25.1 with lung cancer, with and without adjustment for missense variant rs16969968. Black circles depict association of SNPs with lung cancer, adjusted for sex, age, study site, % African ancestry, % European ancestry, and number of pack-years smoked. Open squares depict association of SNPs with lung cancer, adjusted for sex, age, study site, and % African ancestry, % European ancestry, number of pack-years smoked, AND conditioned on rs16969968 (marked with an X).
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- 2023
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21. Data from Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
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Christopher I. Amos, John K. Wiencke, Ann G. Schwartz, Margaret R. Wrensch, Paige M. Bracci, Laura J. Bierut, Michael F. Seldin, Marsha L. Frazier, Wei Chen, Stacy M. Lloyd, Chongjuan Wei, Jennette D. Sison, Angela S. Wenzlaff, Emily Y. Lu, Huifeng Zhang, Margaret R. Spitz, Xifeng Wu, Helen M. Hansen, Ivan P. Gorlov, and Kyle M. Walsh
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Background: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans.Methods: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.Results: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25–1.97; P, 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48–0.85; P, 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73–0.93; P, 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65–0.86; P, 8.1 × 10−5).Conclusions: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma.Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies. Cancer Epidemiol Biomarkers Prev; 22(2); 251–60. ©2012 AACR.
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- 2023
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22. Supplementary Figure 3 from Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
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Christopher I. Amos, John K. Wiencke, Ann G. Schwartz, Margaret R. Wrensch, Paige M. Bracci, Laura J. Bierut, Michael F. Seldin, Marsha L. Frazier, Wei Chen, Stacy M. Lloyd, Chongjuan Wei, Jennette D. Sison, Angela S. Wenzlaff, Emily Y. Lu, Huifeng Zhang, Margaret R. Spitz, Xifeng Wu, Helen M. Hansen, Ivan P. Gorlov, and Kyle M. Walsh
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PDF file - 559K, Association of SNPs on chromosome 15q25.1 with lung cancer, with and without adjustment for pack-years smoked. Black circles depict association of SNPs with lung cancer, adjusted for sex, age, study site, % African ancestry, % European ancestry, and number of pack-years smoked. Open squares depict association of SNPs with lung cancer, adjusted for sex, age, study site, and % African ancestry, % European ancestry, but NOT number of pack-years smoked.
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- 2023
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23. Supplementary Figure 1 from Circulation of Progenitor Cells in Obese and Lean Colorectal Cancer Patients
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Mikhail G. Kolonin, Marsha L. Frazier, Jinyun Chen, Yan Zhang, and Charles F. Bellows
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PDF file - 123K
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- 2023
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24. Supplementary Figure Legend from Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
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Christopher I. Amos, John K. Wiencke, Ann G. Schwartz, Margaret R. Wrensch, Paige M. Bracci, Laura J. Bierut, Michael F. Seldin, Marsha L. Frazier, Wei Chen, Stacy M. Lloyd, Chongjuan Wei, Jennette D. Sison, Angela S. Wenzlaff, Emily Y. Lu, Huifeng Zhang, Margaret R. Spitz, Xifeng Wu, Helen M. Hansen, Ivan P. Gorlov, and Kyle M. Walsh
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PDF file - 57K
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- 2023
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25. Data from Circulation of Progenitor Cells in Obese and Lean Colorectal Cancer Patients
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Mikhail G. Kolonin, Marsha L. Frazier, Jinyun Chen, Yan Zhang, and Charles F. Bellows
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Background: Colorectal cancer (CRC) is a common life-threatening malignancy; risk and progression are elevated in obesity. The purpose of this study was to measure the frequency of circulating CD34-positive endothelial and progenitor cells in the circulation and evaluate their potential values as CRC biomarkers.Methods: Blood was collected from 45 patients with CRC and compared with cancer-free control donors. Detection and enumeration of cells was carried out by flow cytometry on the basis of immunophenotypes established for the cell populations of interest: hematopoietic and endothelial circulating progenitor cells, endothelial cells, mesenchymal stromal cells (MSC), and CD34bright leukocytes (CD34b LC). Groups were compared using multivariate regression analysis. Receiver-operating characteristic (ROC) curve analysis was used to evaluate the diagnostic values.Results: After adjusting for age and body mass index (BMI), the mean frequencies of MSCs and CD34b LCs were significantly higher in the circulation of patients with CRC than in controls. The areas under the ROC curve were 0.77 and 0.82 for MSCs and CD34b LCs, respectively. The frequency of circulating MSCs, but not of the other cell populations, was also found to be significantly higher in the circulation of obese patients with CRC (BMI ≥ 30 kg/m2) than in lean patients with CRC and obese controls.Conclusions: Increased frequency of MSCs and CD34b LCs in the peripheral blood may represent a new diagnostic marker for CRC.Impact: BMI-dependent changes in circulating MSCs, potentially mobilized from white adipose tissue may reveal their trafficking to tumors, which could be one of the mechanistic links between obesity and cancer progression. Cancer Epidemiol Biomarkers Prev; 20(11); 2461–8. ©2011 AACR.
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- 2023
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26. SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions.
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Lei L Chen, Jing Zhu, Jonathan Schumacher, Chongjuan Wei, Latha Ramdas, Victor G Prieto, Arnie Jimenez, Marco A Velasco, Sheryl R Tripp, Robert H I Andtbacka, Launce Gouw, George M Rodgers, Liansheng Zhang, Benjamin K Chan, Pamela B Cassidy, Robert S Benjamin, Sancy A Leachman, and Marsha L Frazier
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Medicine ,Science - Abstract
We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.
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- 2017
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27. Identification of genetic variants predictive of early onset pancreatic cancer through a population science analysis of functional genomic datasets
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Xifeng Wu, Jinyun Chen, Yu-jing Huang, Subrata Sen, Wei V. Chen, Marsha L. Frazier, Randall E. Brand, and Ann M. Killary
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0301 basic medicine ,Male ,Carcinogenesis ,pancreatic cancer ,Gene Dosage ,Cohort Studies ,0302 clinical medicine ,Risk Factors ,Enhancer binding ,Genotype ,2. Zero hunger ,Genetics ,Aged, 80 and over ,education.field_of_study ,Molecular Epidemiology ,Molecular pathology ,Genomics ,Middle Aged ,3. Good health ,Gene Expression Regulation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,age at diagnosis ,Female ,Research Paper ,genetic variant ,Adult ,medicine.medical_specialty ,Population ,Quantitative Trait Loci ,SNP ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Young Adult ,Molecular genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Aged ,Binding Sites ,business.industry ,pathway ,Cancer ,Computational Biology ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Expression quantitative trait loci ,business - Abstract
// Jinyun Chen 1 , Xifeng Wu 1, 4 , Yujing Huang 1 , Wei Chen 1 , Randall E. Brand 2 , Ann M. Killary 3, 4 , Subrata Sen 3, 4 , Marsha L. Frazier 1, 4 1 Department of Epidemiology The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA 2 Department of Gastroenterology, Hepatology, and Nutrition, The University of Pittsburgh, Pittsburgh, Pennsylvania, USA 3 Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA 4 Program in Human and Molecular Genetics, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA Correspondence to: Subrata Sen, email: ssen@mdanderson.org Ann M. Killary, email: akillary@mdanderson.org Keywords: SNP, genetic variant, age at diagnosis, pathway, pancreatic cancer Received: September 14, 2015 Accepted: January 01, 2016 Published: July 29, 2016 ABSTRACT Biomarkers are critically needed for the early detection of pancreatic cancer (PC) are urgently needed. Our purpose was to identify a panel of genetic variants that, combined, can predict increased risk for early-onset PC and thereby identify individuals who should begin screening at an early age. Previously, we identified genes using a functional genomic approach that were aberrantly expressed in early pathways to PC tumorigenesis. We now report the discovery of single nucleotide polymorphisms (SNPs) in these genes associated with early age at diagnosis of PC using a two-phase study design. In silico and bioinformatics tools were used to examine functional relevance of the identified SNPs. Eight SNPs were consistently associated with age at diagnosis in the discovery phase, validation phase and pooled analysis. Further analysis of the joint effects of these 8 SNPs showed that, compared to participants carrying none of these unfavorable genotypes (median age at PC diagnosis 70 years), those carrying 1–2, 3–4, or 5 or more unfavorable genotypes had median ages at diagnosis of 64, 63, and 62 years, respectively ( P = 3.0E–04). A gene-dosage effect was observed, with age at diagnosis inversely related to number of unfavorable genotypes ( P trend = 1.0E–04). Using bioinformatics tools, we found that all of the 8 SNPs were predicted to play functional roles in the disruption of transcription factor and/or enhancer binding sites and most of them were expression quantitative trait loci (eQTL) of the target genes. The panel of genetic markers identified may serve as susceptibility markers for earlier PC diagnosis.
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- 2016
28. CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment
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Christopher J. Logothetis, Yan Zhang, Mikhail G. Kolonin, Chieh Tseng, John M. Davis, Marsha L. Frazier, Elsa M. Li-Ning-Tapia, Olga Sirin, Curtis A. Pettaway, John M. Ward, Patricia Troncoso, Paul G. Corn, and Tao Zhang
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Male ,0301 basic medicine ,Chemokine CXCL1 ,animal diseases ,General Physics and Astronomy ,Adipose tissue ,White adipose tissue ,Receptors, Interleukin-8B ,Receptors, Interleukin-8A ,Mice ,Cell Movement ,Adipocytes ,Tumor Microenvironment ,CXC chemokine receptors ,RNA, Small Interfering ,Aged, 80 and over ,Multidisciplinary ,Neovascularization, Pathologic ,hemic and immune systems ,Middle Aged ,CXCL1 ,Disease Progression ,tissues ,Adult ,endocrine system ,Stromal cell ,Adipose Tissue, White ,Science ,Primary Cell Culture ,Mice, Nude ,Biology ,Diet, High-Fat ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Cell Line, Tumor ,Animals ,Humans ,Obesity ,Interleukin 8 ,Aged ,Tumor microenvironment ,Interleukin-8 ,Mesenchymal stem cell ,Endothelial Cells ,Prostatic Neoplasms ,Mesenchymal Stem Cells ,General Chemistry ,Xenograft Model Antitumor Assays ,Actins ,eye diseases ,Mice, Inbred C57BL ,030104 developmental biology ,Tissue Array Analysis ,Immunology ,Cancer research - Abstract
White adipose tissue (WAT) overgrowth in obesity is linked with increased aggressiveness of certain cancers. Adipose stromal cells (ASCs) can become mobilized from WAT, recruited by tumours and promote cancer progression. Mechanisms underlying ASC trafficking are unclear. Here we demonstrate that chemokines CXCL1 and CXCL8 chemoattract ASC by signalling through their receptors, CXCR1 and CXCR2, in cell culture models. We further show that obese patients with prostate cancer have increased epithelial CXCL1 expression. Concomitantly, we observe that cells with ASC phenotype are mobilized and infiltrate tumours in obese patients. Using mouse models, we show that the CXCL1 chemokine gradient is required for the obesity-dependent tumour ASC recruitment, vascularization and tumour growth promotion. We demonstrate that αSMA expression in ASCs is induced by chemokine signalling and mediates the stimulatory effects of ASCs on endothelial cells. Our data suggest that ASC recruitment to tumours, driven by CXCL1 and CXCL8, promotes prostate cancer progression., Adipose stromal cells (ASC) have been shown to migrate to tumours and promote tumour growth. Using animal models and human tissue samples, the authors show here that ASC recruitment to prostate cancers is mediated by the chemokine CXCL1, which is secreted from tumour cells, and acts on CXCR1 on ASCs.
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- 2016
29. Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers
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Marc Chaussabel, Gail E. Tomlinson, Younghun Han, Joshua Rother, Marsha L. Frazier, Chongjuan Wei, Christopher I. Amos, C. Richard Boland, Bo Peng, and Wei V. Chen
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Whole genome sequencing ,Genetics ,Cancer Research ,Mutation ,Cancer ,Chromoplexy ,Biology ,medicine.disease ,medicine.disease_cause ,Article ,Human genetics ,Prostate cancer ,Oncology ,Genetic linkage ,medicine ,Gene ,Genetics (clinical) - Abstract
We studied a large family that presented a strong familial susceptibility to multiple early onset cancers including prostate, breast, colon, and several other uncommon cancers. Through targeted gene, linkage, and whole genome sequencing analyses, we show that the presence of a variant in the regulatory region of HNRNPA0 associated with elevated cancer incidence in this family (Hazard ratio = 7.20, p = 0.0004). Whole genome sequencing identified a second rare protein changing mutation of WIF1 that interacted with the HNRNPA0 variant resulting in extremely high risk for cancer in carriers of mutations in both genes (p = 1.98 × 10–13). Analysis of downstream targets of the mutations in these two genes showed that the HNRNPA0 mutation affected expression patterns in the PI3 kinase and ERK/MAPK signaling pathways, while the WIF1 variant influenced expression of genes that play a role in NAD biosynthesis. This is a first report of variation in HNRNPA0 influencing common cancers or of a striking interaction between rare variants coexisting in an extended pedigree and jointly affecting cancer risk.
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- 2015
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30. SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions
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Launce Gouw, Sancy A. Leachman, Marco A. De Velasco, Jonathan A. Schumacher, Chongjuan Wei, Robert S. Benjamin, Marsha L. Frazier, Victor G. Prieto, George M. Rodgers, Lei L. Chen, Robert H.I. Andtbacka, Latha Ramdas, Benjamin K. Chan, Jing Zhu, Sheryl R. Tripp, Arnie Jimenez, Pamela B. Cassidy, and Liansheng Zhang
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0301 basic medicine ,Time Factors ,Physiology ,lcsh:Medicine ,Stem cell factor ,Nitric Oxide Synthase Type I ,Biochemistry ,Vascular Medicine ,Epithelium ,Enos ,Animal Cells ,Medicine and Health Sciences ,Homeostasis ,Enzyme-Linked Immunoassays ,lcsh:Science ,Melanoma ,Oligonucleotide Array Sequence Analysis ,Skin ,education.field_of_study ,Endothelin-3 ,Stem Cell Factor ,Multidisciplinary ,biology ,Chemistry ,Nitric Oxide Synthase Type III ,Neurochemistry ,Immunohistochemistry ,Receptor, Endothelin B ,Cell biology ,Up-Regulation ,Vasodilation ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Sunlight ,Melanocytes ,Signal transduction ,Anatomy ,Neurochemicals ,Cellular Types ,Signal Transduction ,Research Article ,Stromal cell ,Endothelium ,Gastrointestinal Stromal Tumors ,Myenteric Plexus ,Enzyme-Linked Immunosorbent Assay ,Nitric Oxide ,Research and Analysis Methods ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,Secretion ,Neoplasm Invasiveness ,Chromatophores ,education ,Immunoassays ,Immunohistochemistry Techniques ,lcsh:R ,Biology and Life Sciences ,Epithelial Cells ,Cell Biology ,biology.organism_classification ,Atherosclerosis ,Endothelin 3 ,Histochemistry and Cytochemistry Techniques ,030104 developmental biology ,Biological Tissue ,Cardiovascular Anatomy ,Immunologic Techniques ,lcsh:Q ,Endothelium, Vascular ,Gastrointestinal Motility ,Physiological Processes ,Neuroscience - Abstract
We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.
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- 2017
31. A Plasma Biomarker Panel to Identify Surgically Resectable Early-Stage Pancreatic Cancer
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Jinyun Chen, Debra KuKuruga, Ying Huang, Marsha L. Frazier, Nanyue Chen, Ann M. Killary, Sudhir Srivastava, Subrata Sen, Sanford A. Stass, Suyu Liu, J. Jack Lee, Tracey Marsh, Randall E. Brand, and Seetharaman Balasenthil
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,CA-19-9 Antigen ,Lipoproteins ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Pancreatic cancer ,Pancreatitis, Chronic ,medicine ,Diabetes Mellitus ,Humans ,Single-Blind Method ,Pancreatitis, chronic ,Stage (cooking) ,Early Detection of Cancer ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Cholestasis ,business.industry ,Area under the curve ,Case-control study ,Age Factors ,Cancer ,Tenascin ,Articles ,Middle Aged ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Solicited Editorial ,ROC Curve ,030220 oncology & carcinogenesis ,Area Under Curve ,Case-Control Studies ,Acute Disease ,Biomarker (medicine) ,Pancreatitis ,Female ,business ,Biomarkers ,Carcinoma, Pancreatic Ductal - Abstract
Background Blood-based biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are urgently needed. Current biomarkers lack high sensitivity and specificity for population screening. The gold-standard biomarker, CA 19-9, also fails to demonstrate the predictive value necessary for early detection. Methods To validate a functional genomics-based plasma migration signature biomarker panel, plasma tissue factor pathway inhibitor (TFPI), tenascin C (TNC-FN III-C), and CA 19-9 levels were measured by enzyme-linked immunosorbent assays in three early-stage PDAC plasma cohorts, including two independent blinded validation cohorts containing a total of 43 stage I, 163 stage II, 86 chronic pancreatitis, 31 acute biliary obstruction, and 108 controls. Logistic regression models developed classification rules combining TFPI and/or TNC-FN III-C with CA 19-9 for patient cases and control subjects, with or without adjustment for age and diabetes status. Model classification performance was evaluated and analyses repeated among subpopulations without diabetes and pancreatitis history. Two-sided P values were calculated using bootstrap method. Results The TFPI/TNC-FN III-C/CA 19-9 panel improved CA 19-9 performance in all early-stage cohorts, including discriminating stage IA/IB/IIA, stage IIB, and all early-stage cancer from healthy controls. Statistical significance was reached for a number of subcohorts, including for all early-stage cancer vs healthy controls (cohort 1 AUC = 0.92, 95% CI = 0.86 to 0.96, P = .04; cohort 3 AUC = 0.83, 95% CI = 0.76 to 0.89, P = .045). Among subcohorts without diabetes and pancreatitis history, the panel approaches potential clinical utility for early detection to discriminate early-stage PDAC from healthy controls including an area under the curve (AUC) of 0.87 (95% CI = 0.77 to 0.95) for stage I/IIA, an AUC of 0.93 (95% CI = 0.87 to 0.98) for stage IIB, and a statistically significant AUC of 0.89 (95% CI = 0.82 to 0.95) for all early-stage cancer ( P = .03). Conclusions TFPI/TNC-FN III-C migration signature adds statistically significantly to CA 19-9's predictive power to detect early-stage PDAC and may have clinical utility for early detection of surgically resectable PDAC, as well as for enhanced survival from this routinely lethal cancer.
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- 2017
32. Circulating microRNAs in Pancreatic Juice as Candidate Biomarkers of Pancreatic Cancer
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Timothy A. Woodward, Michael B. Wallace, Subrata Sen, Xiaoqun Dong, Ann M. Killary, Jinyun Chen, Lixia Diao, Sushovan Guha, Marsha L. Frazier, Jin Wang, Massimo Raimondo, and Jing Wang
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medicine.medical_specialty ,Pathology ,Pancreatic disease ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,pancreatic juice ,Internal medicine ,Pancreatic cancer ,microRNA ,medicine ,circulating ,miRNA ,030304 developmental biology ,0303 health sciences ,pancreatic cancer ,Microarray analysis techniques ,business.industry ,medicine.disease ,3. Good health ,Circulating MicroRNA ,Oncology ,030220 oncology & carcinogenesis ,Pancreatic juice ,biomarker ,Biomarker (medicine) ,Pancreatitis ,business ,Research Paper - Abstract
Development of sensitive and specific biomarkers, preferably those circulating in body fluids is critical for early diagnosis of cancer. This study performed profiling of microRNAs (miRNAs) in exocrine pancreatic secretions (pancreatic juice) by microarray analysis utilizing pancreatic juice from 6 pancreatic ductal adenocarcinoma (PDAC) patients and two pooled samples from 6 non-pancreatic, non-healthy (NPNH) as controls. Differentially circulating miRNAs were subsequently validated in 88 pancreatic juice samples from 50 PDAC, 19 chronic pancreatitis (CP) patients and 19 NPNH controls. A marked difference in the profiles of four circulating miRNAs (miR-205, miR-210, miR-492, and miR-1427) was observed in pancreatic juice collected from patients with PDAC and those without pancreatic disease. Elevated levels of the four miRNAs together predicted PDAC with a specificity of 88% and sensitivity of 87%. Inclusion of serum CA19-9 level increased the sensitivity to 91% and the specificity to 100%. Enrichment of the four miRNAs in pancreatic juice was associated with decreased OS, as was the combination of miR-205 and miR-210. Higher contents of miR-205 and miR-210 were also associated with lymph node metastasis. Elevated levels of circulating miR-205, miR-210, miR-492, and miR-1247 in pancreatic juice are, therefore, promising candidate biomarkers of disease and poor prognosis in patients with PDAC.
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- 2014
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33. Putative tumor suppressor geneSEL1Lwas downregulated by aberrantly upregulated hsa-mir-155 in human pancreatic ductal adenocarcinoma
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Jinyun Chen, Jin Wang, Marsha L. Frazier, Ann M. Killary, Qian Liu, Subrata Sen, Chongjuan Wei, and Christopher I. Amos
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Gene expression profiling ,miR-155 ,Regulation of gene expression ,Cancer Research ,Real-time polymerase chain reaction ,Downregulation and upregulation ,Tumor suppressor gene ,microRNA ,Gene silencing ,Biology ,Molecular Biology ,Molecular biology - Abstract
Sel-1-like (SEL1L) is a putative tumor suppressor gene that is significantly downregulated in human pancreatic ductal adenocarcinoma (PDA). The mechanism of the downregulation is unclear. Here, we investigated whether aberrantly upregulated microRNAs (miRNAs) repressed the expression of SEL1L. From reported miRNA microarray studies on PDA and predicted miRNA targets, we identified seven aberrantly upregulated miRNAs that potentially target SEL1L. We assessed the expression levels of SEL1L mRNA and the seven miRNAs in human PDA tumors and normal adjacent tissues using real-time quantitative polymerase chain reaction. Then statistical methods were applied to evaluate the association between SEL1L mRNA and the miRNAs. Furthermore, the interaction was explored by functional analysis, including luciferase assay and transient miRNA overexpression. SEL1L mRNA expression levels were found to correlate inversely with the expression of hsa-mir-143, hsa-mir-155, and hsa-mir-223 (P
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- 2013
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34. Changes in screening behaviors and attitudes toward screening from pre-test genetic counseling to post-disclosure in Lynch syndrome families
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Susan K. Peterson, Christopher I. Amos, Salma K. Marani, Marsha L. Frazier, Sally W. Vernon, Shelly R. Hovick, Patrick M. Lynch, Ellen R. Gritz, and Allison M. Burton-Chase
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medicine.medical_specialty ,medicine.diagnostic_test ,Crc screening ,business.industry ,Colorectal cancer ,Genetic counseling ,Colonoscopy ,Health knowledge ,medicine.disease ,digestive system diseases ,Lynch syndrome ,Test (assessment) ,Internal medicine ,Genetics ,medicine ,business ,Genetics (clinical) ,Genetic testing - Abstract
The purpose of this study was to examine colonoscopy adherence and attitudes toward colorectal cancer (CRC) screening in individuals who underwent Lynch syndrome genetic counseling and testing. We evaluated changes in colonoscopy adherence and CRC screening attitudes in 78 cancer-unaffected relatives of Lynch syndrome mutation carriers before pre-test genetic counseling (baseline) and at 6 and 12 months post-disclosure of test results (52 mutation negative and 26 mutation positive). While both groups were similar at baseline, at 12 months post-disclosure, a greater number of mutation-positive individuals had had a colonoscopy compared with mutation-negative individuals. From baseline to 12 months post-disclosure, the mutation-positive group demonstrated an increase in mean scores on measures of colonoscopy commitment, self-efficacy, and perceived benefits of CRC screening, and a decrease in mean scores for perceived barriers to CRC screening. Mean scores on colonoscopy commitment decreased from baseline to 6 months in the mutation-negative group. To conclude, adherence to risk-appropriate guidelines for CRC surveillance improved after genetic counseling and testing for Lynch syndrome. Mutation-positive individuals reported increasingly positive attitudes toward CRC screening after receiving genetic test results, potentially reinforcing longer term colonoscopy adherence.
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- 2013
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35. Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 Regions Identifies Functional and Histology-Specific Lung Cancer Susceptibility Loci in African-Americans
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Laura J. Bierut, Helen M. Hansen, Paige M. Bracci, Stacy M. Lloyd, Ivan P. Gorlov, Kyle M. Walsh, Huifeng Zhang, Michael F. Seldin, Marsha L. Frazier, Margaret R. Spitz, John K. Wiencke, Jennette D. Sison, Angela S. Wenzlaff, Ann G. Schwartz, Margaret Wrensch, Chongjuan Wei, Christopher I. Amos, Emily Y. Lu, Xifeng Wu, and Wei V. Chen
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Male ,Oncology ,medicine.medical_specialty ,Linkage disequilibrium ,Pathology ,Lung Neoplasms ,Epidemiology ,Nerve Tissue Proteins ,Genome-wide association study ,Single-nucleotide polymorphism ,Adenocarcinoma ,Receptors, Nicotinic ,Biology ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Article ,Risk Factors ,Internal medicine ,Genotype ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,Lung cancer ,Lung ,Telomerase ,Aged ,Genetic association ,Chromosomes, Human, Pair 15 ,Chromosome Mapping ,Proteins ,Middle Aged ,Prognosis ,medicine.disease ,Small Cell Lung Carcinoma ,Lung cancer susceptibility ,Black or African American ,Case-Control Studies ,Carcinoma, Squamous Cell ,Chromosomes, Human, Pair 5 ,Chromosomes, Human, Pair 6 ,Female ,Genome-Wide Association Study - Abstract
Background: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans. Methods: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate. Results: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25–1.97; P, 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48–0.85; P, 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73–0.93; P, 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65–0.86; P, 8.1 × 10−5). Conclusions: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma. Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies. Cancer Epidemiol Biomarkers Prev; 22(2); 251–60. ©2012 AACR.
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- 2013
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36. Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans
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Margaret R. Spitz, Wei V. Chen, Emily Y. Lu, Marsha L. Frazier, Michael F. Seldin, Ivan P. Gorlov, Stacy M. Lloyd, Xifeng Wu, Helen M. Hansen, Angela S. Wenzlaff, Kyle M. Walsh, John K. Wiencke, Margaret Wrensch, Huifeng Zhang, Chongjuan Wei, Christopher I. Amos, Ann G. Schwartz, Jennette D. Sison, and Paige M. Bracci
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Male ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,genetic association ,Genotype ,African-Americans ,Single-nucleotide polymorphism ,Genome-wide association study ,Locus (genetics) ,Receptors, Nicotinic ,Biology ,Polymorphism, Single Nucleotide ,smoking ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Epidemiology ,medicine ,Humans ,Genetic Predisposition to Disease ,nicotine dependence ,Lung cancer ,030304 developmental biology ,Genetic association ,Genetics ,0303 health sciences ,medicine.disease ,Research Papers ,Lung cancer susceptibility ,3. Good health ,Black or African American ,Case-Control Studies ,030220 oncology & carcinogenesis ,Female ,Genome-Wide Association Study - Abstract
// Kyle M. Walsh 1 †, Christopher I. Amos 2 † * , Angela S. Wenzlaff 3 , Ivan P. Gorlov 4 , Jennette D. Sison 5 , Xifeng Wu 6 , Margaret R. Spitz 7 , Helen M. Hansen 5 , Emily Y. Lu 2 , Chongjuan Wei 6 , Huifeng Zhang 2 , Wei Chen 2 , Stacy M. Lloyd 8 , Marsha L. Frazier 6 , Paige M. Bracci 1 , Michael F. Seldin 9 , Margaret R. Wrensch 1,5 , Ann G. Schwartz 3* , John K. Wiencke 1,5* 1 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 2 Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 3 Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 4 Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 5 Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 6 Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX 7 Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 8 Department of Health Disparities Research, University of Texas M.D. Anderson Cancer Center, Houston, TX 9 Department of Biochemistry and Molecular Medicine, University of California, Davis † denotes equal contribution * CIA, AGS and JKW co-directed this research Correspondence: John K. Wiencke, email: // Keywords : Lung cancer, nicotine dependence, African-Americans, genetic association, smoking Received : November 13, 2012, Accepted : November 14, 2012, Published : November 16, 2012 Abstract Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-American controls from three centers were genotyped for 378 single nucleotide polymorphisms (SNPs) spanning the sixteen human nAChR genes. Associations between SNPs and the risk of lung cancer were estimated using logistic regression, adjusted for relevant covariates. Seven SNPs in three nAChR genes were significantly associated with lung cancer at a strict Bonferroni-corrected level, including a novel association on chromosome 2 near the promoter of CHRNA1 (rs3755486: OR = 1.40, 95% CI = 1.18-1.67, P = 1.0 x 10 -4 ). Association analysis of an additional 305 imputed SNPs on 2q31.1 supported this association. Publicly available expression data demonstrated that the rs3755486 risk allele correlates with increased CHRNA1 gene expression. Additional SNP associations were observed on 15q25.1 in genes previously associated with lung cancer, including a missense variant in CHRNA5 (rs16969968: OR = 1.60, 95% CI = 1.27-2.01, P = 5.9 x 10 -5 ). Risk alleles on 15q25.1 also correlated with an increased number of cigarettes smoked per day among the controls. These findings identify a novel lung cancer risk locus on 2q31.1 which correlates with CHRNA1 expression and replicate previous associations on 15q25.1 in African-Americans.
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- 2012
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37. Cell cycle–related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients
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Mala Pande, Patrick M. Lynch, Marsha L. Frazier, Ivan P. Gorlov, Yu Jing Huang, Bente A. Talseth-Palmer, Jinyun Chen, Rodney J. Scott, Chongjuan Wei, Christopher I. Amos, Cliff Meldrum, and Wei V. Chen
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Genotype ,Colorectal cancer ,Cell Cycle Proteins ,Original Manuscript ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,White People ,Young Adult ,Risk Factors ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,Genotyping ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Genetics ,Proportional hazards model ,Hazard ratio ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Texas ,Lynch syndrome ,Female ,Age of onset ,Colorectal Neoplasms ,Follow-Up Studies - Abstract
Heterogeneity in age of onset of colorectal cancer in individuals with mutations in DNA mismatch repair genes (Lynch syndrome) suggests the influence of other lifestyle and genetic modifiers. We hypothesized that genes regulating the cell cycle influence the observed heterogeneity as cell cycle-related genes respond to DNA damage by arresting the cell cycle to provide time for repair and induce transcription of genes that facilitate repair. We examined the association of 1456 single nucleotide polymorphisms (SNPs) in 128 cell cycle-related genes and 31 DNA repair-related genes in 485 non-Hispanic white participants with Lynch syndrome to determine whether there are SNPs associated with age of onset of colorectal cancer. Genotyping was performed on an Illumina GoldenGate platform, and data were analyzed using Kaplan-Meier survival analysis, Cox regression analysis and classification and regression tree (CART) methods. Ten SNPs were independently significant in a multivariable Cox proportional hazards regression model after correcting for multiple comparisons (P < 5 × 10(-4)). Furthermore, risk modeling using CART analysis defined combinations of genotypes for these SNPs with which subjects could be classified into low-risk, moderate-risk and high-risk groups that had median ages of colorectal cancer onset of 63, 50 and 42 years, respectively. The age-associated risk of colorectal cancer in the high-risk group was more than four times the risk in the low-risk group (hazard ratio = 4.67, 95% CI = 3.16-6.92). The additional genetic markers identified may help in refining risk groups for more tailored screening and follow-up of non-Hispanic white patients with Lynch syndrome.
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- 2012
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38. Circulation of Progenitor Cells in Obese and Lean Colorectal Cancer Patients
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Jinyun Chen, Marsha L. Frazier, Charles F. Bellows, Mikhail G. Kolonin, and Yan Zhang
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Pathology ,Epidemiology ,Colorectal cancer ,Malignancy ,Article ,Body Mass Index ,Immunophenotyping ,Young Adult ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Obesity ,Progenitor cell ,Aged ,Aged, 80 and over ,business.industry ,Stem Cells ,Mesenchymal stem cell ,Cancer ,Middle Aged ,Flow Cytometry ,medicine.disease ,Haematopoiesis ,Female ,Colorectal Neoplasms ,business ,Body mass index - Abstract
Background: Colorectal cancer (CRC) is a common life-threatening malignancy; risk and progression are elevated in obesity. The purpose of this study was to measure the frequency of circulating CD34-positive endothelial and progenitor cells in the circulation and evaluate their potential values as CRC biomarkers. Methods: Blood was collected from 45 patients with CRC and compared with cancer-free control donors. Detection and enumeration of cells was carried out by flow cytometry on the basis of immunophenotypes established for the cell populations of interest: hematopoietic and endothelial circulating progenitor cells, endothelial cells, mesenchymal stromal cells (MSC), and CD34bright leukocytes (CD34b LC). Groups were compared using multivariate regression analysis. Receiver-operating characteristic (ROC) curve analysis was used to evaluate the diagnostic values. Results: After adjusting for age and body mass index (BMI), the mean frequencies of MSCs and CD34b LCs were significantly higher in the circulation of patients with CRC than in controls. The areas under the ROC curve were 0.77 and 0.82 for MSCs and CD34b LCs, respectively. The frequency of circulating MSCs, but not of the other cell populations, was also found to be significantly higher in the circulation of obese patients with CRC (BMI ≥ 30 kg/m2) than in lean patients with CRC and obese controls. Conclusions: Increased frequency of MSCs and CD34b LCs in the peripheral blood may represent a new diagnostic marker for CRC. Impact: BMI-dependent changes in circulating MSCs, potentially mobilized from white adipose tissue may reveal their trafficking to tumors, which could be one of the mechanistic links between obesity and cancer progression. Cancer Epidemiol Biomarkers Prev; 20(11); 2461–8. ©2011 AACR.
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- 2011
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39. Susceptibility Locus for Lung Cancer at 15q25.1 Is Not Associated With Risk of Pancreatic Cancer
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Subrata Sen, Christopher I. Amos, Jinyun Chen, Mala Pande, Marsha L. Frazier, Xifeng Wu, and Ann M. Killary
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Male ,Oncology ,medicine.medical_specialty ,Linkage disequilibrium ,Lung Neoplasms ,Endocrinology, Diabetes and Metabolism ,Nerve Tissue Proteins ,Single-nucleotide polymorphism ,Genome-wide association study ,Receptors, Nicotinic ,Biology ,Polymorphism, Single Nucleotide ,Article ,Linkage Disequilibrium ,Chromosome 15 ,Endocrinology ,Gene Frequency ,Risk Factors ,Pancreatic cancer ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Risk factor ,Lung cancer ,Aged ,Chromosomes, Human, Pair 15 ,Hepatology ,Case-control study ,Middle Aged ,medicine.disease ,Pancreatic Neoplasms ,Haplotypes ,Case-Control Studies ,Female ,Carcinoma, Pancreatic Ductal ,Genome-Wide Association Study - Abstract
Four genome-wide association (GWA) studies have found that variation in a region of strong linkage disequilibrium on the long arm of chromosome 15 (15q24-25.1) containing nicotinic acetylcholine receptor genes contributes to lung cancer risk. Because cigarette smoking is a major risk factor for developing both lung cancer and pancreatic cancer, we hypothesized that variation in this region may also modify individual susceptibility to pancreatic cancer.We conducted a case-control study of 523 patients with pathologically confirmed pancreatic adenocarcinoma and 1046 age-, sex-, ethnicity-, and smoking behavior-matched cancer-free controls.We found that 2 risk single nucleotide polymorphisms reported in the lung cancer GWA studies-rs8034191: AG and rs1051730: GA, located in this 15q24-25.1 region-were not associated with risk of pancreatic cancer.The results of our study suggest that the 2 single nucleotide polymorphisms at 15q25.1 do not modify pancreatic cancer risk.
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- 2011
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40. A single-nucleotide polymorphism in tumor suppressor geneSEL1Las a predictive and prognostic marker for pancreatic ductal adenocarcinoma in Caucasians
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Marsha L. Frazier, Qian Liu, Ann M. Killary, Jinyun Chen, Billy Mai, Subrata Sen, Chongjuan Wei, and Christopher I. Amos
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Biologic marker ,Genetics ,Cancer Research ,medicine.medical_specialty ,Tumor suppressor gene ,Hazard ratio ,Single-nucleotide polymorphism ,Biology ,medicine.disease ,Gastroenterology ,Internal medicine ,Pancreatic cancer ,Genotype ,medicine ,Adenocarcinoma ,SNP ,Molecular Biology - Abstract
SEL1L is a putative tumor suppressor gene that is frequently down-regulated in pancreatic ductal adenocarcinoma (PDA). A single nucleotide polymorphism (SNP) rs12435998 in intron3 of SEL1L has previously been reported to be associated with susceptibility to Alzheimer’s disease. We hypothesized that this SNP may influence clinical outcomes of patients with PDA. We analyzed DNA samples from 497 Caucasian patients with pathologically confirmed primary PDA. Of these, 98 had been enrolled in a clinical trial of neoadjuvant chemo-radiotherapy and 77 of the 98 had subsequently undergone pancreaticoduodenectomy (PD). We performed Kaplan–Meier analysis to evaluate the correlation between different SNP genotypes and age at diagnosis, survival time after diagnosis, and survival time after PD. In nonsmokers, we found a significant difference in median age at diagnosis between variant genotypes (AG/GG) carriers and wild-type genotype (AA) carriers (58 versus 62 years; log-rank test, P=0.017). Patients with variant genotypes also showed an increased hazard ratio (HR) of 1.45 (95% confidence interval [CI], 1.07–1.97) relative to wild-type genotype. Among the patients in the clinical trial, the variant genotypes carriers had a median post-PD survival time that was 34.7 months shorter than wild-type genotype carriers (log-rank test, P=0.019; HR, 1.91; 95% CI, 1.09–3.34). Our results suggest that the rs12435998 SNP in SEL1L gene plays a role in modifying age at diagnosis of PDA in Caucasian nonsmokers. In addition, this SNP may serve as a prognostic marker in PDA patients who undergo the same or similar treatment as the clinical trials.
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- 2011
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41. Evolutionary evidence of the effect of rare variants on disease etiology
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Christopher I. Amos, Olga Y. Gorlova, Margaret R. Spitz, Marsha L. Frazier, and Ivan P. Gorlov
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Genetics ,Genome, Human ,Single-nucleotide polymorphism ,Genome-wide association study ,Disease ,Biology ,Biological Evolution ,Polymorphism, Single Nucleotide ,Article ,Structural variation ,Minor allele frequency ,Gene Frequency ,Humans ,Genetic Predisposition to Disease ,Allele frequency ,Genetics (clinical) ,Genome-Wide Association Study ,Rare disease ,Common disease-common variant - Abstract
The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a relatively large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single-nucleotide polymorphisms (SNPs), i.e., those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common disease from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, plus the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk-associated rare SNPs.
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- 2010
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42. Microsatellite instability in the peripheral blood leukocytes of HNPCC patients
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Brian C. Ramagli, Louis S. Ramagli, Barry W. Brown, Patrick M. Lynch, Mary Coolbaugh-Murphy, Marsha L. Frazier, Jing Ping Xu, Stanley R. Hamilton, and Michael J. Siciliano
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,DNA Mutational Analysis ,Biology ,MLH1 ,Article ,Germline mutation ,Leukocytes ,Genetics ,medicine ,Humans ,Allele ,neoplasms ,Genetics (clinical) ,Aged ,nutritional and metabolic diseases ,Microsatellite instability ,Middle Aged ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,Lynch syndrome ,Gene Expression Regulation, Neoplastic ,MSH2 ,Mutation ,Microsatellite ,Female ,Microsatellite Instability ,DNA mismatch repair ,Colorectal Neoplasms ,Microsatellite Repeats - Abstract
Most hereditary nonpolyposis colorectal cancer (HNPCC) patients inherit a defective allele of a mismatch repair (MMR) gene, usually MLH1 or MSH2, resulting in high levels of microsatellite instability (MSI-H) in the tumors. Presence of MSI in the normal tissues of mutation carriers has been controversial. Here we directly compare MSI in the peripheral blood leukocyte (PBL) DNA of seven HNPCC patients carrying different types of pathogenic MMR mutations in MLH1 and MSH2 genes with the PBL DNA of normal age-matched controls and of patients with sporadic colorectal cancer (SCRC). Small pool PCR (SP-PCR) was used studying three microsatellite loci for at least 100 alleles each in most samples. The average frequencies of mutant microsatellite fragments in each HNPCC patient (0.04-0.24) were significantly higher (p
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- 2010
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43. Smoking and Colorectal Cancer in Lynch Syndrome: Results from the Colon Cancer Family Registry and The University of Texas M.D. Anderson Cancer Center
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Peter T. Campbell, Mark A. Jenkins, Loic LeMarchand, John L. Hopper, Robert W. Haile, Mala Pande, Steve Gallinger, Noralane M. Lindor, Christopher I. Amos, Patrick M. Lynch, John A. Baron, Marsha L. Frazier, John D. Potter, and Polly A. Newcomb
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Gene mutation ,DNA Mismatch Repair ,Risk Assessment ,Article ,Risk Factors ,Internal medicine ,medicine ,Humans ,Risk factor ,neoplasms ,Aged ,Aged, 80 and over ,business.industry ,Smoking ,Hazard ratio ,Microsatellite instability ,Cancer ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,Lynch syndrome ,Surgery ,Mutation ,Female ,Colorectal Neoplasms ,business - Abstract
Purpose: Lynch syndrome family members with inherited germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), and cases typically have tumors that exhibit a high level of microsatellite instability (MSI). There is some evidence that smoking is a risk factor for CRCs with high MSI; however, the association of smoking with CRC among those with Lynch syndrome is unknown. Experimental Design: A multicentered retrospective cohort of 752 carriers of pathogenic MMR gene mutations was analyzed, using a weighted Cox regression analysis, adjusting for sex, ascertainment source, the specific mutated gene, year of birth, and familial clustering. Results: Compared with never smokers, current smokers had a significantly increased CRC risk [adjusted hazard ratio (HR), 1.62; 95% confidence interval (95% CI), 1.01-2.57] and former smokers who had quit smoking for 2 or more years were at decreased risk (HR, 0.53; 95% CI, 0.35-0.82). CRC risk did not vary according to age at starting. However, light smoking ( Conclusions: People with Lynch syndrome may be at increased risk of CRC if they smoke regularly. Although our data suggest that former smokers, short-term smokers, and light smokers are at decreased CRC risk, these findings need further confirmation, preferably using prospective designs. Clin Cancer Res; 16(4); 1331–9
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- 2010
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44. Genetic Variants of p21 and p27 and Pancreatic Cancer Risk in Non-Hispanic Whites
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Jinyun Chen, Christopher I. Amos, Qingyi Wei, Kelly W. Merriman, Ann M. Killary, Subrata Sen, and Marsha L. Frazier
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Cyclin-Dependent Kinase Inhibitor p21 ,Male ,Oncology ,medicine.medical_specialty ,Pathology ,Genotype ,Endocrinology, Diabetes and Metabolism ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Article ,White People ,Endocrinology ,Gene Frequency ,Risk Factors ,Polymorphism (computer science) ,Internal medicine ,Pancreatic cancer ,Odds Ratio ,Internal Medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Alleles ,Aged ,Chi-Square Distribution ,Hepatology ,Smoking ,Case-control study ,Genetic Variation ,Odds ratio ,Middle Aged ,medicine.disease ,Non-Hispanic whites ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Case-Control Studies ,Female ,Pancreas ,Cyclin-Dependent Kinase Inhibitor p27 - Abstract
Objectives—p21 (WAF1/Cip1/CDKN1A) and p27 (Kip1/CDKN1B) are members of the Cip/Kip family of cyclin-dependent kinase inhibitors, which can induce cell cycle arrest and serve as tumor suppressors. We hypothesized that genetic variants in p21 and p27 may modify individual susceptibility to pancreatic cancer. Methods—To test this hypothesis, we evaluated the associations of the Ser31Arg polymorphism in p21 and the Gly109Val polymorphism in p27, as well as their combinations, with pancreatic cancer risk in a case-control study of 509 pathologically confirmed pancreatic adenocarcinoma patients and 462 age- and sex-matched cancer-free controls in non-Hispanic whites. Results—We found that the heterozygous and homozygous variant genotypes combined in a dominant model of the p21 polymorphism were associated with increased risk of pancreatic cancer compared with the homozygous wild-type (odds ratio [ORadjusted] = 1.70; 95% confidence interval [CI], 1.13–2.55). This increased risk was more pronounced in carriers with the p27 homozygous wild-type (ORadjusted, 2.20; 95% CI, 1.32–3.68) as well as in nonsmokers (ORadjusted, 2.16; 95% CI, 1.14–4.10), although the p27 polymorphism alone was not associated with pancreatic cancer risk. Conclusions—These results indicate that the p21 polymorphism may contribute to susceptibility to pancreatic cancer, particularly among p27 homozygous wild-type carriers and nonsmokers.
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- 2010
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45. Health and lifestyle behaviors among persons at risk of Lynch syndrome
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Patrick M. Lynch, Ellen R. Gritz, Salma K. Marani, Marsha L. Frazier, Allison M. Burton, Sally W. Vernon, Christopher I. Amos, and Susan K. Peterson
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Alcohol Drinking ,Genetic counseling ,Health Behavior ,Genetic Counseling ,Risk Assessment ,Article ,Risk Factors ,Internal medicine ,Epidemiology ,Cancer screening ,medicine ,Genetic predisposition ,Humans ,Family ,Genetic Testing ,Life Style ,Genetic testing ,Family Health ,medicine.diagnostic_test ,business.industry ,Public health ,Smoking ,Middle Aged ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,Lynch syndrome ,Regression Analysis ,Female ,Risk assessment ,business ,Clinical psychology - Abstract
OBJECTIVE: The aim of this study was to evaluate health behaviors among colorectal cancer (CRC) patients and their at-risk relatives prior to undergoing genetic counseling and testing for Lynch syndrome and to examine associations between health risk behaviors and specific demographic and psychological variables. METHODS: Participants included CRC patients (n=319) and their cancer-unaffected relatives (n=110) who were enrolled in studies regarding Lynch syndrome genetic testing. Prior to undergoing genetic counseling or testing, participants completed a questionnaire including measures of demographic characteristics, health behaviors, cancer screening practices (Pap test, clinical breast exam, and mammogram), and psychological distress. RESULTS: Unaffected participants scored higher on a risk behavior index (RBI) than CRC patients (1.7 (SD=1.0) vs. 1.4 (SD=.09); p
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- 2009
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46. Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome
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Jinyun Chen, Carol J. Etzel, Noralane M. Lindor, Nancy A. Viscofsky, Qing Zhang, Patrick M. Lynch, Marsha L. Frazier, and Christopher I. Amos
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Pathology ,medicine.medical_specialty ,Adolescent ,Genotype ,Colorectal cancer ,Polymerase Chain Reaction ,Article ,Young Adult ,Molecular genetics ,Humans ,Medicine ,Genetic Predisposition to Disease ,Age of Onset ,Allele ,Aged ,Aged, 80 and over ,Genetics ,Polymorphism, Genetic ,business.industry ,Cell Cycle ,Middle Aged ,Cell cycle ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,digestive system diseases ,Lynch syndrome ,Oncology ,Female ,DNA mismatch repair ,Age of onset ,business - Abstract
Lynch syndrome is an autosomal dominant syndrome of familial malignancies resulting from germ line mutations in DNA mismatch repair (MMR) genes. Our goal was to take a pathway-based approach to investigate the influence of polymorphisms in cell cycle-related genes on age of onset for Lynch syndrome using a tree model.We evaluated polymorphisms in a panel of cell cycle-related genes (AURKA, CDKN2A, TP53, E2F2, CCND1, TP73, MDM2, IGF1, and CDKN2B) in 220 MMR gene mutation carriers from 129 families. We applied a novel statistical approach, tree modeling (Classification and Regression Tree), to the analysis of data on patients with Lynch syndrome to identify individuals with a higher probability of developing colorectal cancer at an early age and explore the gene-gene interactions between polymorphisms in cell cycle genes.We found that the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeatsor=19, E2F2 variant genotype, AURKA wild-type genotype, and CCND1 variant genotype had the youngest age of onset, with a 45-year median onset age, while the subgroup with CDKN2A C580T wild-type genotype, IGF1 CA-repeatsor=19, E2F2 wild-type genotype, and AURKA variant genotype had the latest median age of onset, which was 70 years. Furthermore, we found evidence of a possible gene-gene interaction between E2F2 and AURKA genes related to CRC age of onset.Polymorphisms in these cell cycle-related genes work together to modify the age at the onset of CRC in patients with Lynch syndrome. These studies provide an important part of the foundation for development of a model for stratifying age of onset risk among those with Lynch syndrome.
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- 2009
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47. Chemopreventive efficacy of rapamycin on Peutz–Jeghers syndrome in a mouse model
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Xiaopei Wang, Chongjuan Wei, Christopher I. Amos, Jing Zhu, Nianxiang Zhang, and Marsha L. Frazier
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congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,medicine.medical_specialty ,Peutz-Jeghers Syndrome ,Intestinal polyp ,Peutz–Jeghers syndrome ,AMP-Activated Protein Kinases ,Protein Serine-Threonine Kinases ,Biology ,Article ,Mice ,Germline mutation ,Internal medicine ,medicine ,Animals ,Phosphorylation ,skin and connective tissue diseases ,Germ-Line Mutation ,Mice, Knockout ,Sirolimus ,Antibiotics, Antineoplastic ,TOR Serine-Threonine Kinases ,Intestinal Polyps ,Cancer ,medicine.disease ,digestive system diseases ,Disease Models, Animal ,Phosphotransferases (Alcohol Group Acceptor) ,Endocrinology ,Oncology ,Cancer research ,Signal transduction ,Carrier Proteins ,Signal Transduction ,medicine.drug - Abstract
Germline mutations in LKB1 cause Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder with a predisposition to gastrointestinal polyposis and cancer. Hyperactivation of mTOR-signaling has been associated with PJS. We previously reported that rapamycin treatment of Lkb1(+/-) mice after the onset of polyposis reduced the polyp burden. Here we evaluated the preventive efficacy of rapamycin on Peutz-Jeghers polyposis. We found that rapamycin treatment of Lkb1(+/-) mice initiated before the onset of polyposis in Lkb1(+/-) mice led to a dramatic reduction in both polyp burden and polyp size and this reduction was associated with decreased phosphorylation levels of S6 and 4EBP1. Together, these findings support the use of rapamycin as an option for chemoprevention and treatment of PJS.
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- 2009
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48. Evolution from heterozygous to homozygous KIT mutation in gastrointestinal stromal tumor correlates with the mechanism of mitotic nondisjunction and significant tumor progression
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A. K. Raymond, Jonathan C. Trent, Kelly K. Hunt, Lei L. Chen, John H. Ward, Kimberly A. Jones, Joseph A. Holden, Marsha L. Frazier, R. Lor Randall, Robert H.I. Andtbacka, Courtney L. Scaife, Haesun Choi, Jing Zhu, Wei Zhang, Elsie F. Wu, Robert S. Benjamin, and Victor G. Prieto
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Pathology ,medicine.medical_specialty ,Mitotic crossover ,Genotype ,Proliferative index ,Gastrointestinal Stromal Tumors ,DNA Mutational Analysis ,Molecular Sequence Data ,Mitosis ,Biology ,Polymorphism, Single Nucleotide ,Pathology and Forensic Medicine ,Loss of heterozygosity ,Nondisjunction, Genetic ,Gene duplication ,medicine ,Humans ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Stromal tumor ,Oligonucleotide Array Sequence Analysis ,Oncogene ,Cell cycle ,Proto-Oncogene Proteins c-kit ,Tumor progression ,Mutation ,Disease Progression ,Stromal Cells - Abstract
Activating mutation in KIT or platelet-derived growth factor-alpha can lead to gastrointestinal stromal tumors (GISTs). Eighty-four cases from two institutes were analyzed. Of them, 62 (74%) harbored KIT mutations, 7 of which are previously unreported. One exhibited duplication from both intron 11 and exon 11, which has not been reported in KIT in human cancer. A homozygous/hemizygous KIT-activating mutation was found in 9 of the 62 cases (15%). We identified three GIST patients with heterozygous KIT-activating mutations at initial presentation, who later recurred with highly aggressive clinical courses. Molecular analysis at recurrence showed total dominance of homozygous (diploid) KIT-activating mutation within a short period of 6-13 months, suggesting an important role of oncogene homozygosity in tumor progression. Topoisomerase II is active in the S- and G(2) phases of cell cycle and is a direct and accurate proliferative indicator. Cellular and molecular analysis of serial tumor specimens obtained from consecutive surgeries or biopsy within the same patient revealed that these clones that acquired the homozygous KIT mutation exhibited an increased mitotic count and a striking fourfold increase in topoisomerase II proliferative index (percentage cells show positive topoisomerase II nuclear staining compared to the heterozygous counterpart within the same patient. KIT forms a homodimer as the initial step in signal transduction and this may account for the quadruple increase in proliferation. Using SNPs for allelotyping on the serial tumor specimens, we demonstrate that the mechanism of the second hit resulting in homozygous KIT-activating mutation and loss of heterozygosity is achieved by mitotic nondisjunction, contrary to the commonly reported mechanism of mitotic recombination.
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- 2008
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49. Suppression of Peutz-Jeghers Polyposis by Targeting Mammalian Target of Rapamycin Signaling
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Cheryl L. Walker, Chongjuan Wei, Christopher I. Amos, Nianxiang Zhang, Xiaopei Wang, Asif Rashid, Marsha L. Frazier, and Richard R. Behringer
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congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Peutz-Jeghers Syndrome ,Peutz–Jeghers syndrome ,AMP-Activated Protein Kinases ,Protein Serine-Threonine Kinases ,Biology ,Targeted therapy ,Mice ,Internal medicine ,medicine ,Animals ,skin and connective tissue diseases ,PI3K/AKT/mTOR pathway ,Mice, Knockout ,Sirolimus ,Gastrointestinal tract ,TOR Serine-Threonine Kinases ,medicine.disease ,Immunohistochemistry ,Endocrinology ,Oncology ,Cancer research ,Phosphorylation ,Signal transduction ,Protein Kinases ,Immunosuppressive Agents ,Immunostaining ,Signal Transduction - Abstract
Purpose: Peutz-Jeghers syndrome (PJS) is a unique disorder characterized by the development of hamartomas in the gastrointestinal tract as well as increased risks for variety of malignancies. Germ-line mutations of LKB1 cause PJS. We have generated Lkb1+/− mice, which model human PJS. Rapamycin and its analogues are promising preventive and therapeutic agents that specifically inhibit signaling from mammalian target of rapamycin (mTOR). Hyperactivation of mTOR signaling has been associated with PJS. The objective of the study is to investigate the efficacy of mTOR inhibition in suppressing Peutz-Jeghers polyposis in Lkb1+/− mice.Experimental Design: We initiated a trial of rapamycin in Lkb1+/− mice at 9 months of age (after the onset of polyposis) at the dose of 2 mg/kg/d for a 2-month period. We assessed the efficacy of rapamycin by measuring polyp sizes and tumor burden. To examine the effect of rapamycin on mTOR signaling, phosphorylation levels of S6 were evaluated by immunostaining.Results: We observed a significant decrease in mean tumor burden (Student's t test, P = 0.023) as well as total tumor burden in rapamycin-treated group compared with control group. Comparison of the polyp size observed in both rapamycin-treated and control groups showed that rapamycin efficiently decreased the tumor burden of large polyps (>8 mm). This inhibition of rapamycin was associated with a decrease in phosphorylated S6 levels in the polyps.Conclusions: Rapamycin effectively suppresses Peutz-Jeghers polyposis in a mouse model, suggesting that rapamycin or its analogues may represent a new targeted therapy for the treatment of PJS.
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- 2008
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50. Aurora-A and p16 Polymorphisms Contribute to an Earlier Age at Diagnosis of Pancreatic Cancer in Caucasians
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Marsha L. Frazier, Subrata Sen, Donghui Li, Chongjuan Wei, Christopher I. Amos, James L. Abbruzzese, Douglas B. Evans, Ann M. Killary, and Jinyun Chen
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Male ,Risk ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pancreatic disease ,Genotype ,Protein Serine-Threonine Kinases ,Biology ,Article ,White People ,Aurora Kinases ,Internal medicine ,Pancreatic cancer ,medicine ,Humans ,Centrosome duplication ,Allele ,Cyclin-Dependent Kinase Inhibitor p16 ,Polymorphism, Genetic ,Haplotype ,Hazard ratio ,Age Factors ,Cancer ,medicine.disease ,Pancreatic Neoplasms ,Early Diagnosis ,Haplotypes ,Cancer research ,Female - Abstract
Purpose: Aurora-A and p16 play a major role in cell cycle checkpoint regulation. Both of them are important in the maintenance of centrosome duplication. Therefore, we hypothesized that polymorphisms in the two genes may interact or work together to influence the finely tuned mechanisms of cell cycle regulation that these proteins regulate. The purpose of this study was to investigate the association of the Aurora-A (T91A), and p16 (C540G and C580T) polymorphisms with age at diagnosis of pancreatic cancer. Experimental Design: We genotyped 148 Caucasian patients with a diagnosis of pancreatic cancer for the Aurora-A and p16 polymorphisms using pyrosequencing. We tested the association between age at diagnosis and the Aurora-A and p16 genotypes by comparing Kaplan-Meier curves, evaluating the homogeneity of the curves using the log-rank test. We used Cox proportional hazard regression analysis to estimate the association between time to diagnosis and genotype, adjusting for gender. Results: Patients with the Aurora-A polymorphic genotypes had a median age at diagnosis with pancreatic cancer that was 2.8 years earlier than those with the wild-type genotype [log-rank, P = 0.015; hazard ratio (HR), 1.55; 95% confidence intervals (95% CI), 1.09-2.20]. There was no significant association between the p16 genotypes and age at diagnosis. However, the Aurora-A and p16 C580T polymorphisms combined had a synergistic effect on age-associated risk for early diagnosis of pancreatic cancer. Compared with patients with wild-type genotypes for both genes, the median age at diagnosis for patients with one or two polymorphic alleles for both genes was 12.6 years earlier (log-rank, P = 0.0002; HR, 3.88; 95% CI, 1.94-7.76). No significant associations between the polymorphisms and the cancer metastatic status or survival after diagnosis were found. Conclusions: Our findings suggest that the Aurora-A polymorphism contributes to a significantly earlier age at diagnosis of pancreatic cancer, and that Aurora-A and p16 C580T polymorphisms synergistically contribute to an earlier age at diagnosis of pancreatic cancer.
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- 2007
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