|
1
|
Choudhury S, Ghosh S, Chakraborty P, Pal S, Ghosh K, Saha S, Midha J, Sankar V, Mohata A, Chattopadhyay BK, Ghosh S, Das S, Basu B, Sikdar N. Epidermal Growth Factor Receptor (EGFR) and SMAD4 negatively correlated in the progression of gallbladder cancer in Eastern Indian patients. BMC Gastroenterol 2024; 24:446. [PMID: 39623311 PMCID: PMC11613908 DOI: 10.1186/s12876-024-03485-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 10/28/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND AND INTRODUCTION Two and half percent of the Indian population suffer from gallbladder cancer (GBC). The primary factors that lead GBC are associated with mutation of several protooncogenes such as EGFR, ERBB2, Myc, and CCND1 along with dysregulation of several tumor suppressor genes such as SMAD4 and CDKN2A. Bacterial infection caused by S.typhi and H.pylori are also hypothesized to be potential factors driving GBC. AIMS This study aims to investigate the molecular mechanisms driving the progression of gallbladder adenocarcinoma in Eastern Indian patients. We specifically focussed on analyzing the mutational status of the KRAS gene, examining the amplification of the ERBB2/Her2-neu gene, and evaluating the expression patterns of six dysregulated genes (CCND1, MYC, EGFR, ERBB2/Her2-neu, CDKN2A, SMAD4). Additionally, we assessed the expression status of TGF-beta, the association between bacterial infections (S. Typhi and H. pylori) and GBC, and the impact of single nucleotide polymorphisms in ERBB2/Her2-neu and CCND1 genes within this population. METHODS Sixty-seven samples from GBC-diagnosed patients, 26 other unrelated GBC samples for validation cohort, and 68 gallstone tissue samples were collected for this study. Genomic DNA from normal as well as tumor tissues were isolated, exon 2 and exon 3 of KRAS gene were amplified along, DNA sequenced and analyzed. KRAS codon 12 mutation was detected by allele specific PCR (ASPCR) method. Amplification of UreC A (coding for urease subunit α), VacA (coding for Vacuolating cytotoxin A) and CagA genes (coding for cytotoxin-associated gene A) in H.pylori were amplified using PCR. Similarly, FlicC (coding for flagellin gene C) in S.typhi was amplified using PCR. The ERBB2/Her2-neu SNP I655V, and CCND1 SNP A870G were analyzed using PCR followed by RFLP. Expression studies of CCND1, Myc, CDKN2A, ERBB2/Her2-neu, EGFR, and SMAD4 genes were measured in GBC tumor tissues by sybr green quantitative RT PCR. RESULTS The oncogenes (EGFR and ERBB2/Her2-neu) were statistically significantly overexpressed and the tumor suppressor gene (SMAD4) downregulated in our GBC tumor patient samples. The EGFR and SMAD4 genes were negatively correlated (r = -0.01) in GBC patients and the data is statistically significant and validated through IHC technique. A significant downregulation of TGF-beta had also been observed. Lower frequency (i.e. 11.5%) of KRAS mutation in GBC tumor was observed. CONCLUSIONS EGFR and SMAD4 expression were found to be negatively correlated in GBC tissue samples. ERBB2 overexpression/amplification was observed in 30% of the GBC samples. We also found a low percentage of GBC samples to show KRAS codon 12 mutation in Indian GBC patient population, as had been previously documented in pancreatic cancers.
Collapse
Affiliation(s)
- Sounetra Choudhury
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Sandip Ghosh
- Department of Neuroendocrinology and Experimental Hematology, Chittaranjan National Cancer Research Institute, Kolkata, India
| | - Prosenjeet Chakraborty
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Sayari Pal
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Koustuv Ghosh
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India
| | - Subhankar Saha
- Department of General Surgery, Medical College and Hospital, Kolkata, India
| | - Jitesh Midha
- Department of General Surgery, SSKM Hospital and IPGME&R, Kolkata, India
| | - Vinu Sankar
- Department of General Surgery, Medical College and Hospital, Kolkata, India
| | - Abhisek Mohata
- Department of General Surgery, Medical College and Hospital, Kolkata, India
| | | | - Shibajyoti Ghosh
- Department of General Surgery, Medical College and Hospital, Kolkata, India
| | - Soumen Das
- Department of General Surgery, SSKM Hospital and IPGME&R, Kolkata, India
| | - Biswarup Basu
- Department of Neuroendocrinology and Experimental Hematology, Chittaranjan National Cancer Research Institute, Kolkata, India
| | - Nilabja Sikdar
- Human Genetics Unit, Indian Statistical Institute, 203, B. T. Road, Kolkata, 700108, India.
- Estuarine and Coastal Studies Foundation, Howrah, India.
| |
Collapse
|
|
2
|
Mishra S, Kumari S, Husain N. Liquid biopsy in gallbladder carcinoma: Current evidence and future prospective. THE JOURNAL OF LIQUID BIOPSY 2024; 6:100280. [PMID: 40027313 PMCID: PMC11863890 DOI: 10.1016/j.jlb.2024.100280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 03/05/2025]
Abstract
Although there have been significant advances in the early detection and treatment of gallbladder cancer (GBC), it is still considered a leading cause of morbidity and mortality. Molecular profiling of tumors is generally performed using samples obtained during surgery or biopsy. However, tissue genotyping has its limitations as it only provides a single snapshot and is susceptible to spatial selection bias due to the tumor heterogeneity. Over the past decade, there has been a remarkable transition from invasive diagnostic methods to non-invasive alternatives, including liquid biopsy, for cancer diagnosis and monitoring. Liquid biopsies have ushered in a new era in clinical oncology, enabling convenient tumor sampling, continuous monitoring through repeated analysis, development of personalized treatment regimens, and assessment of therapy resistance. While peripheral blood is the primary medium for these biopsies, other biological fluids, including urine, saliva, and bile, also serve as valuable sources of information. Currently, the focus of blood-based biopsy analyses is on four main sources of biomarkers for cancer detection and stratification: circulating tumor DNA (ctDNA) or circulating free DNA (cfDNA), circulating tumor cells (CTCs), and extracellular vesicle (EVs). There are over 300 clinical trials either ongoing or actively recruiting participants to investigate the diagnostic and prognostic applications of ctDNA/cfDNA in the context of cancer. This review outlines the current standard of care for individuals with GBC, anticipates future treatment developments, and evaluates the potential applications of liquid biopsies in various clinical contexts. The review addresses ctDNA/cfDNA, CTC, and circulating microRNA and highlights their prospective roles in management of GBC.
Collapse
Affiliation(s)
- Sridhar Mishra
- Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India
- Department of Plastic and Reconstructive Surgery, King George Medical University, Lucknow, Uttar 1pradesh, 226003, India
| | - Swati Kumari
- Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India
- Department of Pathology, King George Medical University, Lucknow, Uttar 1pradesh, 226003, India
| | - Nuzhat Husain
- Department of Pathology, Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226010, India
| |
Collapse
|
|
3
|
Kapoor VK. How I Manage My Patients with Gall Bladder Cancer? Indian J Surg Oncol 2024; 15:652-660. [PMID: 39555366 PMCID: PMC11564548 DOI: 10.1007/s13193-024-02008-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/23/2024] [Indexed: 11/19/2024] Open
Abstract
The author outlines his philosophy and practice of management of gall bladder cancer based on his more than three-decade experience at a large tertiary level super-specialty referral hospital attached to a university-status teaching institution at Lucknow in northern India where GBC is very common.
Collapse
Affiliation(s)
- Vinay K. Kapoor
- Surgical Gastroenterology, Mahatma Gandhi Medical College & Hospital (MGMCH), Jaipur, 302004 Rajasthan India
| |
Collapse
|
|
4
|
Kumar A, Sarangi Y, Gupta A, Sharma A. Gallbladder cancer: Progress in the Indian subcontinent. World J Clin Oncol 2024; 15:695-716. [PMID: 38946839 PMCID: PMC11212610 DOI: 10.5306/wjco.v15.i6.695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/25/2024] [Accepted: 05/15/2024] [Indexed: 06/24/2024] Open
Abstract
Gallbladder cancer (GBC) is one of the commonest biliary malignancies seen in India, Argentina, and Japan. The disease has dismal outcome as it is detected quite late due to nonspecific symptoms and signs. Early detection is the only way to improve the outcome. There have been several advances in basic as well as clinical research in the hepatobiliary and pancreatic diseases in the West and other developed countries but not enough has been done in GBC. Therefore, it is important and the responsibility of the countries with high burden of GBC to find solutions to the many unanswered questions like etiopathogenesis, early diagnosis, treatment, and prognostication. As India being one of the largest hubs for GBC in the world, it is important to know how the country has progressed on GBC. In this review, we will discuss the outcome of the publications from India highlighting the work and the developments taken place in past several decades both in basic and clinical research.
Collapse
Affiliation(s)
- Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Yajnadatta Sarangi
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Annapurna Gupta
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Aarti Sharma
- Division of Haematology, Mayo Clinic Arizona, Phoenix, AZ 85054, United States
| |
Collapse
|
|
5
|
Kuipers H, de Bitter TJJ, de Boer MT, van der Post RS, Nijkamp MW, de Reuver PR, Fehrmann RSN, Hoogwater FJH. Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications. Cancers (Basel) 2021; 13:5257. [PMID: 34771420 PMCID: PMC8582530 DOI: 10.3390/cancers13215257] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/14/2021] [Accepted: 10/18/2021] [Indexed: 12/29/2022] Open
Abstract
Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials.
Collapse
Affiliation(s)
- Hendrien Kuipers
- Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.T.d.B.); (M.W.N.)
| | - Tessa J. J. de Bitter
- Department of Pathology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands; (T.J.J.d.B.); (R.S.v.d.P.)
| | - Marieke T. de Boer
- Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.T.d.B.); (M.W.N.)
| | - Rachel S. van der Post
- Department of Pathology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands; (T.J.J.d.B.); (R.S.v.d.P.)
| | - Maarten W. Nijkamp
- Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.T.d.B.); (M.W.N.)
| | - Philip R. de Reuver
- Department of Surgery, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands;
| | - Rudolf S. N. Fehrmann
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
| | - Frederik J. H. Hoogwater
- Department of Surgery, Section Hepato-Pancreato-Biliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (M.T.d.B.); (M.W.N.)
| |
Collapse
|
|
6
|
Srivastava V, Verma K, Puneet. Surgical Management of Gallbladder Carcinoma. Indian J Surg 2021. [DOI: 10.1007/s12262-019-02050-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
|
|
7
|
Dixit R, Pandey M, Tripathi SK, Dwivedi AND, Shukla VK. Genetic mutational analysis of β-catenin gene affecting GSK-3β phosphorylation plays a role in gallbladder carcinogenesis: Results from a case control study. Cancer Treat Res Commun 2020; 23:100173. [PMID: 32344182 DOI: 10.1016/j.ctarc.2020.100173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/21/2020] [Accepted: 03/24/2020] [Indexed: 02/06/2023]
Abstract
UNLABELLED This manuscript has reported different mutations of β-catenin gene in gallbladder cancer patients which affect GSK-3β phosphorylation site. PURPOSE Gallbladder carcinoma (GBC) is a relatively rare and fatal cancer with poor prognosis. The molecular mechanism of gallbladder carcinogenesis is still not clear. Wnt signaling pathway is a highly conserved pathway that regulates proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. β-catenin plays major role in Wnt signaling and aberrations in β-catenin has found to be involved in several cancers pathogenesis. This study was carried out to document the mutations of β-catenin gene in gallbladder cancer and to evaluate its possible role in gallbladder carcinogenesis. METHODS PCR-SSCP (Single Stranded Conformation Polymorphism) for ctnnb1 was performed in 50 patients each of gallbladder cancer, cholelithiasis and 50 healthy controls. Samples that showed variation in banding pattern were sequenced. RESULTS Variation in banding pattern was observed in 9 (18%) samples of GBC, 4 (8%) of cholelithiasis and 2 (4%) of control. Sequencing analysis showed 9 novel mutations of ctnnb1 in exon 3 in 18% of gallbladder cancer (χ2 = 5.778; p < 0.05). Six point mutations, 1 deletion and 1 insertion mutation were found in 9 cases of gallbladder cancer. All point mutations were mis-sense mutation that affected highly conserved serine or threonine region that is important for GSK-3β phosphorylation. CONCLUSION Findings of the study suggests that high frequency of non synonymous mutations of β-catenin gene (ctnnb1) occurs in patients with gallbladder cancer. As these mutations mainly effect GSK 3β phosphorylation, it may be concluded that this might be an important step in gallbladder carcinogenesis. These β-catenin mutations lead to Wnt pathway activation and appear to have a role in progression from inflammation to cancer in gallbladder.
Collapse
Affiliation(s)
- Ruhi Dixit
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Manoj Pandey
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Sunil Kumar Tripathi
- Department of Forensic Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Amit Nandan Dhar Dwivedi
- Department of Radio Diagnosis, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Vijay Kumar Shukla
- Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India.
| |
Collapse
|
|
8
|
Mishra SK, Kumari N, Krishnani N. Molecular pathogenesis of gallbladder cancer: An update. Mutat Res 2019; 816-818:111674. [PMID: 31330366 DOI: 10.1016/j.mrfmmm.2019.111674] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 06/17/2019] [Accepted: 06/24/2019] [Indexed: 01/17/2023]
Abstract
Gallbladder carcinoma (GBC) is the most aggressive gastrointestinal malignancy throughout the world, with wide geographical variance. It is the subtype of biliary tract malignancy that has the poorest prognosis and lower survival among all biliary tract malignancies. Various factors are associated with GBC pathogenesis such as environmental, microbial, metabolic and molecular. Chronic inflammation of gallbladder due to presence of gallstone or microbial infection (eg. Salmonella or H. pylori) results in sustained production of inflammatory mediators in the tissue microenvironment, which can cause genomic changes linked to carcinogenesis. Genetic alterations are one of the major factors, associated with aggressiveness and prognosis. Researches have been done to explore suitable biomarker for early diagnosis and identify altered molecular pathways to develop appropriate biomarkers for early diagnosis, therapy and predicting prognosis. Different agents for targeted therapy against actionable mutations of molecules like EGFR, VEGF, mTOR, HER2, PDL-1, PD-1, MET, PI3K, N-cadherin, VEGFR, MEK1 and MEK2 are being tried. Despite these advancements, there is dismal improvement in the survival of GBC patients. Genetic aberrations other than actionable mutations and epigenetic modification including aberrant expressions of micro-RNAs, are also being studied both as diagnostic biomarker and therapeutic targets. Complex pathogenesis of GBC still needs to be unfolded. In this review we focus on the molecular pathogenesis of GBC elucidated till date along with future directions that can be explored to achieve better management of GBC patients.
Collapse
Affiliation(s)
- Shravan Kumar Mishra
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India.
| | - Niraj Kumari
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India.
| | - Narendra Krishnani
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226014, India.
| |
Collapse
|
|
9
|
Zhang X, Miao R, Liu T, Xiang X, Gu J, Jia Y, Li Z, Fu Y, He Y, Zhang Y, Zhang J, Qu K, Liu C. IDH1 as a frequently mutated gene has potential effect on exosomes releasement by epigenetically regulating P2RX7 in intrahepatic cholangiocarcinoma. Biomed Pharmacother 2019; 113:108774. [DOI: 10.1016/j.biopha.2019.108774] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/11/2019] [Accepted: 03/13/2019] [Indexed: 02/07/2023] Open
|
|
10
|
Narayan RR, Creasy JM, Goldman DA, Gönen M, Kandoth C, Kundra R, Solit DB, Askan G, Klimstra DS, Basturk O, Allen PJ, Balachandran VP, D'Angelica MI, DeMatteo RP, Drebin JA, Kingham TP, Simpson AL, Abou-Alfa GK, Harding JJ, O'Reilly EM, Butte JM, Matsuyama R, Endo I, Jarnagin WR. Regional differences in gallbladder cancer pathogenesis: Insights from a multi-institutional comparison of tumor mutations. Cancer 2018; 125:575-585. [PMID: 30427539 DOI: 10.1002/cncr.31850] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/24/2018] [Accepted: 09/25/2018] [Indexed: 01/02/2023]
Abstract
BACKGROUND Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens. METHODS Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations. RESULTS A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors. CONCLUSIONS Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials.
Collapse
Affiliation(s)
- Raja R Narayan
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, Stanford University School of Medicine, Stanford, California
| | - John M Creasy
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York
| | - Debra A Goldman
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mithat Gönen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Cyriac Kandoth
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ritika Kundra
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David B Solit
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Gokce Askan
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David S Klimstra
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Peter J Allen
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vinod P Balachandran
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael I D'Angelica
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronald P DeMatteo
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jeffrey A Drebin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - T Peter Kingham
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Amber L Simpson
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ghassan K Abou-Alfa
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - James J Harding
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eileen M O'Reilly
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jean M Butte
- Department of Gastrointestinal Surgery, Arturo Lopez Perez Foundation Cancer Institute, Santiago, Chile
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - William R Jarnagin
- Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| |
Collapse
|
|
11
|
Kaavya J, Mahalaxmi I, Devi SM, Santhy KS, Balachandar V. Targeting phosphoinositide-3-kinase pathway in biliary tract cancers: A remedial route? J Cell Physiol 2018; 234:8259-8273. [PMID: 30370571 DOI: 10.1002/jcp.27673] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 10/04/2018] [Indexed: 01/17/2023]
Abstract
Biliary tract cancers (BTC) are aggressive tumours with a low survival rate. At the advent of the genomic era, various genetic mutations in cell signalling pathways have been incriminated in carcinogenesis. Genomic analysis studies have connected main components of the phosphoinositide-3-kinase (PI3K) signalling pathway to BTC. PI3K pathway playing a central role in cell signalling and being deregulated in various tumours has been studied as a target for chemotherapy. Novel compounds have also been identified in preclinical trials that specifically target the PI3K pathway in BTCs, but these studies have not accelerated to clinical use. These novel compounds can be examined in upcoming studies to validate them as potential therapeutic agents, as further research is required to combat the growing need for adjuvant chemotherapy to successfully battle this tumour type. Furthermore, these molecules could also be used along with gemcitabine, cisplatin and 5-fluorouracil to improve sensitivity of the tumour tissue to chemotherapy. This review focuses on the basics of PI3K signalling, genetic alterations of this pathway in BTCs and current advancement in targeting this pathway in BTCs. It emphasizes the need for gene-based drug screening in BTC. It may reveal various novel targets and drugs for amelioration of survival in patients with BTC and serve as a stepping stone for further research.
Collapse
Affiliation(s)
- Jayaramayya Kaavya
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Avinashilingam University for Women, Coimbatore, India
| | - Iyer Mahalaxmi
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Avinashilingam University for Women, Coimbatore, India
| | | | - K S Santhy
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Avinashilingam University for Women, Coimbatore, India
| | - Vellingiri Balachandar
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, India
| |
Collapse
|
|
12
|
Mehrotra R, Tulsyan S, Hussain S, Mittal B, Singh Saluja S, Singh S, Tanwar P, Khan A, Javle M, Hassan MM, Pant S, De Aretxabala X, Sirohi B, Rajaraman P, Kaur T, Rath GK. Genetic landscape of gallbladder cancer: Global overview. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2018; 778:61-71. [PMID: 30454684 DOI: 10.1016/j.mrrev.2018.08.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/17/2018] [Accepted: 08/22/2018] [Indexed: 12/13/2022]
Abstract
Gallbladder cancer (GBC) is a rare malignancy of biliary tract cancer (BTC), characterized by late presentation and poor prognosis. It exhibits wide geographical as well as ethnical variations. So, diverse epidemiology along with etiological factors have been discussed in the current article. Present review unravels the germ line polymorphisms contributing to GBC susceptibility through candidate gene approach and GWAS. GBC is enriched with multiple mutations consisting of both passenger and driver mutations. The identification of the hotspot driver mutations which are involved in the etiopathogenesis of this cancer is necessary, before targeted therapies could be implemented clinically. Thus, this review sheds lights on both traditional low throughput methods along with high throughput NGS used to determine somatic mutations in cancer. With the advent of GWAS and high throughput sequencing methods, it is possible to comprehend the mutational landscape of this enigmatic disease. This article is the first one to provide insights into the genetic heterogeneity of GBC along with somatic mutational data from Catalogue of Somatic Mutations in Cancer (COSMIC) database. In addition, management of tumor heterogeneity as a therapeutic challenge has been discussed. Future goals involve liquid biopsy based research for better clinical management of the disease. Therefore, research efforts involving discovery of non- invasive markers for early stage cancer detection along with novel therapies should be directed.
Collapse
Affiliation(s)
- Ravi Mehrotra
- Division of Preventive Oncology, National Institute of Cancer Prevention and Research, Noida, India.
| | - Sonam Tulsyan
- Division of Preventive Oncology, National Institute of Cancer Prevention and Research, Noida, India
| | - Showket Hussain
- Division of Molecular Oncology, National Institute of Cancer Prevention and Research, Noida, India
| | - Balraj Mittal
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, India
| | - Sundeep Singh Saluja
- Department of Surgical Gastroenterology & Hepatology, GB Pant Hospital, New Delhi, India
| | - Sandeep Singh
- Clinical Epidemiology, Biostatics and Bioinformatics Academic Medical Center, Amsterdam, Netherlands
| | - Pranay Tanwar
- Laboratory Oncology Unit, Rotary Cancer Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Asiya Khan
- Laboratory Oncology Unit, Rotary Cancer Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Centre, USA
| | - Manal M Hassan
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Centre, USA
| | - Shubham Pant
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, MD Anderson Cancer Centre, USA
| | | | - Bhawna Sirohi
- New India Cancer Charity Initiative, Research and Education in Cancer and Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Preetha Rajaraman
- U.S. Health Attache, India & Regional Representative, South Asia, Office of Global Affairs, DHHS, New Delhi, Delhi, India
| | | | - G K Rath
- Laboratory Oncology Unit, Rotary Cancer Center, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| |
Collapse
|
|
13
|
Papadopoulou K, Murray S, Manousou K, Tikas I, Dervenis C, Sgouros J, Rontogianni D, Lakis S, Bobos M, Poulios C, Pervana S, Lazaridis G, Fountzilas G, Kotoula V. Genotyping and mRNA profiling reveal actionable molecular targets in biliary tract cancers. Am J Cancer Res 2018; 8:2-15. [PMID: 29416916 PMCID: PMC5794717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 06/13/2017] [Indexed: 06/08/2023] Open
Abstract
Biliary tract cancer (BTC) represents a heterogeneous disease with dismal outcome. Herein, we examined genotype and angiogenesis features in BTC. We applied genotyping (Sanger, qPCR, 101-gene panel NGS), mRNA relative quantification methods, and β-catenin immunohistochemistry in 84 FFPE BTC (55 gallbladder [GBC], 14 intrahepatic [ICC], 15 extrahepatic [ECC] carcinomas). We identified 541 mutations in 68 (81%) tumors. Top mutated genes were CTNNB1 (36%); PTEN (33%); TP53 (31%); PIK3R1 (29%); PIK3CA (13%); BRCA2 and KRAS (12%); BRCA1 (11%). Six GBCs were hypermutated [hm] displaying a distinct mutational pattern. Mutations in TP53 and PI3K, Wnt and RAS components were prevalent among non-hypermutated tumors. All hmGBCs carried mutations in BRCA2 and other homologous recombination repair (HRR) genes, in PD1, but not in CTNNB1 and KRAS. None of the pathogenic BRCA2 p.D2723G and BRCA1 p.Q563* and c.5266dupC was present at frequencies expected for germline mutations. We observed copy gains (>6 copies) in EGFR (9% of informative tumors), PRKAR1A (7%), PIK3CA (6%), ERBB2 (5%) and MET (4%). TP53 mutations were prevalent in GBC (P<0.001) and PRKAR1A copy gains in ICC (P=0.007). PTEN was frequently co-mutated with CTNNB1 (P<0.001). Unrelated to CTNNB1 mutations, nuclear β-catenin was detected in 45% of tumors, among them in 5/6 hmGBC. We observed strong mRNA expression correlation of the two neuropilins (NRP1 and NRP2) with each other (Spearman's rho 0.59) and with the endothelin receptor (NRP2 rho 0.66; NRP2 rho 0.51), and between VEGFA and its receptors (FLT1 rho 0.49; KDR rho 0.45). All PIK3CA mutated tumors expressed endothelin 1 mRNA (P=0.010). Most tumors expressing nuclear β-catenin were negative for VEGFC (P=0.009) and FLT4 (P=0.002) mRNA expression. In conclusion, we confirmed the presence of known genomic aberrations in BTC and different genotypes between BTC subsets. Novel findings are the coexistence of PI3K and WNT pathway gene alterations in BTC, their association with angiogenesis, and the hypermutated GBCs with HRR gene mutations, all of which may be considered for new treatment options in this difficult to treat disease.
Collapse
Affiliation(s)
- Kyriaki Papadopoulou
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece
| | | | - Kyriaki Manousou
- Section of Biostatistics, Hellenic Cooperative Oncology Group, Data OfficeAthens, Greece
| | - Ioannis Tikas
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece
| | - Christos Dervenis
- First Department of Surgery, General Hospital Konstantopouleio Agia OlgaAthens, Greece
| | - Joseph Sgouros
- Third Department of Medical Oncology, Agii Anargiri Cancer HospitalAthens, Greece
| | | | - Sotirios Lakis
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece
| | - Mattheos Bobos
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece
| | - Christos Poulios
- Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of MedicineThessaloniki, Greece
| | | | - Georgios Lazaridis
- Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of MedicineThessaloniki, Greece
| | - George Fountzilas
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece
- Aristotle University of ThessalonikiThessaloniki, Greece
| | - Vassiliki Kotoula
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessaloniki, Greece
- Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of MedicineThessaloniki, Greece
| |
Collapse
|
|
14
|
Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World J Gastroenterol 2017; 23:3978-3998. [PMID: 28652652 PMCID: PMC5473118 DOI: 10.3748/wjg.v23.i22.3978] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 02/01/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.
Collapse
|
|
15
|
Noguchi R, Yamaguchi K, Ikenoue T, Terakado Y, Ohta Y, Yamashita N, Kainuma O, Yokoi S, Maru Y, Nagase H, Furukawa Y. Genetic alterations in Japanese extrahepatic biliary tract cancer. Oncol Lett 2017; 14:877-884. [PMID: 28693246 DOI: 10.3892/ol.2017.6224] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 11/30/2016] [Indexed: 02/07/2023] Open
Abstract
Biliary tract cancer (BTC) is one of the most devastating types of malignant neoplasms worldwide. However, the mechanisms underlying the development and progression of BTC remain unresolved. BTC includes extrahepatic bile duct carcinoma (EBDC), gallbladder carcinoma (GBC) and ampulla of Vater carcinoma (AVC), named according to the location of the tumor. Although genetic alterations of intrahepatic cholangiocarcinoma have been investigated, those of EBDC, GBC and AVC have not yet been fully understood. The present study analyzed somatic mutations of 50 cancer-associated genes in 27 Japanese BTC cells, including: 11 EBDC, 14 GBC and 2 AVC. Next-generation sequencing using an Ion AmpliSeq Cancer Panel identified a total of 44 somatic mutations across 14 cancer-associated genes. Among the 44 mutations, 42 were judged as pathological mutations. Frequent mutations were identified in tumor protein 53 (TP53) (14/27), SMAD family member 4 (SMAD4) (6/27), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA) (6/27), and Kirsten rat sarcoma (KRAS) (6/27); no significant differences were identified between EBDC and GBC tissues. Notably, the frequency of the PIK3CA mutation was higher when compared with previous reports. This result may suggest that the activation of the PIK3CA-protein kinase B signaling pathway, in addition to the abrogation of p53, SMAD4 and RAS mitogen-activated protein kinase may have a crucial role in the carcinogenesis of Japanese BTC. These findings may be useful for the development of personalized therapies for BTC.
Collapse
Affiliation(s)
- Rei Noguchi
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Kiyoshi Yamaguchi
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Tsuneo Ikenoue
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Yumi Terakado
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Yasunori Ohta
- Department of Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Naohide Yamashita
- Department of Advanced Medical Science, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Osamu Kainuma
- Department of Gastroenterological Surgery, Chiba Cancer Center Hospital, Chiba 260-8718, Japan
| | - Sana Yokoi
- Division of Translational Genetics, Chiba Cancer Center Research Institute, Chiba 260-8718, Japan
| | - Yoshiaki Maru
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8718, Japan
| | - Hiroki Nagase
- Division of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8718, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| |
Collapse
|
|
16
|
Tanveer SM, Mukarram HS, Nayyar HS, Ul Ain MQ, Neelofar S. Incidental gallbladder cancer: Missing links in Pakistani population. INTERNATIONAL JOURNAL OF HEPATOBILIARY AND PANCREATIC DISEASES 2017. [DOI: 10.5348/ijhpd-2017-65-oa-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
|
|
17
|
Singh A, Mishra PK, Saluja SS, Talikoti MA, Kirtani P, Najmi AK. Prognostic Significance of HER-2 and p53 Expression in Gallbladder Carcinoma in North Indian Patients. Oncology 2016; 91:354-360. [PMID: 27784017 DOI: 10.1159/000450999] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 09/11/2016] [Indexed: 11/19/2022]
Abstract
BACKGROUND/OBJECTIVE Proto-oncogenes (HER-2) and tumor suppressor genes (p53) are commonly deregulated in gallbladder cancer (GBC). Available literature discloses skewed data from endemic Asian countries, especially north India. This study evaluates the prognostic significance of HER-2 and p53 in GBC patients from two major hospitals. METHODS Sixty resectable tumor and control specimens were prospectively collected from December 2012 to January 2016. Immunohistochemical staining was done using monoclonal antibodies to semiquantitatively evaluate HER-2 and p53 protein expression. The criterion for HER-2 positivity was set at >30% tumor cells showing complete, membranous staining while p53 positivity was established at <50% tumor cells showing complete nuclear staining. Clinicopathological correlations were drawn with major clinical outcomes. RESULTS It was observed that 36.67% (22/60) tumor cases and 5% (3/60) control cases showed strong HER-2 overexpression significantly correlating with sex, T-stage, nodal spread and distant metastasis (p < 0.05), while 33.3% (20/60) positivity was observed for p53 in tumor cases and 1.7% (1/60) in control cases. Multivariate analysis showed HER-2 (p = 0.04; hazard ratio: 2.36; 95% confidence interval: 1.04-5.33) and p53 (p = 0.03; hazard ratio: 5.63; 95% confidence interval: 1.21-26.26) expression to be independent prognostic factors. CONCLUSION Our study thus suggests the plausible role of HER-2 and p53 expression in worse prognosis of GBC in a north Indian population.
Collapse
Affiliation(s)
- Anjali Singh
- Department of Pharmaceutical Medicine, Faculty of Pharmacy, Jamia Hamdard, New Delhi, India
| | | | | | | | | | | |
Collapse
|
|
18
|
Qu K, Zhang X, Cui R, Liu C. Meta-signature of mutated genes in gallbladder cancer: evidence based high throughput screening assays. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:229. [PMID: 27384460 DOI: 10.21037/atm.2016.05.57] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Kai Qu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Xing Zhang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Ruixia Cui
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Chang Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| |
Collapse
|
|
19
|
Roa I, Garcia H, Game A, de Toro G, de Aretxabala X, Javle M. Somatic Mutations of PI3K in Early and Advanced Gallbladder Cancer. J Mol Diagn 2016; 18:388-394. [DOI: 10.1016/j.jmoldx.2015.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 12/02/2015] [Accepted: 12/11/2015] [Indexed: 02/06/2023] Open
|
|
20
|
Hong H, Jiang L, Lin Y, He C, Zhu G, Du Q, Wang X, She F, Chen Y. TNF-alpha promotes lymphangiogenesis and lymphatic metastasis of gallbladder cancer through the ERK1/2/AP-1/VEGF-D pathway. BMC Cancer 2016; 16:240. [PMID: 26992854 PMCID: PMC4799527 DOI: 10.1186/s12885-016-2259-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 03/08/2016] [Indexed: 12/21/2022] Open
Abstract
Background Tumor necrosis factor-alpha (TNF-α), a key player in cancer-related inflammation, was recently demonstrated to be involved in the lymphatic metastasis of gallbladder cancer (GBC). Vascular endothelial growth factor D (VEGF-D) is a key lymphangiogenic factor that is associated with lymphangiogenesis and lymph node metastasis in GBC. However, whether VEGF-D is involved in TNF-α-induced lymphatic metastasis of GBC remains undetermined. Methods The expression of VEGF-D in patient specimens was detected by immunohistochemistry and the relationship between VEGF-D in the tissue and TNF-α in the bile of the matching patients was analyzed. The VEGF-D mRNA and protein levels after treatment with exogenous TNF-α in NOZ, GBC-SD and SGC-996 cell lines were measured by real-time PCR and ELISA. The promoter activity and transcriptional regulation of VEGF-D were analyzed with the relative luciferase reporter assay, mutant constructs, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) assay, RNA interference and Western blotting. Inhibitors of JNK, p38 MAPK and ERK1/2 were used to explore the upstream signaling effector of AP-1. We used lentiviral vector expressing a VEGF-D shRNA construct to knockdown VEGF-D gene in NOZ and GBC-SD cells. The role of the TNF-α-VEGF-D axis in the tube formation of human dermal lymphatic endothelial cells (HDLECs) was determined using a three-dimensional coculture system. The role of the TNF-α - VEGF-D axis in lymphangiogenesis and lymph node metastasis was studied via animal experiment. Results TNF-α levels in the bile of GBC patients were positively correlated with VEGF-D expression in the clinical specimens. TNF-α can upregulate the protein expression and promoter activity of VEGF-D through the ERK1/2 - AP-1 pathway. Moreover, TNF-α can promote tube formation of HDLECs, lymphangiogenesis and lymph node metastasis of GBC by upregulation of VEGF-D in vitro and in vivo. Conclusion Taken together, our data suggest that TNF-α can promote lymphangiogenesis and lymphatic metastasis of GBC through the ERK1/2/AP-1/VEGF-D pathway.
Collapse
Affiliation(s)
- HaiJie Hong
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou, 350108, China
| | - Lei Jiang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou, 350108, China
| | - YanFei Lin
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou, 350108, China
| | - CaiLong He
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou, 350108, China
| | - GuangWei Zhu
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou, 350108, China
| | - Qiang Du
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China.,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou, 350108, China
| | - XiaoQian Wang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
| | - FeiFei She
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou, 350108, China. .,Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou, 350108, China.
| | - YanLing Chen
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China. .,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xueyuan Road, Minhou, Fuzhou, 350108, China.
| |
Collapse
|
|
21
|
Abstract
OPINION STATEMENT A paradigm shift towards molecular-based, personalized cancer therapeutics has occurred in recent years and a number of targeted drugs have emerged. Various targeted therapies like erlotinib, trastuzumab, and cetuximab have been approved in lung, breast, and colon cancers, respectively. Numerous clinical trials involving targeted drugs in biliary tract cancers are currently in progress, though none have been approved for this disease. Biliary tract cancers are divided into separate entities both anatomically and in terms of pathogenesis but are grouped together in most trials given their rarity. Combination chemotherapy involving cisplatin and gemcitabine is the current standard of care in the metastatic setting. In this review, we will discuss the various molecular pathways implicated in biliary tract cancers and potential therapeutic targets.
Collapse
Affiliation(s)
- Amartej Merla
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
| | - Kenneth G. Liu
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
| | - Lakshmi Rajdev
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
| |
Collapse
|
|
22
|
Abstract
PURPOSE OF REVIEW Gallbladder cancer (GBC) should be considered an orphan disease in oncology and represent a unique carcinogenetic model. This review will analyse some of the current aspects of GBC. RECENT FINDINGS Chile has the highest incidence and mortality of GBC in the world. Most patients are diagnosed in advanced stages with few treatment options. During the last two decades, little progress has been made in early diagnosis and treatment. At the molecular level, recent access to next-generation sequencing and other techniques for detecting the mutations of multiple genes have made advances in this area. SUMMARY The use of therapies targeted according to the detection of specific molecular alterations is in the early stages of evaluation and could represent a significant advance in the treatment of a large number of patients from developing countries.
Collapse
|
|
23
|
Dwivedi AND, Jain S, Dixit R. Gall bladder carcinoma: Aggressive malignancy with protean loco-regional and distant spread. World J Clin Cases 2015; 3:231-244. [PMID: 25789296 PMCID: PMC4360495 DOI: 10.12998/wjcc.v3.i3.231] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 11/21/2014] [Accepted: 12/16/2014] [Indexed: 02/05/2023] Open
Abstract
The most common malignancy of biliary tract is gallbladder cancer (GBC) which is the third most common cancer in gastrointestinal tract. It is a lethal disease for most patients in spite of growing awareness and improved diagnostic techniques. GBC has a very poor prognosis and the 5 year survival rate is < 10%. Although etiology of the carcinoma of the gallbladder is still obscure, various factors have been implicated, cholelithiasis being the most frequent. The incidence of GBC worldwide is based on the gender, geography and ethnicity which suggest that both genetic and environmental factors can cause GBC. The major route of spread of gallbladder cancer (GC) is loco-regional rather than distant. It spreads by lymphatic, vascular, neural, intraperitoneal, and intraductal routes. Sonography is usually the most common imaging test to evaluate symptoms of biliary tract disease including suspected GC. With recent advances in imaging modalities like multi-detector computed tomography (CT) scanners, magnetic resonance imaging-positron emission tomography/CT diagnosis of gallbladder cancer has improved. Studies have also targeted molecular and genetic pathways. Treatment options have included extended and radical surgeries and adjuvant chemotherapy. This review article deals in detail with important aspects of carcinoma gallbladder and its manifestations and challenges. Role of various imaging modalities in characterization and accurate staging has been discussed. The loco-regional spread of this aggressive malignancy is dealt explicitly.
Collapse
|
|
24
|
Bizama C, García P, Espinoza JA, Weber H, Leal P, Nervi B, Roa JC. Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy. Cancer Treat Rev 2015; 41:222-34. [PMID: 25639632 DOI: 10.1016/j.ctrv.2015.01.003] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Revised: 01/12/2015] [Accepted: 01/13/2015] [Indexed: 02/07/2023]
Abstract
Gallbladder cancer is the most common and aggressive malignancy of the biliary tract. The complete surgical resection is the only potentially curative approach in early stage; however, most cases are diagnosed in advanced stages and the response to traditional chemotherapy and radiotherapy is extremely limited, with modest impact in overall survival. The recent progress in understanding the molecular alterations of gallbladder cancer has shown great promise for the development of more effective treatment strategies. This has mainly resulted from the identification of molecular alterations in relevant intracellular signaling pathways-Hedgehog, PI3K/AKT/mTOR, Notch, ErbB, MAPK and angiogenesis-which are potential tailored targets for gallbladder cancer patients. This review discusses the recent remarkable progress in understanding the molecular alterations that represent novel prognosis molecular markers and therapeutic targets for gallbladder cancer, which will provide opportunities for research and for developing innovative strategies that may enhance the benefit of conventional chemotherapy, or eventually modify the fatal natural history of this orphan disease.
Collapse
Affiliation(s)
- Carolina Bizama
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Patricia García
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Jaime A Espinoza
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Helga Weber
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco 4811230, Chile
| | - Pamela Leal
- Department of Pathology, School of Medicine, Universidad de La Frontera, CEGIN-BIOREN, Temuco 4811230, Chile
| | - Bruno Nervi
- Department of Hematology Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 26767000, Chile
| | - Juan Carlos Roa
- Department of Pathology, Center for Investigation in Translational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Santiago 8330024, Chile.
| |
Collapse
|