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Bartoloni B, Mannelli M, Gamberi T, Fiaschi T. The Multiple Roles of Lactate in the Skeletal Muscle. Cells 2024; 13:1177. [PMID: 39056759 PMCID: PMC11274880 DOI: 10.3390/cells13141177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/27/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Believed for a long time to be merely a waste product of cell metabolism, lactate is now considered a molecule with several roles, having metabolic and signalling functions together with a new, recently discovered role as an epigenetic modulator. Lactate produced by the skeletal muscle during physical exercise is conducted to the liver, which uses the metabolite as a gluconeogenic precursor, thus generating the well-known "Cori cycle". Moreover, the presence of lactate in the mitochondria associated with the lactate oxidation complex has become increasingly clear over the years. The signalling role of lactate occurs through binding with the GPR81 receptor, which triggers the typical signalling cascade of the G-protein-coupled receptors. Recently, it has been demonstrated that lactate regulates chromatin state and gene transcription by binding to histones. This review aims to describe the different roles of lactate in skeletal muscle, in both healthy and pathological conditions, and to highlight how lactate can influence muscle regeneration by acting directly on satellite cells.
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Affiliation(s)
| | | | | | - Tania Fiaschi
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche “M. Serio”, Università degli Studi di Firenze, 50134 Firenze, Italy; (B.B.); (M.M.); (T.G.)
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Ntwasa M, Dlamini Z. Editorial: Molecular targets for anticancer drug discovery and development. Front Genet 2024; 15:1374867. [PMID: 38633405 PMCID: PMC11021751 DOI: 10.3389/fgene.2024.1374867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 03/14/2024] [Indexed: 04/19/2024] Open
Affiliation(s)
- Monde Ntwasa
- Department of Life and Consumer Sciences, University of South Africa, Florida, South Africa
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), University of Pretoria, Pretoria, South Africa
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Siddique A, Bashir S, Abbas M. Pharmacogenetics of Anticancer Drugs: Clinical Response and Toxicity. Cancer Treat Res 2023; 185:141-175. [PMID: 37306909 DOI: 10.1007/978-3-031-27156-4_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Cancer is the most challenging disease for medical professionals to treat. The factors underlying the complicated situation include anticancer drug-associated toxicity, non-specific response, low therapeutic window, variable treatment outcomes, development of drug resistance, treatment complications, and cancer recurrence. The remarkable advancement in biomedical sciences and genetics, over the past few decades, however, is changing the dire situation. The discovery of gene polymorphism, gene expression, biomarkers, particular molecular targets and pathways, and drug-metabolizing enzymes have paved the way for the development and provision of targeted and individualized anticancer treatment. Pharmacogenetics is the study of genetic factors having the potential to affect clinical responses and pharmacokinetic and pharmacodynamic behaviors of drugs. This chapter emphasizes pharmacogenetics of anticancer drugs and its applications in improving treatment outcomes, selectivity, toxicity of the drugs, and discovering and developing personalized anticancer drugs and genetic methods for prediction of drug response and toxicity.
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Affiliation(s)
- Ammara Siddique
- Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Samra Bashir
- Faculty of Pharmacy, Capital University of Science and Technology, Islamabad, Pakistan.
| | - Mateen Abbas
- Faculty of Pharmacy, Capital University of Science and Technology, Islamabad, Pakistan
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Almekkawi AK, AlJardali MW, Daadaa HM, Lane AL, Worner AR, Karim MA, Scheck AC, Frye RE. Folate Pathway Gene Single Nucleotide Polymorphisms and Neural Tube Defects: A Systematic Review and Meta-Analysis. J Pers Med 2022; 12:1609. [PMID: 36294748 PMCID: PMC9605131 DOI: 10.3390/jpm12101609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/05/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Neural tube defects (NTDs) are congenital abnormalities in the central nervous system. The exact etiology of NTDs is still not determined, but several genetic and epigenetic factors have been studied. Folate supplementation during gestation is recommended to reduce the risk of NTDs. In this review we examine single nucleotide polymorphisms (SNPs) of the genes in the folate pathway associated with NTD. We reviewed the literature for all papers discussing both NTDs and SNPs in the folate pathway. Data were represented through five different genetic models. Quality assessment was performed using the Newcastle-Ottawa Scale (NOS) and Cohen's Kappa inter-rater coefficient assessed author agreement. Fifty-nine papers were included. SNPs in MTHFR, MTRR, RFC genes were found to be highly associated with NTD risk. NOS showed that high quality papers were selected, and Kappa Q-test was 0.86. Our combined results support the notion that SNPs significantly influence NTDs across the population, particularly in Asian ethnicity. Additional high-quality research from diverse ethnicities is needed and meta-regression analysis based on a range of criteria may provide a more complete understanding of the role of folate metabolism in NTDs.
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Affiliation(s)
- Ahmad K. Almekkawi
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
| | - Marwa W. AlJardali
- Rose-Marie Chagoury School of Medicine, Lebanese American University Gilbert, Byblos 1102 2801, Lebanon
| | - Hicham M. Daadaa
- Department of Oncology, St James University Hospital, Beckett St., Harehills, Leeds LS9 7TF, UK
| | - Alison L. Lane
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
| | - Ashley R. Worner
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
| | - Mohammad A. Karim
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
| | - Adrienne C. Scheck
- Phoenix Children’s Hospital, 1919 E. Thomas Rd, Ambulatory Building, Phoenix, AZ 85016, USA
- College of Medicine, Department of Child Health, University of Arizona, 475 N. 5th Street, Phoenix, AZ 85004, USA
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5
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Ong SS, Ho PJ, Khng AJ, Lim EH, Wong FY, Tan BKT, Lim SH, Tan EY, Tan SM, Tan VKM, Dent R, Tan TJY, Ngeow J, Madhukumar P, Hamzah JLB, Sim Y, Lim GH, Pang JS, Alcantara VS, Chan PMY, Chen JJC, Kuah S, Seah JCM, Buhari SA, Tang SW, Ng CWQ, Li J, Hartman M. Association between Breast Cancer Polygenic Risk Score and Chemotherapy-Induced Febrile Neutropenia: Null Results. Cancers (Basel) 2022; 14:cancers14112714. [PMID: 35681694 PMCID: PMC9179461 DOI: 10.3390/cancers14112714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/17/2022] [Accepted: 05/26/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients. METHODS This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t-tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls. RESULTS PRS distributions were not significantly different in any of the comparisons. Higher PRSoverall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79-1.06]; FNc: 0.87 [0.73-1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRSER-pos) and ER-negative weighted PRS (PRSER-neg). CONCLUSION BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.
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Affiliation(s)
- Seeu Si Ong
- Women’s Health and Genetics, Genome Institute of Singapore, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore; (S.S.O.); (P.J.H.); (A.J.K.)
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore;
| | - Peh Joo Ho
- Women’s Health and Genetics, Genome Institute of Singapore, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore; (S.S.O.); (P.J.H.); (A.J.K.)
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore;
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore
| | - Alexis Jiaying Khng
- Women’s Health and Genetics, Genome Institute of Singapore, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore; (S.S.O.); (P.J.H.); (A.J.K.)
| | - Elaine Hsuen Lim
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; (E.H.L.); (R.D.); (T.J.Y.T.); (J.N.)
| | - Fuh Yong Wong
- Division of Radiation Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore;
| | - Benita Kiat-Tee Tan
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; (B.K.-T.T.); (V.K.M.T.); (P.M.); (J.L.B.H.); (Y.S.)
- Department of Breast Surgery, Singapore General Hospital, Singapore 169608, Singapore
- Department of General Surgery, Sengkang General Hospital, Singapore 544886, Singapore
| | - Swee Ho Lim
- KK Breast Department, KK Women’s and Children’s Hospital, Singapore 229899, Singapore; (S.H.L.); (G.H.L.); (J.S.P.); (V.S.A.)
| | - Ern Yu Tan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore; (E.Y.T.); (P.M.Y.C.); (J.J.C.C.); (S.K.)
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- Institute of Molecular and Cell Biology, Singapore 138673, Singapore
| | - Su-Ming Tan
- Division of Breast Surgery, Changi General Hospital, Singapore 529889, Singapore; (S.-M.T.); (J.C.M.S.)
| | - Veronique Kiak Mien Tan
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; (B.K.-T.T.); (V.K.M.T.); (P.M.); (J.L.B.H.); (Y.S.)
- Department of Breast Surgery, Singapore General Hospital, Singapore 169608, Singapore
| | - Rebecca Dent
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; (E.H.L.); (R.D.); (T.J.Y.T.); (J.N.)
| | - Tira Jing Ying Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; (E.H.L.); (R.D.); (T.J.Y.T.); (J.N.)
| | - Joanne Ngeow
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; (E.H.L.); (R.D.); (T.J.Y.T.); (J.N.)
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- Institute of Molecular and Cell Biology, Singapore 138673, Singapore
| | - Preetha Madhukumar
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; (B.K.-T.T.); (V.K.M.T.); (P.M.); (J.L.B.H.); (Y.S.)
- Department of Breast Surgery, Singapore General Hospital, Singapore 169608, Singapore
| | - Julie Liana Bte Hamzah
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; (B.K.-T.T.); (V.K.M.T.); (P.M.); (J.L.B.H.); (Y.S.)
- Department of Breast Surgery, Singapore General Hospital, Singapore 169608, Singapore
| | - Yirong Sim
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore; (B.K.-T.T.); (V.K.M.T.); (P.M.); (J.L.B.H.); (Y.S.)
- Department of Breast Surgery, Singapore General Hospital, Singapore 169608, Singapore
| | - Geok Hoon Lim
- KK Breast Department, KK Women’s and Children’s Hospital, Singapore 229899, Singapore; (S.H.L.); (G.H.L.); (J.S.P.); (V.S.A.)
| | - Jinnie Siyan Pang
- KK Breast Department, KK Women’s and Children’s Hospital, Singapore 229899, Singapore; (S.H.L.); (G.H.L.); (J.S.P.); (V.S.A.)
| | - Veronica Siton Alcantara
- KK Breast Department, KK Women’s and Children’s Hospital, Singapore 229899, Singapore; (S.H.L.); (G.H.L.); (J.S.P.); (V.S.A.)
| | - Patrick Mun Yew Chan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore; (E.Y.T.); (P.M.Y.C.); (J.J.C.C.); (S.K.)
| | - Juliana Jia Chuan Chen
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore; (E.Y.T.); (P.M.Y.C.); (J.J.C.C.); (S.K.)
| | - Sherwin Kuah
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore; (E.Y.T.); (P.M.Y.C.); (J.J.C.C.); (S.K.)
| | - Jaime Chin Mui Seah
- Division of Breast Surgery, Changi General Hospital, Singapore 529889, Singapore; (S.-M.T.); (J.C.M.S.)
| | - Shaik Ahmad Buhari
- Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Singapore; (S.A.B.); (S.W.T.); (C.W.Q.N.)
| | - Siau Wei Tang
- Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Singapore; (S.A.B.); (S.W.T.); (C.W.Q.N.)
| | - Celene Wei Qi Ng
- Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Singapore; (S.A.B.); (S.W.T.); (C.W.Q.N.)
| | - Jingmei Li
- Women’s Health and Genetics, Genome Institute of Singapore, 60 Biopolis Street, Genome, #02-01, Singapore 138672, Singapore; (S.S.O.); (P.J.H.); (A.J.K.)
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore;
- Correspondence: ; Tel.: +65-6808-8312
| | - Mikael Hartman
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore;
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore
- Department of Surgery, University Surgical Cluster, National University Health System, Singapore 119228, Singapore; (S.A.B.); (S.W.T.); (C.W.Q.N.)
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Li J, Chen B, Wen-Qi X, Jia W, Zhang WX, Bian XL. Drug-Drug Interactions and Disease Status Are Associated with Irinotecan-induced Hepatotoxicity: A Cross-Sectional Study in Shanghai. J Clin Pharmacol 2022; 62:1160-1169. [PMID: 35396702 DOI: 10.1002/jcph.2059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 04/04/2022] [Indexed: 11/05/2022]
Abstract
Irinotecan-induced hepatotoxicity can cause severe clinical complications in patients; however, the underlying mechanism and factors affecting hepatotoxicity have rarely been investigated. In this cross-sectional study, we screened all clinical, demographic, medication and genetic variables among 126 patients receiving irinotecan and explored potential associations with the incidence and time to onset of irinotecan-induced hepatotoxicity. Approximately 38.9% of the patients suffered from hepatotoxicity after irinotecan administration. The presence of cardiovascular diseases (CVDs) increases the incidence of hepatotoxicity approximately 2.9-fold and doubles the hazard of time to hepatotoxicity. Patients with liver metastasis had a more than 4-fold higher risk of hepatotoxicity and a 3.5-fold increased hazard of time to hepatotoxicity compared to those without liver metastasis. Patients who took CYP3A inducers had a 4.4-fold increased incidence of hepatotoxicity, and furthermore, concomitant use of platinum-based antineoplastics revealed 4.2 times the hazard of time to hepatotoxicity compared to those receiving antimetabolites. The cumulative dose of irinotecan (5-9 cycles) increased hepatotoxicity by 8.5 times. However, the genotypes and phenotypes of UGT1A1*28/*6 failed to be predictive factors of hepatotoxicity. The findings of this study suggest that irinotecan-induced hepatotoxicity is not directly associated with genetic variables but is mostly related to concomitant use of CYP3A inducers and platinum, as well as the presence of liver metastasis and CVD. Thus, close monitoring of liver function is recommended, especially in patients with liver impairment or using CYP3A inducers and platinum antineoplastic drugs, which may be the best way to prevent hepatotoxicity. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Juan Li
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Bing Chen
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xi Wen-Qi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Wan Jia
- Department of Pharmacy, Wuxi Branch of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Wuxi, People's Republic of China
| | - Wei-Xia Zhang
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Xiao-Lan Bian
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
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Kumbrink J, Li P, Pók-Udvari A, Klauschen F, Kirchner T, Jung A. p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy. Int J Mol Sci 2021; 22:ijms222212364. [PMID: 34830244 PMCID: PMC8625396 DOI: 10.3390/ijms222212364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/31/2021] [Accepted: 11/10/2021] [Indexed: 11/30/2022] Open
Abstract
p130 Crk-associated substrate (p130Cas) is associated with poor prognosis and treatment resistance in breast and lung cancers. To elucidate p130Cas functional and clinical role in colorectal cancer (CRC) progression/therapy resistance, we performed cell culture experiments and bioinformatic/statistical analyses of clinical data sets. p130Cas expression was associated with poor survival in the cancer genome atlas (TCGA) data set. Knockdown/reconstitution experiments showed that p130Cas drives migration but, unexpectedly, inhibits proliferation in CRC cells. TCGA data analyses identified the growth factor epiregulin (EREG) as inversely correlated with p130Cas. p130Cas knockdown and simultaneous EREG treatment further enhanced proliferation. RNA interference and EREG treatment experiments suggested that p130Cas/EREG limit each other’s expression/activity. Inverse p130Cas/EREG Spearman correlations were prominent in right-sided and earlier stage CRC. p130Cas was inducible by 5-fluorouracil (5-FU) and FOLFIRI (folinic acid, 5-FU, irinotecan), and p130Cas and EREG were upregulated in distant metastases (GSE121418). Positive p130Cas/EREG correlations were observed in metastases, preferentially in post-treatment samples (especially pulmonary metastases). p130Cas knockdown sensitized CRC cells to FOLFIRI independent of EREG treatment. RNA sequencing and gene ontology analyses revealed that p130Cas is involved in cytochrome P450 drug metabolism and epithelial-mesenchymal transition. p130Cas expression was associated with poor survival in right-sided, stage I/II, MSS (microsatellite stable), or BRAF-mutated CRC. In summary, p130Cas represents a prognostic factor and potential therapeutic target in CRC.
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Affiliation(s)
- Jörg Kumbrink
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
- Correspondence:
| | - Pan Li
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
| | - Agnes Pók-Udvari
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
| | - Frederick Klauschen
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
| | - Thomas Kirchner
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
| | - Andreas Jung
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
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8
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Wu J, Yuan Y, Long Priel DA, Fink D, Peer CJ, Sissung TM, Su YT, Pang Y, Yu G, Butler MK, Mendoza TR, Vera E, Ahmad S, Bryla C, Lindsley M, Grajkowska E, Mentges K, Boris L, Antony R, Garren N, Siegel C, Lollo N, Cordova C, Aboud O, Theeler BJ, Burton EM, Penas-Prado M, Leeper H, Gonzales J, Armstrong TS, Calvo KR, Figg WD, Kuhns DB, Gallin JI, Gilbert MR. Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas. Clin Cancer Res 2021; 27:3298-3306. [PMID: 33785481 PMCID: PMC8197750 DOI: 10.1158/1078-0432.ccr-20-4730] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 02/03/2021] [Accepted: 03/24/2021] [Indexed: 01/31/2023]
Abstract
PURPOSE To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. PATIENTS AND METHODS This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. RESULTS Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. CONCLUSIONS Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.
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Affiliation(s)
- Jing Wu
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.
| | - Ying Yuan
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Debra A Long Priel
- Neutrophil Monitoring Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Danielle Fink
- Neutrophil Monitoring Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Cody J Peer
- Clinical Pharmacology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Tristan M Sissung
- Clinical Pharmacology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Yu-Ting Su
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Ying Pang
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Guangyang Yu
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Madison K Butler
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Tito R Mendoza
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Elizabeth Vera
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | | | - Christine Bryla
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Matthew Lindsley
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Ewa Grajkowska
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Kelly Mentges
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Lisa Boris
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Ramya Antony
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Nancy Garren
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Christine Siegel
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Nicole Lollo
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Christine Cordova
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Orwa Aboud
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Brett J Theeler
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Eric M Burton
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Marta Penas-Prado
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Heather Leeper
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Javier Gonzales
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Terri S Armstrong
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | | | - William D Figg
- Clinical Pharmacology Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Douglas B Kuhns
- Neutrophil Monitoring Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | | | - Mark R Gilbert
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
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9
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Deyme L, Barbolosi D, Mbatchi LC, Tubiana-Mathieu N, Ychou M, Evrard A, Gattacceca F. Population pharmacokinetic model of irinotecan and its four main metabolites in patients treated with FOLFIRI or FOLFIRINOX regimen. Cancer Chemother Pharmacol 2021; 88:247-258. [PMID: 33912999 DOI: 10.1007/s00280-021-04255-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 03/07/2021] [Indexed: 11/28/2022]
Abstract
PURPOSE The aim of the present study was to characterize the pharmacokinetics of irinotecan and its four main metabolites (SN-38, SN-38G, APC and NPC) in metastatic colorectal cancer patients treated with FOLFIRI and FOLFIRINOX regimens and to quantify and explain the inter-individual pharmacokinetic variability in this context. METHODS A multicenter study including 109 metastatic colorectal cancer patients treated with FOLFIRI or FOLFIRINOX regimen, associated or not with a monoclonal antibody, was conducted. Concentrations of irinotecan and its four main metabolites were measured in 506 blood samples during the first cycle of treatment. Collected data were analyzed using the population approach. First, fixed and random effects models were selected using statistical and graphical methods; second, the impact of covariates on pharmacokinetic parameters was evaluated to explain the inter-individual variability in pharmacokinetic parameters. RESULTS A seven-compartment model best described the pharmacokinetics of irinotecan and its four main metabolites. First-order rates were assigned to distribution, elimination, and metabolism processes, except for the transformation of irinotecan to NPC which was nonlinear. Addition of a direct conversion of NPC into SN-38 significantly improved the model. Co-administration of oxaliplatin significantly modified the distribution of SN-38. CONCLUSION To our knowledge, the present model is the first to allow a simultaneous description of irinotecan pharmacokinetics and of its four main metabolites. Moreover, a direct conversion of NPC into SN-38 had never been described before in a population pharmacokinetic model of irinotecan. The model will be useful to develop pharmacokinetic-pharmacodynamic models relating SN-38 concentrations to efficacy and digestive toxicities. CLINICAL TRIALS REGISTRATION NUMBER ClinicalTrials.gov identifier: NCT00559676.
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Affiliation(s)
- Laure Deyme
- SMARTc, Centre de Recherche en Cancérologie de Marseille (CRCM), Faculté de Pharmacie, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
| | - Dominique Barbolosi
- SMARTc, Centre de Recherche en Cancérologie de Marseille (CRCM), Faculté de Pharmacie, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Litaty Céphanoée Mbatchi
- Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes-Carémeau, Nîmes, France.,IRCM, Inserm U1194, Université de Montpellier, Montpellier, France
| | | | - Marc Ychou
- Institut Régional du Cancer de Montpellier (ICM)-Val d'Aurelle, Montpellier, France
| | - Alexandre Evrard
- Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes-Carémeau, Nîmes, France.,IRCM, Inserm U1194, Université de Montpellier, Montpellier, France
| | - Florence Gattacceca
- SMARTc, Centre de Recherche en Cancérologie de Marseille (CRCM), Faculté de Pharmacie, INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
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10
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Vural S, Palmisano A, Reinhold WC, Pommier Y, Teicher BA, Krushkal J. Association of expression of epigenetic molecular factors with DNA methylation and sensitivity to chemotherapeutic agents in cancer cell lines. Clin Epigenetics 2021; 13:49. [PMID: 33676569 PMCID: PMC7936435 DOI: 10.1186/s13148-021-01026-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 02/10/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Altered DNA methylation patterns play important roles in cancer development and progression. We examined whether expression levels of genes directly or indirectly involved in DNA methylation and demethylation may be associated with response of cancer cell lines to chemotherapy treatment with a variety of antitumor agents. RESULTS We analyzed 72 genes encoding epigenetic factors directly or indirectly involved in DNA methylation and demethylation processes. We examined association of their pretreatment expression levels with methylation beta-values of individual DNA methylation probes, DNA methylation averaged within gene regions, and average epigenome-wide methylation levels. We analyzed data from 645 cancer cell lines and 23 cancer types from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer datasets. We observed numerous correlations between expression of genes encoding epigenetic factors and response to chemotherapeutic agents. Expression of genes encoding a variety of epigenetic factors, including KDM2B, DNMT1, EHMT2, SETDB1, EZH2, APOBEC3G, and other genes, was correlated with response to multiple agents. DNA methylation of numerous target probes and gene regions was associated with expression of multiple genes encoding epigenetic factors, underscoring complex regulation of epigenome methylation by multiple intersecting molecular pathways. The genes whose expression was associated with methylation of multiple epigenome targets encode DNA methyltransferases, TET DNA methylcytosine dioxygenases, the methylated DNA-binding protein ZBTB38, KDM2B, SETDB1, and other molecular factors which are involved in diverse epigenetic processes affecting DNA methylation. While baseline DNA methylation of numerous epigenome targets was correlated with cell line response to antitumor agents, the complex relationships between the overlapping effects of each epigenetic factor on methylation of specific targets and the importance of such influences in tumor response to individual agents require further investigation. CONCLUSIONS Expression of multiple genes encoding epigenetic factors is associated with drug response and with DNA methylation of numerous epigenome targets that may affect response to therapeutic agents. Our findings suggest complex and interconnected pathways regulating DNA methylation in the epigenome, which may both directly and indirectly affect response to chemotherapy.
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Affiliation(s)
- Suleyman Vural
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA
| | - Alida Palmisano
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA
- General Dynamics Information Technology (GDIT), 3150 Fairview Park Drive, Falls Church, VA, 22042, USA
| | - William C Reinhold
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Yves Pommier
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA
| | - Beverly A Teicher
- Molecular Pharmacology Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Julia Krushkal
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD, 20850, USA.
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11
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Krushkal J, Negi S, Yee LM, Evans JR, Grkovic T, Palmisano A, Fang J, Sankaran H, McShane LM, Zhao Y, O'Keefe BR. Molecular genomic features associated with in vitro response of the NCI-60 cancer cell line panel to natural products. Mol Oncol 2021; 15:381-406. [PMID: 33169510 PMCID: PMC7858122 DOI: 10.1002/1878-0261.12849] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/29/2020] [Accepted: 11/06/2020] [Indexed: 12/17/2022] Open
Abstract
Natural products remain a significant source of anticancer chemotherapeutics. The search for targeted drugs for cancer treatment includes consideration of natural products, which may provide new opportunities for antitumor cytotoxicity as single agents or in combination therapy. We examined the association of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 1302 small molecules which included natural products, semisynthetic natural product derivatives, and synthetic compounds based on a natural product pharmacophore from the Developmental Therapeutics Program of the US National Cancer Institute's database. These compounds were obtained from a variety of plant, marine, and microbial species. Molecular information utilized for the analysis included expression measures for 23059 annotated transcripts, lncRNAs, and miRNAs, and data on protein-changing single nucleotide variants in 211 cancer-related genes. We found associations of expression of multiple genes including SLFN11, CYP2J2, EPHX1, GPC1, ELF3, and MGMT involved in DNA damage repair, NOTCH family members, ABC and SLC transporters, and both mutations in tyrosine kinases and BRAF V600E with NCI-60 responses to specific categories of natural products. Hierarchical clustering identified groups of natural products, which correlated with a specific mechanism of action. Specifically, several natural product clusters were associated with SLFN11 gene expression, suggesting that potential action of these compounds may involve DNA damage. The associations between gene expression or genome alterations of functionally relevant genes with the response of cancer cells to natural products provide new information about potential mechanisms of action of these identified clusters of compounds with potentially similar biological effects. This information will assist in future drug discovery and in design of new targeted cancer chemotherapy agents.
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Affiliation(s)
- Julia Krushkal
- Biometric Research ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteNIHRockvilleMDUSA
| | - Simarjeet Negi
- Biometric Research ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteNIHRockvilleMDUSA
| | - Laura M. Yee
- Biometric Research ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteNIHRockvilleMDUSA
| | - Jason R. Evans
- Natural Products BranchDevelopmental Therapeutics ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteFrederickMDUSA
| | - Tanja Grkovic
- Natural Products Support GroupFrederick National Laboratory for Cancer ResearchFrederickMDUSA
| | - Alida Palmisano
- Biometric Research ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteNIHRockvilleMDUSA
- General Dynamics Information Technology (GDIT)Falls ChurchVAUSA
| | - Jianwen Fang
- Biometric Research ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteNIHRockvilleMDUSA
| | - Hari Sankaran
- Biometric Research ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteNIHRockvilleMDUSA
| | - Lisa M. McShane
- Biometric Research ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteNIHRockvilleMDUSA
| | - Yingdong Zhao
- Biometric Research ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteNIHRockvilleMDUSA
| | - Barry R. O'Keefe
- Natural Products BranchDevelopmental Therapeutics ProgramDivision of Cancer Treatment and DiagnosisNational Cancer InstituteFrederickMDUSA
- Molecular Targets ProgramCenter for Cancer ResearchNational Cancer InstituteFrederickMDUSA
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12
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Aboul-Soud MAM, Alzahrani AJ, Mahmoud A. Decoding variants in drug-metabolizing enzymes and transporters in solid tumor patients by whole-exome sequencing. Saudi J Biol Sci 2021; 28:628-634. [PMID: 33424349 PMCID: PMC7783809 DOI: 10.1016/j.sjbs.2020.10.052] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 10/21/2020] [Accepted: 10/25/2020] [Indexed: 11/25/2022] Open
Abstract
Background Pharmacogenetics is involved in customizing therapy according to the genetic makeup of an individual, and is applicable for chemotherapy, radiotherapy as well as targeted therapy. Drug metabolizing enzymes (DMEs) involving both phase I, and phase II reactions are widely studied. Our study was involved in whole exome sequencing (WES) of cancer patients, followed by analysis for identifying key variations in DMEs, and associated transporters that have a potential impact on treatment outcome. Methodology A total of 181 solid tumor patients at stage >/= III were subjected to WES by the SureSelectXT Human All Exon V6 + UTR library preparation kit, and sequencing in the Illumina NextSeq 550 system. Bioinformatics analysis involved use of GATK pipeline, and the variants were further assessed for population frequency, functional impact with annovar insilico algorithms. Further variant information from significant DMEs, and transporters were extracted and analyzed with PharmGKB to assess level of evidence and infer their impact on the pathways involved in drug response. Results The total study cohort of 181 solid tumor patients included 60 males, and 121 females respectively. Among DMEs, deleterious mutation in dihydropyrimidine dehydrogenase (DPYD; rs67376798), solute carrier organic anion transporter family member 1B1 (SLCO1B1*5), and cytochrome P450 2D6 (CYP2D6*10) associated with metabolism of anticancer drugs was detected to be in high frequency of 26%, 21% and 25% respectively. Conclusion Our analysis detected variations in both phase I and phase II DMEs, as well as associated transporter genes which has been documented to reduce drug efficacy, as well as cause grade 3 and 4 toxicity. Our study reiterates the significance of pharmacogenomics in stratifying patients for appropriate therapy regimen focused at better treatment outcome and quality of life.
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Affiliation(s)
- Mourad A M Aboul-Soud
- Chair of Medical and Molecular Genetics Research, Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia
| | - Alhussain J Alzahrani
- Department of Microbiology, College of Applied Medical Sciences, University of Hafre Al Batin, Hafre Al Batin, Saudi Arabia
| | - Amer Mahmoud
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, P.O. Box 2925 (28), Riyadh 11461, Saudi Arabia
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13
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Escalante PI, Quiñones LA, Contreras HR. Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX. Pharmaceutics 2021; 13:pharmaceutics13010075. [PMID: 33429840 PMCID: PMC7827270 DOI: 10.3390/pharmaceutics13010075] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/21/2020] [Accepted: 12/25/2020] [Indexed: 12/14/2022] Open
Abstract
The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.
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Affiliation(s)
- Paula I. Escalante
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics (CQF), Department of Basic and Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, 8500000 Santiago, Chile;
- Laboratory of Cellular and Molecular Oncology (LOCYM), Department of Basic and Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, 8380453 Santiago, Chile
| | - Luis A. Quiñones
- Laboratory of Chemical Carcinogenesis and Pharmacogenetics (CQF), Department of Basic and Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, 8500000 Santiago, Chile;
- Latin American Network for the Implementation and Validation of Pharmacogenomic Clinical Guidelines (RELIVAF-CYTED), 28015 Madrid, Spain
- Correspondence: (L.A.Q.); (H.R.C.); Tel.: +56-2-29770741 or +56-2-29770743 (L.A.Q.); +56-2-29786862 or +56-2-29786861 (H.R.C.)
| | - Héctor R. Contreras
- Laboratory of Cellular and Molecular Oncology (LOCYM), Department of Basic and Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, 8380453 Santiago, Chile
- Correspondence: (L.A.Q.); (H.R.C.); Tel.: +56-2-29770741 or +56-2-29770743 (L.A.Q.); +56-2-29786862 or +56-2-29786861 (H.R.C.)
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14
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Zhang Y, Wu Y, Jia Z, Cao D, Yang N, Wang Y, Cao X, Jiang J. Long non-coding RNA polymorphisms on 8q24 are associated with the prognosis of gastric cancer in a Chinese population. PeerJ 2020; 8:e8600. [PMID: 32117633 PMCID: PMC7039120 DOI: 10.7717/peerj.8600] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 01/19/2020] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer (GC) remains the third leading cause of cancer death in China. Although genome-wide association studies have identified the association between several single nucleotide polymorphisms (SNPs) on 8q24 and the risk of GC, the role of these SNPs in the prognosis of GC in Chinese populations has not yet been fully evaluated. Therefore, this study was conducted to explore the association between long non-coding RNA (lncRNA) polymorphisms on 8q24 and the prognosis of GC. Methods We genotyped 726 surgically resected GC patients to explore the association between eight SNPs in the lncRNAs CCAT1 (rs10087719, rs7816475), PCAT1 (rs1026411), PRNCR1 (rs12682421, rs13252298), and CASC8 (rs1562430, rs4871789, rs6983267) transcribed from the 8q24 locus and the prognosis of GC in a Chinese population. Results We found that the patients carrying rs12682421 AA genotypes survived for a shorter time than those with the GG/GA genotype (HR = 1.39, 95% confidence interval (CI) [1.09-1.78]). Compared with the CC/CT genotype, the TT genotype of rs1562430 was associated with an increased risk of death (HR = 1.38, 95% CI [1.06-1.80]). Furthermore, the results also identified the rs1026411 SNP as an independent prognostic factor for poor survival in GC patients. Patients carrying AA/AG variant genotypes had a 36% increased risk of death compared to those carrying the GG genotype (HR = 1.36, 95% CI [1.06-1.74]). These findings suggested that the rs12682421, rs1026411 and rs1562430 SNPs may contribute to the survival of GC and be prognostic markers for GC.
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Affiliation(s)
- Yangyu Zhang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Yanhua Wu
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhifang Jia
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Donghui Cao
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Na Yang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Yueqi Wang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xueyuan Cao
- Department of Gastric and Colorectal Surgery, First Hospital of Jilin University, Changchun, Jilin, China
| | - Jing Jiang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin, China
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15
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Min DJ, Vural S, Krushkal J. Association of transcriptional levels of folate-mediated one-carbon metabolism-related genes in cancer cell lines with drug treatment response. Cancer Genet 2019; 237:19-38. [DOI: 10.1016/j.cancergen.2019.05.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/09/2019] [Accepted: 05/29/2019] [Indexed: 02/08/2023]
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16
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Semlali A, Almutairi M, Pathan AAK, Azzi A, Parine NR, AlAmri A, Arafah M, Aljebreen AM, alharbi O, Almadi MA, Azzam NA, Alanazi M, Rouabhia M. Toll-like receptor 6 expression, sequence variants, and their association with colorectal cancer risk. J Cancer 2019; 10:2969-2981. [PMID: 31281474 PMCID: PMC6590037 DOI: 10.7150/jca.31011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 04/25/2019] [Indexed: 12/13/2022] Open
Abstract
This is the first study to examine the potential correlation of the rs3796508 and rs5743810 SNPs of the TLR6 gene in patients with colorectal cancer (CRC) in a subset of the Saudi population. TLR6 gene expression was studied by real-time PCR assaysin 10 matching normal and cancer colon tissues. TLR6 expression at the protein level was determined by immunohistochemistry. A case-control search was conductedon 115 case patients and 102 controls. All samples were genotyped with the TaqMan assay for the TLR6 gene. Odds ratios and 95% confidence interval were computed from logistic regression models after adjusting for age, sex, and tumor localization. Our findings showed a decrease in TLR6 expression (p <0.001) in colon cancer tissues when compared to normal colon tissues. Global analysis revealed no significant association between the TLR6 rs3796508 and rs5743810 and CRC in this population. However, the Val/Met genotype of rs3796508 had a significantly higher frequency in the control group than in the cases for the male group (OR= 0.095, and p= 0.03385) or the volunteers aged more than 57 years OR= 0.152; and p= 0.04069, respectively). Two non-synonymous single nucleotide polymorphisms (SNP; S249P and V327M) were common in a few patients and were predicted as damaging by SIFT and Polyphen and were further analyzed for their protein stability and function using advanced bioinformatics tools. The results suggest that TLR6 rs3796508 has a crucial role as a protective factor against colorectal cancer in the older Saudi male population.
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Affiliation(s)
- Abdelhabib Semlali
- Groupe de Recherche en Écologie Buccale, Département de stomatologie, Faculté de Médecine Dentaire, Université Laval, Québec, Québec, Canada
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mikhlid Almutairi
- Zoology Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Akbar Ali Khan Pathan
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
- Integrated Gulf Biosystems (IGB), Riyadh, Kingdom of Saudi Arabia
| | - Arezki Azzi
- Pharmacology department, College of Medicine, Imam Mohammed Ibn Saud Islamic University (IMSIU), Riyadh, Kingdom of Saudi Arabia
| | - Narasimha Reddy Parine
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Abdullah AlAmri
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Maha Arafah
- College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Abdulrahman M Aljebreen
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Othman alharbi
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Majid A Almadi
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Nahla Ali Azzam
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad Alanazi
- Department of Biochemistry, College of Science King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mahmoud Rouabhia
- Groupe de Recherche en Écologie Buccale, Département de stomatologie, Faculté de Médecine Dentaire, Université Laval, Québec, Québec, Canada
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Boige V, Mollevi C, Gourgou S, Azria D, Seitz JF, Vincent M, Bigot L, Juzyna B, Miran I, Gerard JP, Laurent-Puig P. Impact of single-nucleotide polymorphisms in DNA repair pathway genes on response to chemoradiotherapy in rectal cancer patients: Results from ACCORD-12/PRODIGE-2 phase III trial. Int J Cancer 2019; 145:3163-3172. [PMID: 31107542 DOI: 10.1002/ijc.32417] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 04/09/2019] [Accepted: 04/17/2019] [Indexed: 01/07/2023]
Abstract
We examined whether 66 germline single-nucleotide polymorphisms (SNPs) in 10 candidate genes would predict clinical outcome in 316 patients with resectable locally advanced rectal cancer (LARC) enrolled in the ACCORD-12 phase III trial who were randomly treated with preoperative radiotherapy plus capecitabine (CAP45; n = 155) or dose-intensified radiotherapy plus capecitabine and oxaliplatin (CAPOX50; n = 161). The primary endpoint was tumor response according to the Dworak score. Multivariate logistic regression models adjusted on treatment arm and T stage determined the SNPs prognostic and predictive values for tumor response. In univariate analysis, five SNPs in ERCC2, XPA, MTHFR and ERCC1 were associated with the Dworak score in the CAPOX50 arm. In the overall population, interaction with treatment arm was significant for ERCC2 rs1799787 (pinteraction = 0.05) and XPA rs3176683 (pinteraction = 0.008), suggesting a predictive effect for response to oxaliplatin-based chemoradiotherapy (CRT). All but XPA rs3176683 had a prognostic effect on tumor response. In a multivariate model, interaction remained significant for XPA rs3176683 ([OR 7.33, 95% CI 1.40-38.23], pinteraction = 0.018) and the prognostic effect significant for ERCC2 rs1799787 ([OR 0.55, 95%CI 0.32-0.93], p = 0.027) and ERCC1 rs10412761 ([OR 0.57, 95%CI 0.34-0.98], p = 0.042). Patients with the T/G haplotype of rs1799787 and rs10412761 had a 60% decrease in odds of response (p < 0.001). None of the five SNPs were associated with toxicity, overall and disease-free survival. These data suggest that genetic variation in DNA repair genes influences response to preoperative CRT in LARC and identify patients who benefit from the addition of oxaliplatin to CRT.
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Affiliation(s)
- Valérie Boige
- Department of Oncologic Medicine, Gustave-Roussy, Villejuif, France.,Université Paris Descartes; Paris Sorbonne Cité INSERM UMR-S775, Paris, France
| | - Caroline Mollevi
- Biometry Unit, Institut du Cancer Montpellier, Université de Montpellier, Montpellier, France.,Institut de Recherche en Cancérologie de Montpellier Inserm U1194, Université de Montpellier, Montpellier, France
| | - Sophie Gourgou
- Biometry Unit, Institut du Cancer Montpellier, Université de Montpellier, Montpellier, France.,Institut de Recherche en Cancérologie de Montpellier Inserm U1194, Université de Montpellier, Montpellier, France
| | - David Azria
- Department of Radiation Oncology, Institut du Cancer Montpellier, Univ Montpellier, Inserm U1194 IRCM, Montpellier, France
| | - Jean-François Seitz
- Department of Digestive Oncology, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Marc Vincent
- Université Paris Descartes; Paris Sorbonne Cité INSERM UMR-S775, Paris, France
| | - Ludovic Bigot
- Inserm U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | | | - Isabelle Miran
- Inserm U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Jean-Pierre Gerard
- Department of Radiation Oncology, Centre Antoine Lacassagne, Université Côte d'azur, Nice, France
| | - Pierre Laurent-Puig
- Université Paris Descartes; Paris Sorbonne Cité INSERM UMR-S775, Paris, France
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18
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Abstract
Abstract
The field of biotechnology is large and could be considered tritely as simply the development of technology that is based on biology. It is clear that the concepts of biotechnology can spread to cover many different fields of application and so the future developments in biotechnology will be similarly wide-ranging across many fields of applications. Here we focus onto medical biotechnology and further refine our discussion onto considering aspects of genetics and nanotechnologies that could impact on the development of future biotechnologies in the medical field. These areas that we consider in this brief article provide the basis for a panel discussion on Future Biotechnology at the European Biotechnology Congress held in Valencia, Spain in April 2019.
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19
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Yang J, Huang Y, Feng Y, Li H, Feng T, Chen J, Yin L, Wang W, Wang S, Liu Y, Song Y, Li Y, Jin J, Tan W, Lin D. Associations of Genetic Variations in Mismatch Repair Genes MSH3 and PMS1 with Acute Adverse Events and Survival in Patients with Rectal Cancer Receiving Postoperative Chemoradiotherapy. Cancer Res Treat 2018; 51:1198-1206. [PMID: 30590005 PMCID: PMC6639227 DOI: 10.4143/crt.2018.527] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 12/24/2018] [Indexed: 12/20/2022] Open
Abstract
Purpose Mismatch repair (MMR) deficiency plays a critical role in rectal cancer. This study aimed to explore the associations between genetic variations in seven MMR genes and adverse events (AEs) and survival of patients with rectal cancer treated with postoperative chemoradiotherapy (CRT). Materials and Methods Fifty single nucleotide polymorphisms in seven MMR (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) genes were genotyped by Sequenom MassARRAY method in 365 patients with locally advanced rectal cancer receiving postoperative CRT. The associations between genotypes and AEs were measured by odds ratios and 95% confidence intervals (CIs) by unconditional logistic regression model. The associations between genetic variations and survival were computed by the hazard ratios and 95% CIs by Cox proportional regression model. Results The most common grade ≥ 2 AEs in those 365 patients, in decreasing order, were diarrhea (44.1%), leukopenia (29.6%), and dermatitis (18.9%). Except 38 cases missing, 61 patients (18.7%) died during the follow-up period. We found MSH3 rs12513549, rs33013 and rs6151627 significantly associated with the risk of grade ≥ 2 diarrhea. PMS1 rs1233255 had an impact on the occurrence of grade ≥2 dermatitis. Meanwhile, PMS1 rs4920657, rs5743030, and rs5743100 were associated with overall survival (OS) time of rectal cancer. Conclusion These results suggest that MSH3 and PMS1 polymorphisms may play important roles in AEs prediction and prognosis of rectal cancer patients receiving postoperative CRT, which can be potential genetic biomarkers for rectal cancer personalized treatment.
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Affiliation(s)
- Jie Yang
- State Key Laboratory of Molecular Oncology, Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Huang
- State Key Laboratory of Molecular Oncology, Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanru Feng
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongmin Li
- State Key Laboratory of Molecular Oncology, Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ting Feng
- State Key Laboratory of Molecular Oncology, Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinna Chen
- State Key Laboratory of Molecular Oncology, Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Luxi Yin
- State Key Laboratory of Molecular Oncology, Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weihu Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shulian Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yueping Liu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongwen Song
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yexiong Li
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Jin
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wen Tan
- State Key Laboratory of Molecular Oncology, Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dongxin Lin
- State Key Laboratory of Molecular Oncology, Department of Etiology & Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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20
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Ose J, Botma A, Balavarca Y, Buck K, Scherer D, Habermann N, Beyerle J, Pfütze K, Seibold P, Kap EJ, Benner A, Jansen L, Butterbach K, Hoffmeister M, Brenner H, Ulrich A, Schneider M, Chang‐Claude J, Burwinkel B, Ulrich CM. Pathway analysis of genetic variants in folate-mediated one-carbon metabolism-related genes and survival in a prospectively followed cohort of colorectal cancer patients. Cancer Med 2018; 7:2797-2807. [PMID: 29845757 PMCID: PMC6051204 DOI: 10.1002/cam4.1407] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 01/13/2018] [Accepted: 01/23/2018] [Indexed: 01/15/2023] Open
Abstract
Folate-mediated one-carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5-fluorouracil (5-FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM-related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM-related genes for associations with overall- (OS) and disease-free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5-FU-based chemotherapy and assessed pathway-specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow-up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HRhet = 0.81, 95% CI: 0.67-0.97; TYMS: rs1001761: HRhet = 0.82, 95% CI: 0.68-0.99 and rs2847149: HRhet = 0.82, 95% CI: 0.68-0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HRhet = 1.28, 95% CI: 1.07-1.53; HRhzv = 2.02, 95% CI:1.46-2.80; HRlogAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P < 0.01) with significant gene-chemotherapy interactions, including PON1 rs3917538. This study supports the concept that FOCM-related genes could be associated with CRC survival and may modify effects of 5-FU-based chemotherapy in genes in pyrimidine and fluorouracil metabolism, which are relevant targets for therapeutic response and prognosis in CRC. These results require confirmation in additional clinical studies.
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Affiliation(s)
- Jennifer Ose
- Department of Population Health SciencesHuntsman Cancer InstituteUniversity of UtahSalt Lake CityUtah
| | - Akke Botma
- Division of Preventive OncologyNational Center for Tumor Diseases and German Cancer Research CenterHeidelbergGermany
| | - Yesilda Balavarca
- Division of Preventive OncologyNational Center for Tumor Diseases and German Cancer Research CenterHeidelbergGermany
| | - Katharina Buck
- Division of Preventive OncologyNational Center for Tumor Diseases and German Cancer Research CenterHeidelbergGermany
| | - Dominique Scherer
- Institute of Medical Biometry and InformaticsUniversity of HeidelbergHeidelbergGermany
| | - Nina Habermann
- Genome Biology, European Molecular Biology LaboratoryGerman Cancer Research Center and National Center for Tumor DiseasesHeidelbergGermany
- Division of Molecular EpidemiologyGerman Cancer Research CenterHeidelbergGermany
| | - Jolantha Beyerle
- Division of Preventive OncologyNational Center for Tumor Diseases and German Cancer Research CenterHeidelbergGermany
| | - Katrin Pfütze
- Division of Preventive OncologyNational Center for Tumor Diseases and German Cancer Research CenterHeidelbergGermany
- Division Molecular Biology of Breast CancerDepartment of Gynecology and ObstetricsUniversity of HeidelbergHeidelbergGermany
| | - Petra Seibold
- Division of Cancer Epidemiology German Cancer Research CenterHeidelbergGermany
| | - Elisabeth J. Kap
- Division of Cancer Epidemiology German Cancer Research CenterHeidelbergGermany
| | - Axel Benner
- Division of BiostatisticsGerman Cancer Research CenterHeidelbergGermany
| | - Lina Jansen
- Division of Cancer Epidemiology German Cancer Research CenterHeidelbergGermany
| | - Katja Butterbach
- Division of Cancer Epidemiology German Cancer Research CenterHeidelbergGermany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research CenterHeidelbergGermany
| | - Hermann Brenner
- Division of Preventive OncologyNational Center for Tumor Diseases and German Cancer Research CenterHeidelbergGermany
- Division of Clinical Epidemiology and Aging ResearchGerman Cancer Research CenterHeidelbergGermany
| | - Alexis Ulrich
- Clinic for General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Martin Schneider
- Clinic for General, Visceral and Transplantation SurgeryHeidelberg University HospitalHeidelbergGermany
| | - Jenny Chang‐Claude
- Division Molecular Biology of Breast CancerDepartment of Gynecology and ObstetricsUniversity of HeidelbergHeidelbergGermany
| | - Barbara Burwinkel
- Division of Molecular EpidemiologyGerman Cancer Research CenterHeidelbergGermany
- Division Molecular Biology of Breast CancerDepartment of Gynecology and ObstetricsUniversity of HeidelbergHeidelbergGermany
| | - Cornelia M. Ulrich
- Department of Population Health SciencesHuntsman Cancer InstituteUniversity of UtahSalt Lake CityUtah
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Luo C, Liu A, Long W, Liao H, Yang Y. Transcriptome analysis of Cyrtotrachelus buqueti in two cities in China. Gene 2018; 647:1-12. [PMID: 29274908 DOI: 10.1016/j.gene.2017.12.041] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 12/14/2017] [Accepted: 12/20/2017] [Indexed: 12/20/2022]
Abstract
In order to reduce the Cyrtotrachelus buqueti population, which is a serious pest in the bamboo industry, a range of approaches is required, which will be dependent on diverse gene expression influenced by environmental factors. In this study, samples from two regions of China, Muchuan in Sichuan Province and Chishui in Guizhou Province, were investigated through RNA-seq. Approximately 44 million high-quality reads were generated and 94.2% of the data was mapped to the transcriptome. A total of 15,641 out of the 29,406 identified genes were predicted. Moreover, 348 genes were differentially expressed between the two groups of imagoes (77 upregulated and 271 downregulated). The functional analysis showed that these genes were significantly enriched in the ribosome and metabolic pathway categories. The candidate genes contributing to the reduction in C. buqueti included 41 genes involved in the ribosome constitution category, five in the one‑carbon pool pathway by folate category, and five heat shock protein genes. The downregulation of these candidate genes seems to have impaired metabolic processes, such as protein, DNA, RNA, and purine synthesis, as well as carbon and folate metabolism, subsequently resulting in the observed population reduction of C. buqueti. Furthermore, temperature, heavy metal content, and pH might influence the population by altering the expressions of genes involved in these metabolic processes.
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Affiliation(s)
- Chaobing Luo
- Bamboo Diseases and Pests Control and Resources Development Key Laboratory of Sichuan Province, Leshan Normal University, Leshan 614000, Sichuan, China; College of Life Science, Leshan Normal University, Leshan 614000, Sichuan, China
| | - Anxuan Liu
- Bamboo Diseases and Pests Control and Resources Development Key Laboratory of Sichuan Province, Leshan Normal University, Leshan 614000, Sichuan, China; College of Life Science, Leshan Normal University, Leshan 614000, Sichuan, China; College of Food and Bioengineering, Xihua University, Chengdu 6110039, Sichuan, China
| | - Wencong Long
- Bamboo Diseases and Pests Control and Resources Development Key Laboratory of Sichuan Province, Leshan Normal University, Leshan 614000, Sichuan, China; College of Life Science, Leshan Normal University, Leshan 614000, Sichuan, China; College of Food and Bioengineering, Xihua University, Chengdu 6110039, Sichuan, China
| | - Hong Liao
- Bamboo Diseases and Pests Control and Resources Development Key Laboratory of Sichuan Province, Leshan Normal University, Leshan 614000, Sichuan, China; College of Life Science, Leshan Normal University, Leshan 614000, Sichuan, China; College of Food and Bioengineering, Xihua University, Chengdu 6110039, Sichuan, China
| | - Yaojun Yang
- Bamboo Diseases and Pests Control and Resources Development Key Laboratory of Sichuan Province, Leshan Normal University, Leshan 614000, Sichuan, China.
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22
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Huang Y, Feng Y, Ren H, Zhang M, Li H, Qiao Y, Feng T, Yang J, Wang W, Wang S, Liu Y, Song Y, Li Y, Jin J, Tan W, Lin D. Associations of Genetic Variations in MicroRNA Seed Regions With Acute Adverse Events and Survival in Patients With Rectal Cancer Receiving Postoperative Chemoradiation Therapy. Int J Radiat Oncol Biol Phys 2018; 100:1026-1033. [PMID: 29485044 DOI: 10.1016/j.ijrobp.2017.12.256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 12/06/2017] [Accepted: 12/11/2017] [Indexed: 01/05/2023]
Abstract
PURPOSE The aim of this study was to investigate the associations between single nucleotide polymorphisms (SNPs) in the seed regions of microRNAs and acute adverse events (AEs) and survival in patients with rectal cancer receiving postoperative chemoradiation therapy. METHODS AND MATERIALS Eighteen SNPs were genotyped in 365 patients with rectal cancer receiving postoperative chemoradiation therapy. The associations between genotypes and AEs were estimated by odds ratios and 95% confidence intervals (CIs), which were computed by using multivariate logistic regression models. The hazard ratios and 95% CIs to assess the death of patients for different genotypes were calculated by Cox proportional regression models. Overall survival and disease-free survival of patients with different genotypes were estimated by Kaplan-Meier plots, and the statistical significance was determined by using the log-rank test. RESULTS In these patients, the most common grade ≥2 AEs were diarrhea (44.1%), leukopenia (29.6%), and dermatitis (18.9%). With false discovery rate correction, SNP rs2273626 was significantly associated with a decreased risk of grade ≥2 leukopenia (odds ratio, 0.48; 95% CI, 0.31-0.74; P = .0009). In addition, SNP rs202195689 was associated with overall survival and disease-free survival in patients receiving postoperative chemoradiation therapy, with the hazard ratios for death being 2.02 (95% CI, 1.36-3.01; P = .0006) and 1.91 (95% CI, 1.36-2.70; P = .0002), respectively. However, no significant association between these SNPs and diarrhea and dermatitis was observed. CONCLUSIONS These results suggest that rs2273626 and rs202195689 in microRNA seed regions might serve as independent biomarkers for predicting AEs and prognosis in patients with rectal cancer receiving postoperative chemoradiation therapy. Independent replication of these findings is required to confirm these results.
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Affiliation(s)
- Ying Huang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology & Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanru Feng
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hua Ren
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Meng Zhang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology & Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongmin Li
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology & Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Qiao
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology & Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ting Feng
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology & Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Yang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology & Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weihu Wang
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shulian Wang
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yueping Liu
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongwen Song
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yexiong Li
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Jin
- Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Wen Tan
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology & Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Dongxin Lin
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Etiology & Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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23
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Bidadi B, Liu D, Kalari KR, Rubner M, Hein A, Beckmann MW, Rack B, Janni W, Fasching PA, Weinshilboum RM, Wang L. Pathway-Based Analysis of Genome-Wide Association Data Identified SNPs in HMMR as Biomarker for Chemotherapy- Induced Neutropenia in Breast Cancer Patients. Front Pharmacol 2018; 9:158. [PMID: 29593529 PMCID: PMC5859084 DOI: 10.3389/fphar.2018.00158] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 02/13/2018] [Indexed: 12/14/2022] Open
Abstract
Neutropenia secondary to chemotherapy in breast cancer patients can be life-threatening and there are no biomarkers available to predict the risk of drug-induced neutropenia in those patients. We previously performed a genome-wide association study (GWAS) for neutropenia events in women with breast cancer who were treated with 5-fluorouracil, epirubicin and cyclophosphamide and recruited to the SUCCESS-A trial. A genome-wide significant single-nucleotide polymorphism (SNP) signal in the tumor necrosis factor superfamily member 13B (TNFSF13B) gene, encoding the cytokine B-cell activating factor (BAFF), was identified in that GWAS. Taking advantage of these existing GWAS data, in the present study we utilized a pathway-based analysis approach by leveraging knowledge of the pharmacokinetics and pharmacodynamics of drugs and breast cancer pathophysiology to identify additional SNPs/genes associated with the underlying etiology of chemotherapy-induced neutropenia. We identified three SNPs in the hyaluronan mediated motility receptor (HMMR) gene that were significantly associated with neutropenia (p < 1.0E-04). Those three SNPs were trans-expression quantitative trait loci for the expression of TNFSF13B (p < 1.0E-04). The minor allele of these HMMR SNPs was associated with a decreased TNFSF13B mRNA level. Additional functional studies performed with lymphoblastoid cell lines (LCLs) demonstrated that LCLs possessing the minor allele for the HMMR SNPs were more sensitive to drug treatment. Knock-down of TNFSF13B in LCLs and HL-60 promyelocytic cells and treatment of those cells with BAFF modulated the cell sensitivity to chemotherapy treatment. These results demonstrate that HMMR SNP-dependent cytotoxicity of these chemotherapeutic agents might be related to TNFSF13B expression level. In summary, utilizing a pathway-based approach for the analysis of GWAS data, we identified additional SNPs in the HMMR gene that were associated with neutropenia and also were correlated with TNFSF13B expression.
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Affiliation(s)
- Behzad Bidadi
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Duan Liu
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Krishna R Kalari
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
| | - Matthias Rubner
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Alexander Hein
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Matthias W Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Brigitte Rack
- Department of Gynecology and Obstetrics, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Richard M Weinshilboum
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Liewei Wang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
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24
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Influence of the ABCB1 polymorphisms on the response to Taxane-containing chemotherapy: a systematic review and meta-analysis. Cancer Chemother Pharmacol 2017; 81:315-323. [PMID: 29209772 DOI: 10.1007/s00280-017-3496-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 11/28/2017] [Indexed: 10/18/2022]
Abstract
PURPOSE Multidrug resistance mediated by ABCB1 has been perceived to be one of the obstacles for cancer chemotherapy. This meta-analysis was performed to verify the effect of the ABCB1 rs1045642 and rs1128503 polymorphisms on the response to Taxane-containing chemotherapy. METHODS Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were employed to evaluate the impact of these two ABCB1 polymorphisms. R scripts were developed to perform the meta-analysis. RESULTS A total of nine articles (including nine studies for rs1045642 and five for rs1128503) were collected in our systematic review. However, our meta-analysis showed no significant effect of these two ABCB1 polymorphisms on the response to Taxane-containing regimens. CONCLUSIONS This study highlights the unsuitability of relying on the ABCB1 rs1045642 and rs1128503 polymorphisms as therapeutic response biomarkers of Taxane-containing chemotherapy. Further polycentric studies in larger and multiracial populations are needed to validate the conclusions.
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25
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Li Q, Qu F, Li R, He X, Zhai Y, Chen W, Zheng Y. A functional polymorphism of SSBP1 gene predicts prognosis and response to chemotherapy in resected gastric cancer patients. Oncotarget 2017; 8:110861-110876. [PMID: 29340022 PMCID: PMC5762290 DOI: 10.18632/oncotarget.22864] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 11/03/2017] [Indexed: 12/17/2022] Open
Abstract
Growing evidence has indicated that single-stranded DNA-binding proteins 1 (SSBP1) is involved in tumor initiation and progression. However, effects of single nucleotide polymorphisms (SNPs) in SSBP1 gene on gastric cancer (GC) prognosis are still unknown. In present study, two functional SNPs from SSBP1 were selected and genotyped in a large cohorts of 1030 resected GC patients (326 in the training set, 704 in the validation set) to explore the association of SNPs with patients’ survival. The rs6976500 G allele (CG/GG) genotypes were found significantly associated with both worse overall survival (OS) and recurrence-free survival (RFS) in the training and the independent validation set when compared to C allele genotype, which reaching a more robust statistical significance in the pooled analysis. Furthermore, integration of rs6976500 genotypes and TNM stage significantly improved the prognosis prediction models based on TNM stage alone. In addition, only carriers with at least one G allele of rs6976500 gained significant survival benefit from FOLFOX-based ACT. Mechanistically, SNP rs6976500 G allele genotype could significantly decrease promoter transcriptional activity and markedly reduce expression level of SSBP1 compared with the C allele genotype in GC cells. This was further substantiated by immunohistochemical assay in 70 GC tissue samples. Our study presents the first evidence that SNP rs6976500 G allele genotypes might contribute to GC prognosis by attenuating SSBP1 promoter activity and gene expression, and provides the guidance in refining therapeutic decisions of GC patients. Further exploration on its function is needed to clarify the exact biological mechanism behind.
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Affiliation(s)
- Qiuchen Li
- Department of Gastroenterology, First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, 832008, China
| | - Falin Qu
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710038, China
| | - Renli Li
- Department of General Surgery, The Fourth Hospital of Chinese PLA, Xining, Qinghai, 810007, China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710038, China
| | - Yulong Zhai
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710038, China
| | - Weigang Chen
- Department of Gastroenterology, First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, 832008, China
| | - Yong Zheng
- Department of Gastroenterology, First Affiliated Hospital of the Medical College, Shihezi University, Shihezi, Xinjiang, 832008, China
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Affiliation(s)
- Pascal Pineau
- Organisation nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, Paris Cedex, France
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Chen XQ, Mao JY, Li WB, Li J, Yang H, Qian JM, Li JN. Association between CYP24A1 polymorphisms and the risk of colonic polyps and colon cancer in a Chinese population. World J Gastroenterol 2017; 23:5179-5186. [PMID: 28811712 PMCID: PMC5537184 DOI: 10.3748/wjg.v23.i28.5179] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 05/15/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the pathogenesis and potential single nucleotide polymorphisms (SNPs) as screening sites for colonic polyps, colon cancer and ulcerative colitis, and to analyze the possible association between these genetic polymorphisms and the three diseases.
METHODS We evaluated genetic polymorphisms in 144 newly diagnosed colonic polyp patients, 96 colon cancer patients and 44 ulcerative colitis patients. The four SNPs genotyped were rs4809957, rs6068816, rs6091822 and rs8124792. The control group consisted of 504 East Asians enrolled in the 1000 Genomes Project. Correlations between CYP24A1 SNPs and the diseases were analyzed by Fisher’s exact probability test.
RESULTS CYP24A1 polymorphisms rs4809957 A/G and rs6068816 C/T showed a statistically significant association with risk of the three diseases, when both the genotypes and allele frequencies were considered. With regard to rs6091822 G/T, all three diseases were related to risk allele carriers (GT + TT) vs wild-type (GG), but the associations between the allele frequencies and the diseases were not significant. The risk of colonic polyps and colon cancer was related to the allele frequencies of rs8124792 G/A, and this association remained for genotype frequencies of this SNP.
CONCLUSION Four SNPs are related to the risk of colonic polyps and colon cancer. G allele in rs6091822 G/T may play an anti-cancer role only if it is homozygous. The A allele, which is a minor component of rs8124792, may be indicated in the diagnosis of colonic polyps or colon cancer rather than ulcerative colitis.
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How gene polymorphisms can influence clinical response and toxicity following R-CHOP therapy in patients with diffuse large B cell lymphoma. Blood Rev 2017; 31:235-249. [DOI: 10.1016/j.blre.2017.02.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Revised: 12/07/2016] [Accepted: 02/03/2017] [Indexed: 12/20/2022]
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Vrbanac A, Debelius JW, Jiang L, Morton JT, Dorrestein P, Knight R. An Elegan(t) Screen for Drug-Microbe Interactions. Cell Host Microbe 2017; 21:555-556. [PMID: 28494234 DOI: 10.1016/j.chom.2017.04.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Microbes affect drug responses, but mechanisms remain elusive. Two papers in Cell exploit C. elegans to infer anticancer drug mechanisms. Through high-throughput screens of drug-microbe-host interactions, García-González et al. (2017) and Scott et al. (2017) determine that bacterial metabolism underpins fluoropyrimidine cytotoxicity, providing a paradigm for unraveling bacterial mechanisms in drug metabolism.
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Affiliation(s)
- Alison Vrbanac
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Justine W Debelius
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Lingjing Jiang
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - James T Morton
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Pieter Dorrestein
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA
| | - Rob Knight
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
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Nakao H, Wakai K, Ishii N, Kobayashi Y, Ito K, Yoneda M, Mori M, Nojima M, Kimura Y, Endo T, Matsuyama M, Ishii H, Ueno M, Kuruma S, Egawa N, Matsuo K, Hosono S, Ohkawa S, Nakamura K, Tamakoshi A, Takahashi M, Shimada K, Nishiyama T, Kikuchi S, Lin Y. Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects. BMC Gastroenterol 2016; 16:83. [PMID: 27473058 PMCID: PMC4966808 DOI: 10.1186/s12876-016-0503-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 07/26/2016] [Indexed: 12/12/2022] Open
Abstract
Background Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects. Methods Our case-control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk. Results Overall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk. Conclusions Our data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk.
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Affiliation(s)
- Haruhisa Nakao
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Norimitsu Ishii
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan
| | - Yuji Kobayashi
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan
| | - Kiyoaki Ito
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan
| | - Masashi Yoneda
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan
| | - Mitsuru Mori
- Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, 060-0061, Japan
| | - Masanori Nojima
- Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, 060-0061, Japan
| | - Yasutoshi Kimura
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, 060-8543, Japan
| | - Takao Endo
- Sapporo Shirakaba-dai Hospital, Sapporo, 062-0052, Japan
| | - Masato Matsuyama
- Hepatobiliary and Pancreatic Section, Gastroenterological Division, Cancer Institute Hospital, Tokyo, 135-8550, Japan
| | - Hiroshi Ishii
- Clinical Research Center, National Hospital Organization Shikoku Cancer Center, Matsuyama, 791-0280, Japan
| | - Makoto Ueno
- Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center Hospital, Kanagawa, 241-8515, Japan
| | - Sawako Kuruma
- Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, 113-8677, Japan
| | - Naoto Egawa
- Tokyo Metropolitan Otsuka Hospital, Tokyo, 170-8476, Japan
| | - Keitaro Matsuo
- Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, 762-6111, Japan.,Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Satoyo Hosono
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 762-6111, Japan
| | - Shinichi Ohkawa
- Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center Hospital, Kanagawa, 241-8515, Japan
| | - Kozue Nakamura
- Department of Food and Nutrition, Gifu City Women's College, Gifu, 501-2592, Japan
| | - Akiko Tamakoshi
- Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan
| | - Mami Takahashi
- Central Animal Division, National Cancer Center Research Institute, Tokyo, 104-0045, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, 104-0045, Japan
| | - Takeshi Nishiyama
- Department of Public Health, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan
| | - Shogo Kikuchi
- Department of Public Health, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan
| | - Yingsong Lin
- Department of Public Health, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan.
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Krushkal J, Zhao Y, Hose C, Monks A, Doroshow JH, Simon R. Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment. Clin Epigenetics 2016; 8:73. [PMID: 27347216 PMCID: PMC4919895 DOI: 10.1186/s13148-016-0240-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Aberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Genetic components of the folate-mediated one-carbon metabolism pathway can affect DNA methylation and other vital cell functions, including DNA synthesis, amino acid biosynthesis, and cell growth. RESULTS We used a bioinformatics tool, the Transcriptional Pharmacology Workbench, to analyze temporal changes in gene expression among epigenetic regulators of DNA methylation and demethylation, and one-carbon metabolism genes in response to cancer drug treatment. We analyzed gene expression information from the NCI-60 cancer cell line panel after treatment with five antitumor agents, 5-azacytidine, doxorubicin, vorinostat, paclitaxel, and cisplatin. Each antitumor agent elicited concerted changes in gene expression of multiple pathway components across the cell lines. Expression changes of FOLR2, SMUG1, GART, GADD45A, MBD1, MTR, MTHFD1, and CTH were significantly correlated with chemosensitivity to some of the agents. Among many genes with concerted expression response to individual antitumor agents were genes encoding DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, epigenetic and DNA repair factors MGMT, GADD45A, and MBD1, and one-carbon metabolism pathway members MTHFD1, TYMS, DHFR, MTR, MAT2A, SLC19A1, ATIC, and GART. CONCLUSIONS These transcriptional changes are likely to influence vital cellular functions of DNA methylation and demethylation, cellular growth, DNA biosynthesis, and DNA repair, and some of them may contribute to cytotoxic and apoptotic action of the drugs. This concerted molecular response was observed in a time-dependent manner, which may provide future guidelines for temporal selection of genetic drug targets for combination drug therapy treatment regimens.
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Affiliation(s)
- Julia Krushkal
- />Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD 20850 USA
| | - Yingdong Zhao
- />Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD 20850 USA
| | - Curtis Hose
- />Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702 USA
| | - Anne Monks
- />Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702 USA
| | - James H. Doroshow
- />Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892 USA
| | - Richard Simon
- />Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD 20850 USA
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Bao G, Qu F, He L, Zhao H, Wang N, Ji G, He X. Prognostic Significance of Tag SNP rs1045411 in HMGB1 of the Aggressive Gastric Cancer in a Chinese Population. PLoS One 2016; 11:e0154378. [PMID: 27116470 PMCID: PMC4845981 DOI: 10.1371/journal.pone.0154378] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 04/12/2016] [Indexed: 12/21/2022] Open
Abstract
Compelling evidences have suggested that high mobility group box-1 (HMGB1) gene plays a crucial role in cancer development and progression. This study aimed to evaluate the effects of single nucleotide polymorphisms (SNPs) in HMGB1 gene on the survival of gastric cancer (GC) patients. Three tag SNPs from HMGB1 gene were selected and genotyped using Sequenom iPEX genotyping system in a cohort of 1030 GC patients (704 in training set, 326 in validation set). Multivariate Cox proportional hazard model and Kaplan-Meier Curve were used for prognosis analysis. AG/AA genotypes of SNP rs1045411 in HMGB1 gene were significantly associated with better overall survival (OS) in a set of 704 GC patients when compared with GG genotypes (HR = 0.77, 95% CI: 0.60-0.97, P = 0.032). This prognostic effect was verified in an independent validation set and pooled analysis (HR = 0.80, 95% CI: 0.62-0.99, P = 0.046; HR = 0.78, 95% CI: 0.55-0.98, P = 0.043, respectively). In stratified analysis, the protective effect of rs1045411 AG/AA genotypes was more prominent in patients with adverse strata, compared with patients with favorable strata. Furthermore, strong joint predictive effects on OS of GC patients were noted between rs1045411 genotypes and Lauren classification, differentiation, stage or adjuvant chemotherapy. Additionally, functional assay indicated a significant effect of rs1045411 on HMGB1 expression. Our results suggest that rs1045411 in HMGB1 is significantly associated with clinical outcomes of Chinese GC patients after surgery, especially in those with aggressive status, which warrants further validation in other ethnic populations.
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Affiliation(s)
- Guoqiang Bao
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710032, China
- * E-mail: (GB); (XH)
| | - Falin Qu
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710032, China
| | - Li He
- Department of Ophthalmology, School of Medicine, Emory University, Atlanta, GA 30322, United States of America
| | - Huadong Zhao
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710032, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710032, China
| | - Gang Ji
- Xijing Hospital of Digestive Disease, The Fourth Military Medical University, Xi'an, 710032, China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, 710032, China
- * E-mail: (GB); (XH)
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Qu F, Qiao Q, Wang N, Ji G, Zhao H, He L, Wang H, Bao G. Genetic polymorphisms in circadian negative feedback regulation genes predict overall survival and response to chemotherapy in gastric cancer patients. Sci Rep 2016; 6:22424. [PMID: 26927666 PMCID: PMC4772484 DOI: 10.1038/srep22424] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 02/15/2016] [Indexed: 12/15/2022] Open
Abstract
Circadian negative feedback loop (CNFL) genes play important roles in cancer development and progression. To evaluate the effects of single nucleotide polymorphisms (SNPs) in CNFL genes on the survival of GC patients, 13 functional SNPs from 5 CNFL genes were genotyped in a cohort of 1030 resected GC patients (704 in the training set, 326 in the validation set) to explore the association of SNPs with overall survival (OS). Among the 13 SNPs, three SNPs (rs1056560 in CRY1, rs3027178 in PER1 and rs228729 in PER3) were significantly associated with OS of GC in the training set, and verified in the validation set and pooled analysis. Furthermore, a dose-dependent cumulative effect of these SNPs on GC survival was observed, and survival tree analysis showed higher order interactions between these SNPs. In addition, protective effect conferred by adjuvant chemotherapy (ACT) on GC was observed in patients with variant alleles (TG/GG) of rs1056560, but not in those with homozygous wild (TT) genotype. Functional assay suggested rs1056560 genotypes significantly affect CRY1 expression in cancer cells. Our study presents that SNPs in the CNFL genes may be associated with GC prognosis, and provides the guidance in selecting potential GC patients most likely responsive to ACT.
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Affiliation(s)
- Falin Qu
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, China.,93926 Army Hospital of PLA, Hetian 848000, China
| | - Qing Qiao
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, China
| | - Nan Wang
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, China
| | - Gang Ji
- Xijing Hospital of Digestive Disease, The Fourth Military Medical University, Xi'an, 710032 China
| | - Huadong Zhao
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, China
| | - Li He
- Department of Ophthalmology, School of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Haichao Wang
- Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY 11030, USA
| | - Guoqiang Bao
- Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, China
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Al-Harras MF, Houssen ME, Shaker ME, Farag K, Farouk O, Monir R, El-Mahdy R, Abo-Hashem EM. Polymorphisms of glutathione S-transferase π 1 and toll-like receptors 2 and 9: Association with breast cancer susceptibility. Oncol Lett 2016; 11:2182-2188. [PMID: 26998146 DOI: 10.3892/ol.2016.4159] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 09/04/2015] [Indexed: 12/24/2022] Open
Abstract
Polymorphisms in antioxidant enzymes and innate immune receptors have been implicated in the development of various types of cancer. The present study aimed to investigate whether polymorphisms of glutathione S-transferase π 1 (GSTP1) and toll-like receptors (TLRs) 2 and 9 are associated with susceptibility to breast cancer among females. The study was conducted on 72 Egyptian female patients with breast cancer, along with 100 healthy volunteers. Polymorphisms of GSTP1 (codon 105 Ile/Val) and TLR9 rs187084 (1237T/C) genes were assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, while the -196 to -174 deletion/insertion (del/ins) polymorphism of TLR2 was detected by PCR. The results indicated a decrease in GSTP1 Val allele frequency in breast cancer patients compared with healthy controls, at rates of 22.9 vs. 32.5%, respectively. In addition, the breast cancer group demonstrated a decreased TLR9 C allele frequency compared with the control group, at rates of 36.1 vs. 51.5%, respectively (P=0.0047). A non-significant difference was detected in the frequency of the TLR2 -196 to -174 del allele in breast cancer patients when compared to normal controls. In conclusion, these results suggested that the GSTP1 Val and TLR9 1237C alleles, but not TLR2 -196 to -174 del, are likely to be associated with breast cancer development among females.
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Affiliation(s)
- Mohammad F Al-Harras
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Maha E Houssen
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour 71515, Egypt
| | - Mohamed E Shaker
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Kamel Farag
- Department of Oncology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Omar Farouk
- Surgical Oncology and Breast Surgery, Oncology Center, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Rehan Monir
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Rasha El-Mahdy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Ekbal M Abo-Hashem
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
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Wang Y, Ha M, Liu J, Li P, Zhang W, Zhang X. Role of BCL2-associated athanogene in resistance to platinum-based chemotherapy in non-small-cell lung cancer. Oncol Lett 2015; 11:984-990. [PMID: 26893680 PMCID: PMC4734146 DOI: 10.3892/ol.2015.4003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 07/07/2015] [Indexed: 01/29/2023] Open
Abstract
The present study aimed to address the pharmacogenetic role of BAG1 in platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC) and in cultured human lung adenocarcinoma A549 cells. A total of 108 NSCLC patients (stages I-IIIA) were treated with a standard chemotherapy regimen of cisplatin plus vinorelbine. Additionally, in vitro cultured A549 cells were treated with cisplatin in the presence or absence of tunicamycin. Cell proliferation was determined by MTT assay and protein levels were assessed via western blot analysis. Patients with BAG1-positive expression were revealed to have a prolonged survival time (progression-free survival, 24.0 months) compared with that of patients without BAG1 expression (21.6 months; χ2=18.018, P<0.05). Treatment of A549 cells with tunicamycin followed by cisplatin resulted in elevated BAG1 levels. In addition, tunicamycin was found to significantly enhance cisplatin-induced growth inhibition and apoptosis in A549 cells. The results indicate that BAG1 is important in cisplatin-induced cell death in lung adenocarcinoma, suggesting that endoplasmic reticulum stress may promote the sensitivity of NSCLC patients to chemotherapy.
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Affiliation(s)
- Yadi Wang
- Department of Oncology, Third Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Minwen Ha
- Department of Oncology, First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Jingsong Liu
- Department of Heart Surgery, First Affiliated Hospital of Xuzhou Medical College, Jinzhou, Liaoning 121000, P.R. China
| | - Ping Li
- Department of Oncology, First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Wenlu Zhang
- Department of Oncology, First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Xuan Zhang
- Department of Oncology, First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121000, P.R. China
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Dong G, He X, Chen Y, Cao H, Wang J, Liu X, Wang S, Wan S, Xing J. Genetic variations in genes of metabolic enzymes predict postoperational prognosis of patients with colorectal cancer. Mol Cancer 2015; 14:171. [PMID: 26377099 PMCID: PMC4574264 DOI: 10.1186/s12943-015-0442-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 09/03/2015] [Indexed: 12/13/2022] Open
Abstract
Background Genetic alterations in tricarboxylic acid (TCA) cycle metabolic enzymes were recently linked to various cancers. However, the associations of single nucleotide polymorphisms (SNPs) in genes of these enzymes have not been well studied. Methods We genotyped 16 SNPs from 7 genes encoding TCA cycle metabolic enzymes in 697 colorectal carcinoma (CRC) patients receiving surgical resection and analyzed their associations with clinical outcomes by multivariate Cox proportional hazard model. Then, the significant results were validated in another cohort of 256 CRC patients. Results We identified 4 SNPs in 2 genes had significant associations with CRC death risk and 5 SNPs in 3 genes had significant associations with CRC recurrence risk. Similar significant results were confirmed for rs4131826 in SDHC gene, rs544184 in SDHD gene and rs12071124 in FH gene in a validation cohort. Further analysis indicated that unfavorable genotypes exhibited a significant cumulative effect on overall and recurrence-free survival in a dose-dependent manner. Moreover, survival tree analysis indicated that SNP rs4131826 in SDHC gene and SNP rs12071124 in FH gene were the primary factors contributing to the different overall survival time and recurrence-free survival time of CRC patients, respectively. Immunohistochemical analysis further validated the effect of rs4131826 and rs544184 on expression of SDHC and SDHD in tissue samples. Conclusions Our study suggests that SNPs in TCA cycle metabolic enzymes might be significantly associated with clinical outcomes in Chinese population diagnosed with CRC. Further functional and validated studies are warranted to expend our results to clinical utility. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0442-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Guanglong Dong
- Department of General Surgery, The General Hospital of PLA, Beijing, 100853, China
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yibing Chen
- State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, 710032, China
| | - Haiyan Cao
- State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, 710032, China
| | - Jiaojiao Wang
- State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, 710032, China
| | - Xiaonan Liu
- Xijing Hospital of Digestive Disease, Fourth Military Medical University, Xi'an, 710032, China
| | - Shukui Wang
- Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Shaogui Wan
- Institute of Pharmacy, Pharmaceutical College of Henan University, 85 Minglun Street, Kaifeng, Henan, 475001, China.
| | - Jinliang Xing
- State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, 169 Changle West Road, Xi'an, Shaanxi, 710032, China.
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Wang Y, Liu Y, Ji W, Qin H, Wu H, Xu D, Tukebai T, Wang Z. Analysis of MTR and MTRR Polymorphisms for Neural Tube Defects Risk Association. Medicine (Baltimore) 2015; 94:e1367. [PMID: 26334892 PMCID: PMC4616500 DOI: 10.1097/md.0000000000001367] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Neural tube defects (NTDs) are the most common congenital defects of the central nervous system among neonates and the folate status during pregnancy was considered as the most important etiopathogenesis of NTDs. Besides, methionine synthase (MTR) gene and methionine synthase reductase (MTRR) gene were folate metabolism involved genes and had been investigated in several previous studies with inconsistent results. Hence, we aimed to explore the association of 4 selected single-nucleotide polymorphisms (SNPs) on MTRR/MTR gene and the susceptibility of NTDs in a Chinese population.Seven SNPs were selected from HapMap databases with Haploview 4.2 software. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to genotype the polymorphisms from blood samples of 165 NTDs patients and 280 healthy controls. The correlation between these SNPs and NTDs risk was tested by Student t test and Chi-square test by STATA 11.0 software. Furthermore, we performed a meta-analysis of relevant studies to investigate the association between the SNPs MTRR 66A>G and MTR 2756A>G and the susceptibility of NTDs.An increased risk of NTDs was verified to be significantly associated with MTRR 66A>G (G allele vs. A allele: OR = 1.36 (1.03-1.80), P = 0.028; GG + AG vs. AA: OR = 1.60 (1.05-2.43), P = 0.027) and MTR 2756A>G (G allele vs. A allele: OR = 1.45 (1.06-1.98), P = 0.021; GG + AG vs. AA: OR = 1.51 (1.02-2.23), P = 0.038) in our study. However, the other SNPs in our analysis showed no significant association with NTDs risk (all P > 0.05). Furthermore, the result of the meta-analysis supported the association between MTRR 66A>G and NTDs risk (G allele vs. A allele: OR = 1.32, 95% CI = 1.09-1.61, GG + GA vs. AA: OR = 1.49, 95% CI = 1.06-2.09, GG vs. AA: OR = 1.61, 95% CI = 1.04-2.49).Our study confirmed that the MTRR 66A>G and MTR 2756A>G were significantly associated with the increased NTDs risk in a Chinese population. The further meta-analysis enhance that MTRR 66A>G was connected with the susceptibility of NTDs widely. Further investigations based on more detailed stratification were recommended.
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Affiliation(s)
- Yongxin Wang
- From the Neurosurgical Department, the 1st Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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Cheng TYD, Makar KW, Neuhouser ML, Miller JW, Song X, Brown EC, Beresford SAA, Zheng Y, Poole EM, Galbraith RL, Duggan DJ, Habermann N, Bailey LB, Maneval DR, Caudill MA, Toriola AT, Green R, Ulrich CM. Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study. Cancer 2015; 121:3684-91. [PMID: 26108676 DOI: 10.1002/cncr.29465] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 03/26/2015] [Accepted: 04/16/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations. METHODS Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations. RESULTS Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P < .05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-β-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3β (DNMT3B), methionine adenosyltransferase I α (MAT1A), MTHFD1, and MTRR (nominal P < .05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS). CONCLUSIONS Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk.
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Affiliation(s)
- Ting-Yuan David Cheng
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York
| | - Karen W Makar
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Marian L Neuhouser
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Joshua W Miller
- Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey.,Department of Pathology and Laboratory Medicine, University of California Davis, Davis, California
| | - Xiaoling Song
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Elissa C Brown
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Shirley A A Beresford
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Yingye Zheng
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Elizabeth M Poole
- Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Rachel L Galbraith
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - David J Duggan
- Translational Genomics Research Institute, Phoenix, Arizona
| | - Nina Habermann
- Department of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany
| | - Lynn B Bailey
- Department of Foods and Nutrition, University of Georgia, Athens, Georgia
| | - David R Maneval
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, Florida
| | - Marie A Caudill
- Division of Nutritional Sciences, Cornell University, Ithaca, New York
| | - Adetunji T Toriola
- Department of Surgery, Division of Public Health Sciences and Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
| | - Ralph Green
- Department of Pathology and Laboratory Medicine, University of California Davis, Davis, California
| | - Cornelia M Ulrich
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.,Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
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Fei F, Guo X, Chen Y, Liu X, Tu J, Xing J, Chen Z, Ji J, He X. Polymorphisms of monocarboxylate transporter genes are associated with clinical outcomes in patients with colorectal cancer. J Cancer Res Clin Oncol 2015; 141:1095-102. [PMID: 25492048 DOI: 10.1007/s00432-014-1877-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 11/13/2014] [Indexed: 11/27/2022]
Abstract
PURPOSE Previous studies have demonstrated that monocarboxylate transporters (MCTs) play important roles in the development and progression of many cancers. The purpose of this study was to assess the effects of single-nucleotide polymorphisms (SNPs) of MCT genes on prognosis of colorectal cancer (CRC) patients. PATIENTS AND METHODS Nine functional SNPs in three MCT genes (MCT1, MCT2 and MCT4) were selected and genotyped using Sequenom iPLEX genotyping system in 697 Chinese CRC patients receiving surgery. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognostic analysis. RESULTS One SNP (MCT1: rs1049434/exon) was significantly associated with overall survival of CRC patients (HR 0.74; P = 0.046). Two other SNPs (MCT1: rs60844753/5' near gene and MCT2: rs995343/intron) exhibited associations with recurrence-free survival of CRC patients (HR 0.67; P = 0.078 and HR 0.74; P = 0.036, respectively). Our study also showed that MCT1 rs1049434, rs60844753 and MCT2 rs995343 SNPs had a cumulative effect on CRC recurrence-free survival (P for trend 0.011). Those who carrying three unfavorable genotypes (WW for all SNPs) had a 2.06-fold increased risk of recurrence compared with patients carrying no unfavorable genotypes (P = 0.016). Moreover, we found that patients carrying no <2 risk genotypes showed significant OS and RFS benefits from adjuvant chemotherapy. CONCLUSIONS Our findings suggest that SNPs in MCT1 and MCT2 genes may affect clinical outcomes and can be used to predict the response to adjuvant chemotherapy in CRC patients who received surgical treatment once validated in future study.
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Affiliation(s)
- Fei Fei
- State Key Laboratory of Cancer Biology, Cell Engineering Research Center, Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
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Zhu G, Wang L, Guo H, Lu L, Yang S, Wang T, Guo H, Wang H, Min J, Yang K, Chen X, Liu Y, Wang Z, Su H. DNA repair genes XRCC1 and ERCC1 polymorphisms and the risk of sporadic breast cancer in Han women in the Gansu Province of China. Genet Test Mol Biomarkers 2015; 19:387-93. [PMID: 25961110 DOI: 10.1089/gtmb.2015.0001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
AIMS Polymorphisms in DNA damage repair genes may affect DNA repair capacity and modulate breast cancer susceptibility. In this study, we aimed to analyze two polymorphisms for each of the DNA repair genes X-ray repair cross-complementing group 1 (XRCC1) rs25487 and rs1799782 and excision repair cross-complementing group 1 (ERCC1) rs3212964 and rs11615, to evaluate their associations with the risk of sporadic breast cancer in Han women in the Gansu Province of China. METHODS Genotypes were determined by a polymerase chain reaction-based approach for 101 patients with breast cancer and in 101 disease-free controls. RESULTS We found that individuals with the AA genotype at XRCC1 rs25487 had a significantly increased risk of breast cancer compared with GG genotype (p<0.001, odds ratio [OR]=6.39, 95% confidence interval [CI]: 2.18-18.65). The dominant model showed that the combined rs25487 genotypes (AA+AG) increased the disease risk (p<0.001, OR=3.17, 95% CI: 1.76-5.72). However, no statistical associations were found between rs1799782 in XRCC1, or rs3212964 and rs11615 in ERCC1 and the risk of disease. In haplotype analysis, the GC haplotype in XRCC1 conferred an increased risk (p<0.001) with a 4.78-fold increase for each copy (95% CI: 2.52-8.72). Significant associations were also shown between the single nucleotide polymorphisms (SNPs) and the status of estrogen receptor (ER), progesterone receptor (PR), and HER-2. CONCLUSIONS The results suggest that the XRCC1 rs25487 polymorphism may increase the risk of breast cancer.
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Affiliation(s)
- Gongjian Zhu
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China .,2 School of Life Sciences, Lanzhou University , Lanzhou, China
| | - Lan Wang
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Hongyun Guo
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Lingeng Lu
- 3 Department of Chronic Disease Epidemiology, School of Public Health, School of Medicine, Yale Cancer Center, Yale University , New Haven, Connecticut
| | - Suisheng Yang
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Tao Wang
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Huan Guo
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Haitao Wang
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Jianping Min
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Kai Yang
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Xuezhong Chen
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Yuanqiang Liu
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
| | - Zhiping Wang
- 4 Institute of Urology, The Second Hospital of Lanzhou University , Lanzhou, China
| | - Haixiang Su
- 1 Gansu Provincial Academy of Medical Sciences, Gansu Provincial Cancer Hospital , Lanzhou, People's Republic of China
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Wan S, Wu Y, Zhou X, Chen Y, An J, Yu X, Zhang H, Yang H, Xing J. Polymorphisms in Genes of Tricarboxylic Acid Cycle Key Enzymes Are Associated with Early Recurrence of Hepatocellular Carcinoma. PLoS One 2015; 10:e0124471. [PMID: 25894340 PMCID: PMC4404327 DOI: 10.1371/journal.pone.0124471] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 03/01/2015] [Indexed: 02/06/2023] Open
Abstract
Alterations of activity and expression in tricarboxylic acid (TCA) cycle key enzymes have been indicated in several malignancies, including hepatocellular carcinoma (HCC). They play an important role in the progression of cancer. However, the impact of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes on the recurrence of HCC has not been investigated. In this study, we genotyped 17 SNPs in genes encoding TCA cycle key enzymes and analyzed their association with recurrence-free survival (RFS) in a cohort of 492 Chinese HCC patients by Cox proportional hazard model and survival tree analysis. We identified 7 SNPs in SDHC, SDHD, FH, and IDH2 genes to be significantly associated with the RFS of HCC patients. Moreover, all these SNPs were associated with the early recurrence (within 2 years after surgery) risk of diseases. Cumulative effect analysis showed that these SNPs exhibited a dose-dependent effect on the overall and early recurrence. Further stratified analysis suggested that number of risk genotypes modified the protective effect on HCC recurrence conferred by transcatheter arterial chemoembolization treatment. Finally, the survival tree analysis revealed that SNP rs10789859 in SDHD gene was the primary factor contributing to HCC recurrence in our population. To the best of our knowledge, we for the first time observed the association between SNPs in genes encoding TCA cycle key enzymes and HCC recurrence risk. Further observational and functional studies are needed to validate our findings and generalize its clinical usage.
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Affiliation(s)
- Shaogui Wan
- Institute of Pharmacy, Pharmaceutical College of Henan University, Kaifeng, Henan, China
| | - Yousheng Wu
- State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xingchun Zhou
- State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yibing Chen
- State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jiaze An
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaohe Yu
- Department of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Huiqing Zhang
- Department of Pain treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Hushan Yang
- Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
- * E-mail: (HY); (JX)
| | - Jinliang Xing
- State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China
- * E-mail: (HY); (JX)
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Genome-wide analysis of methotrexate pharmacogenomics in rheumatoid arthritis shows multiple novel risk variants and leads for TYMS regulation. Pharmacogenet Genomics 2015; 24:211-9. [PMID: 24583629 DOI: 10.1097/fpc.0000000000000036] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Methotrexate (MTX) is the drug of first choice for the treatment of rheumatoid arthritis (RA), but is effective only in around 60% of the patients. Identification of genetic markers to predict response is essential for effective treatment within a critical window period of 6 months after diagnosis, but have been hitherto elusive. In this study, we used genome-wide genotype data to identify the potential risk variants associated with MTX (poor)response in a north Indian RA cohort. MATERIALS AND METHODS Genome-wide genotyping data for a total of 457 RA patients [297 good (DAS28-3≤3.2) and 160 poor (DAS28-3≥5.1) responders] on MTX monotherapy were tested for association using an additive model. Support vector machine and genome-wide pathway analysis were used to identify additional risk variants and pathways. All risk loci were imputed to fine-map the association signals and identify causal variant(s) of therapeutic/diagnostic relevance. RESULTS Seven novel suggestive loci from genome-wide (P≤5×10(-5)) and three from support vector machine analysis were associated with MTX (poor)response. The associations of published candidate genes namely DHFR (P=0.014), FPGS (P=0.035), and TYMS (P=0.005) and purine and nucleotide metabolism pathways were reconfirmed. Imputation, followed by bioinformatic analysis indicated possible interaction between two reversely oriented overlapping genes namely ENOSF1 and TYMS at the post-transcriptional level. CONCLUSION In this first ever genome-wide analysis on MTX treatment response in RA patients, 10 new risk loci were identified. These preliminary findings warrant replication in independent studies. Further, TYMS expression at the post-transcriptional level seems to be probably regulated through an antisense-RNA involving the 6-bp ins/del marker in the overlapping segment at 3'UTR of TYMS-ENOSF1, a finding with impending pharmacogenetic applications.
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Bohanes P, Rankin CJ, Blanke CD, Winder T, Ulrich CM, Smalley SR, Rich TA, Martensen JA, Benson AB, Mayer RJ, Cripps CM, Danenberg K, Makar KW, Zhang W, Benedetti JK, Lenz HJ. Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation. Clin Cancer Res 2015; 21:1583-90. [PMID: 25589620 DOI: 10.1158/1078-0432.ccr-14-0857] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 12/12/2014] [Indexed: 12/16/2022]
Abstract
PURPOSE We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)-based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy. EXPERIMENTAL DESIGN DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3-5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004). CONCLUSION rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule.
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Affiliation(s)
- Pierre Bohanes
- University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California
| | | | - Charles D Blanke
- SWOG Group Chair's Office/Oregon Health & Science University, Portland, Oregon
| | - Thomas Winder
- University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California
| | - Cornelia M Ulrich
- University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington; and Division of Preventive Oncology at the National Center of Tumor Diseases, Heidelberg, Germany
| | | | - Tyvin A Rich
- University of Virginia Health System, Charlottesville, Virginia
| | | | | | | | | | | | - Karen W Makar
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Wu Zhang
- University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California
| | | | - Heinz-Josef Lenz
- University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
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Genetic variations in monocarboxylate transporter genes as predictors of clinical outcomes in non-small cell lung cancer. Tumour Biol 2015; 36:3931-9. [PMID: 25578492 DOI: 10.1007/s13277-014-3036-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Accepted: 12/30/2014] [Indexed: 01/06/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict clinical outcomes. Previous studies have demonstrated that monocarboxylate transporters (MCTs) play important roles in the development and progression of many cancers. The purpose of this study was to assess the effects of single nucleotide polymorphisms (SNPs) of MCT genes on prognosis of NSCLC patients in Chinese Han population. Nine functional SNPs in MCT1, MCT2, and MCT4 genes were selected and genotyped using Sequenom iPLEX genotyping system in 500 Chinese NSCLC patients receiving surgery. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognostic analysis. TT genotype of SNP rs1049434 (MCT1) was significantly associated with better overall survival (OS) (HR = 0.56, P = 0.026) and recurrence-free survival (RFS) (HR = 0.57, P = 0.016) of NSCLC patients. TT genotype of another SNP rs995343 (MCT2) exhibited an association with worse RFS of NSCLC patients (HR = 1.46, P = .039). Unfavorable genotypes of SNP rs1049434 and rs995343 showed a significant cumulative effect on OS and RFS of NSCLC patients. Moreover, we found that patients carrying AA+AT genotypes of rs1049434 showed significant OS and RFS benefits from adjuvant chemotherapy, but those with TT genotype did not. Our findings suggest that SNPs in MCT1 and MCT2 genes may affect clinical outcomes and can be used to predict the response to adjuvant chemotherapy in NSCLC patients who received surgical treatment once validated in future study.
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Ding X, Chen W, Fan H, Zhu B. Cytidine deaminase polymorphism predicts toxicity of gemcitabine-based chemotherapy. Gene 2015; 559:31-7. [PMID: 25582275 DOI: 10.1016/j.gene.2015.01.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Revised: 01/06/2015] [Accepted: 01/07/2015] [Indexed: 10/24/2022]
Abstract
BACKGROUND The aim of this study was to ascertain whether single nucleotide polymorphisms of cytidine deaminase (CDA), a key enzyme in the metabolism pathway of gemcitabine, could predict clinical outcomes of cancer patients with gemcitabine-based chemotherapy. METHODS We searched MEDLINE and EMBASE up to January 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according to the Newcastle-Ottawa Quality Assessment Scale. For each included study, the overall survival (OS), overall response rate (ORR) and toxicities were extracted and pooled using random-effects model. RESULTS In total, data from 13 studies were included. CDA 208A>G and CDA 435C>T were not included in quantified synthesis due to limited data. CDA 79A>C polymorphism was not significantly associated with OS; however, patients carrying the variant CDA 79C allele were likely to have a poor survival, hazard ratio (HR)=1.03, 95% CI 0.957-1.27 (AC+CC vs. AA). CDA 79A>C polymorphism did not correlated with ORR, odds ratio (OR)=0.719, 95% CI 0.363-1.425 (AC+CC vs. AA). However, patients with the variant CDA 79C allele would experience more grade ≥ 3 leucopenia (OR=2.933, 95% CI 1.357-6.605) and tended to have more severe neutropenia (OR=1.313, 95% CI 0.157-10.981). CONCLUSIONS These results suggest that CDA 79A>C polymorphisms is a potential biomarker for toxicity of gemcitabine-based chemotherapy and a CDA testing before gemcitabine administration is preferred.
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Affiliation(s)
- Xiangxiang Ding
- First Clinical College, Nanjing Medical University, Nanjing 210029, China; Department of Radiology, Nanjing Drum Tower Hospital, Nanjing 210008, China
| | - Wenwei Chen
- First Clinical College, Nanjing Medical University, Nanjing 210029, China; Department of Oncology, Nanjing Drum Tower Hospital, Nanjing 210008, China
| | - Haijian Fan
- Department of Radiology, Nanjing Drum Tower Hospital, Nanjing 210008, China
| | - Bin Zhu
- Department of Radiology, Nanjing Drum Tower Hospital, Nanjing 210008, China.
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Ulrich CM, Rankin C, Toriola AT, Makar KW, Altug-Teber Ö, Benedetti JK, Holmes RS, Smalley SR, Blanke CD, Lenz HJ. Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among patients with stage II or III rectal cancer (INT-0144; SWOG 9304). Cancer 2014; 120:3329-3337. [PMID: 25041994 PMCID: PMC4259283 DOI: 10.1002/cncr.28830] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 04/08/2014] [Accepted: 04/11/2014] [Indexed: 01/03/2023]
Abstract
BACKGROUND Recurrence and toxicity occur commonly among patients with rectal cancer who are treated with 5-fluorouracil (5-FU). The authors hypothesized that genetic variation in folate-metabolizing genes could play a role in interindividual variability. The objective of the current study was to evaluate the associations between genetic variants in folate-metabolizing genes and clinical outcomes among patients with rectal cancer treated with 5-FU. METHODS The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [MTHFR] [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], dihydrofolate reductase [DHFR] [Del19bp], TS 1494del,and TSER) involved in folate metabolism in 745 patients with TNM stage II or III rectal cancer enrolled in a phase 3 adjuvant clinical trial of 3 regimens of 5-FU and radiotherapy (INT-0144 and SWOG 9304). RESULTS There were no statistically significant associations noted between polymorphisms in any of the genes and overall survival, disease-free survival (DFS), and toxicity in the overall analyses. Nevertheless, there was a trend toward worse DFS among patients with the variant allele of MTHFR C677T compared with wild-type, particularly in treatment arm 2, in which patients with the MTHFR C677T TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06-2.93 [P = .03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12-3.03 [P = .02]) compared with those with homozygous wild-type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of SLC19A1 G80A in treatment arm 1 (P for trend, .06) and reduced esophagitis/stomatitis noted among patients with variants of TSER in treatment arm 3 (P for trend, .06). CONCLUSIONS Genetic variability in folate-metabolizing enzymes was found to be associated only to a limited degree with clinical outcomes among patients with rectal cancer treated with 5-FU.
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Affiliation(s)
- Cornelia M Ulrich
- Division of Preventive Oncology, National Center for Tumor Diseases, Heidelberg, Germany
- German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Cathryn Rankin
- Southwest Oncology Group Statistical Center, Seattle, WA
| | - Adetunji T Toriola
- Department of Surgery, Division of Public Health Sciences and Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
| | - Karen W Makar
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Özge Altug-Teber
- Division of Preventive Oncology, National Center for Tumor Diseases, Heidelberg, Germany
- German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
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Zhang Z, Ma F, Zhou F, Chen Y, Wang X, Zhang H, Zhu Y, Bi J, Zhang Y. Functional polymorphisms of circadian negative feedback regulation genes are associated with clinical outcome in hepatocellular carcinoma patients receiving radical resection. Med Oncol 2014; 31:179. [PMID: 25344870 DOI: 10.1007/s12032-014-0179-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 08/10/2014] [Indexed: 01/27/2023]
Abstract
Previous studies have demonstrated that circadian negative feedback loop genes play an important role in the development and progression of many cancers. However, the associations between single-nucleotide polymorphisms (SNPs) in these genes and the clinical outcomes of hepatocellular carcinoma (HCC) after surgical resection have not been studied so far. Thirteen functional SNPs in circadian genes were genotyped using the Sequenom iPLEX genotyping system in a cohort of 489 Chinese HCC patients who received radical resection. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis. Cumulative effect analysis and survival tree analysis were used for the multiple SNPs analysis. Four individual SNPs, including rs3027178 in PER1, rs228669 and rs2640908 in PER3 and rs3809236 in CRY1, were significantly associated with overall survival (OS) of HCC patients, and three SNPs, including rs3027178 in PER1, rs228729 in PER3 and rs3809236 in CRY1, were significantly associated with recurrence-free survival (RFS). Moreover, we observed a cumulative effect of significant SNPs on OS and RFS (P for trend < 0.001 for both). Survival tree analysis indicated that wild genotype of rs228729 in PER3 was the primary risk factor contributing to HCC patients' RFS. Our study suggests that the polymorphisms in circadian negative feedback loop genes may serve as independent prognostic biomarkers in predicting clinical outcomes for HCC patients who received radical resection. Further studies with different ethnicities are needed to validate our findings and generalize its clinical utility.
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Affiliation(s)
- Zhaohui Zhang
- Department of Surgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China
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48
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Pardini B, Bermejo JL, Naccarati A, Di Gaetano C, Rosa F, Legrand C, Novotny J, Vodicka P, Kumar R. Inherited variability in a master regulator polymorphism (rs4846126) associates with survival in 5-FU treated colorectal cancer patients. Mutat Res 2014; 766-767:7-13. [PMID: 25847265 DOI: 10.1016/j.mrfmmm.2014.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 04/23/2014] [Accepted: 05/30/2014] [Indexed: 06/04/2023]
Abstract
BACKGROUND Treatment with 5-fluorouracil (5-FU) is known to improve survival in many cancers including colorectal cancer. Response to the treatment, overall survival and recurrence show inter-individual variation. METHODS In this study we employed a strategy to search eQTL variants influencing the expression of a large number of genes. We identified four single nucleotide polymorphisms, defined as master regulators of transcription, and genotyped them in a set of 218 colorectal cancer patients undergoing adjuvant 5-FU based therapy. RESULTS Our results showed that the minor allele variant of the rs4846126 polymorphism was associated with poor overall and progression-free survival. Patients that were homozygous for the variant allele showed an over two fold increased risk of death (HR 2.20 95%CI 1.05-4.60) and progression (HR 2.88, 95% 1.47-5.63). The integration of external information from publicly available gene expression repositories suggested that the rs4846126 polymorphism deserves further investigation. This variant potentially regulates the gene expression of 273 genes with some of them possibly associated to the patient's response to 5-FU treatment or colorectal cancer. CONCLUSIONS Present results show that mining of public data repositories in combination with own data can be a fruitful approach to identify markers that affect therapy outcome. In particular, a genetic screen of master regulators may help in order to search for the polymorphisms involved in treatment response in cancer patients.
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Affiliation(s)
- Barbara Pardini
- Human Genetics Foundation, Turin, Italy; Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
| | - Justo Lorenzo Bermejo
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Alessio Naccarati
- Human Genetics Foundation, Turin, Italy; Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Cornelia Di Gaetano
- Human Genetics Foundation, Turin, Italy; Department of Medical Sciences, University of Turin, Turin, Italy
| | | | - Carine Legrand
- Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Jan Novotny
- Department of Oncology, General Teaching Hospital, Prague, Czech Republic
| | - Pavel Vodicka
- Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; First Medical Faculty, Charles University, Prague, Czech Republic
| | - Rajiv Kumar
- German Cancer Research Center (DKFZ), Heidelberg, Germany
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Choi MK, Kim MH, Maeng HJ, Song IS. Contribution of CNT1 and ENT1 to ribavirin uptake in human hepatocytes. Arch Pharm Res 2014; 38:904-13. [PMID: 25011570 DOI: 10.1007/s12272-014-0437-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 06/26/2014] [Indexed: 10/25/2022]
Abstract
The objective of this study was to investigate the contributions of a sodium-dependent concentrative nucleoside transporter (CNT) 1 and an equilibrative nucleoside transporter (ENT) 1 to ribavirin uptake in human hepatocytes. The initial studies in oocytes expressing CNT1 and ENT1 showed increases in ribavirin uptake, indicating that ribavirin was a substrate for both CNT1 and ENT1. The CNT1- and ENT1-mediated ribavirin uptake showed concentration dependency with the following kinetics parameters: Km 26.3 μM and Vmax 426.2 fmol/min/oocyte for CNT1; Km 70.5 μM and Vmax 134.3 fmol/min/oocyte for ENT1. Ribavirin uptake clearance in six human hepatocytes ranged from 21.3 to 300.7 μL/min. Estimation of the contributions of CNT1 and ENT1 to the hepatic uptake of ribavirin by using a relative activity factor method indicated that the relative contribution of ENT1 to the ribavirin uptake was 82.8 ± 3.9%. Real-time polymerase chain reaction analysis of CNT1 and ENT1 expressions in the hepatocytes showed that ENT1 mRNA expression was closely correlated with ribavirin uptake (R = 0.95, P = 0.003) while CNT1 was not. The findings indicated that ENT1 was the major transporter controlling the hepatic uptake of ribavirin.
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Affiliation(s)
- Min-Koo Choi
- College of Pharmacy, Dankook University, 119 Dandaero, Cheonan, Chungnam, 330-714, Korea
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Afruza R, Suzuki F, Nabi A. PHARMACOGENETICS AND PHARMACOGENOMICS IN PERSONALIZED MEDICINE: ROLE OF GENE POLYMORPHISM IN DRUG RESPONSE. BIOTECHNOLOGY AND BIOINFORMATICS 2014:35-71. [DOI: 10.1201/b17104-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
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