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Kuang J, Li J, Zhou S, Li Y, Lin J, Huang W, Yuan X. Genomic and micro-environmental insights into drug resistance in colorectal cancer liver metastases. Discov Oncol 2025; 16:241. [PMID: 40009285 DOI: 10.1007/s12672-025-01976-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is known for its high heterogeneity, with liver metastases significantly impairing survival outcomes. Understanding the tumor microenvironment (TME) and genomic alterations in metastatic sites is crucial for developing personalized therapies that overcome drug resistance and improve prognosis. METHODS We profiled 54 CRC liver metastases, comparing them with 198 other metastatic lesions and normal liver tissues. By analyzing immune cell infiltration, stromal interactions, and key genomic alterations, we constructed an 11-gene prognostic model to predict survival and immunotherapy outcomes. RESULTS CRC liver metastases with high-risk profiles demonstrated enriched follicular helper T cells, activated dendritic cells, and M2 macrophages in the TME. Frequent mutations in APC, TP53, KRAS, and PIK3CA were identified, alongside altered EGFR signaling. The 11-gene model effectively stratified patients by prognosis and predicted immunotherapy responses, emphasizing the therapeutic potential of targeting resistance mechanisms. CONCLUSIONS This study reveals how genomic and TME-driven factors contribute to drug resistance in CRC liver metastases. Integrating these insights with clinical data could advance precision therapies, addressing the evolving challenge of tumor drug resistance in CRC.
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Affiliation(s)
- Junjie Kuang
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Jun Li
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Siwei Zhou
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Yi Li
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Jinbo Lin
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China
| | - Weizhen Huang
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China.
| | - Xia Yuan
- The Second Department of Oncology, Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China.
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Nosalova N, Majirska M, Keselakova A, Martinkova M, Fabianova D, Mirossay A, Pilatova MB, Kello M. Pyrrolidine SS13 induces oxidative stress and autophagy-mediated cell death in colorectal cancer cells. Eur J Pharm Sci 2025; 205:106982. [PMID: 39644983 DOI: 10.1016/j.ejps.2024.106982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/19/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
INTRODUCTION Pyrrolidines, nitrogenous organic compounds, are among the most intensively studied agents because of their antibacterial, antiviral, neurological, and promising antitumor effects. Moreover, many medicinal drugs contain pyrrolidine moiety such as sunitinib (anticancer drug), telaprevir and ombitasvir (antiviral drugs) or ramipril (antihypertensive drug). RATIONALE OF THE STUDY Based on the pro-apoptotic effect of pyrrolidine SS13, this study focuses on the pro-oxidative properties of the tested pyrrolidine SS13 on colorectal cancer cells to deepen the understanding of its mechanisms of action. RESEARCH HYPOTHESIS We hypothesize that SS13 induces oxidative stress and autophagy activation in HCT116 and Caco-2 cell lines, thus contributing to antiproliferative effects. METHODS Flow cytometry, western blot, fluorescence microscopy and qRT-PCR were used to evaluate the effect of pyrrolidine SS13. CONCLUSION AND FUTURE DIRECTIONS Pyrrolidine SS13 induced oxidative stress through the accumulation of reactive oxygen and nitrogen species in both cell lines and the modulation of both superoxide dismutase isoenzymes (SOD1, SOD2). Oxidative stress was also associated with the activation of DNA damage response system and modulation of stress/survival pathways. We demonstrated for the first time that pyrrolidine SS13 is involved in the induction of autophagy accompanied by increased levels of autophagic markers (p-AMPK, p-ULK, LC3I/II and ATG7) and a significant decrease in p62 protein levels in both cell lines. Finally, chloroquine, an inhibitor of autophagy, enhanced cell survival and suppressed the cytotoxic effect of SS13 in HCT116 and Caco-2 cells, indicating that SS13 contributes to autophagy-mediated cell death. Taken together, our results suggest that oxidative stress and autophagy participate in the antiproliferative effect of pyrrolidine SS13 on colorectal cancer cells. Further research using primary cell cultures obtained from different animal tissues as well as performing in vivo experiments is needed to understand these processes in detail and to investigate the potential therapeutic application of new pyrrolidine derivatives.
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Affiliation(s)
- Natalia Nosalova
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Monika Majirska
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Alexandra Keselakova
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Miroslava Martinkova
- Institute of Chemical Sciences, Department of Organic Chemistry, Faculty of Science, P.J. Šafárik University, Košice, Slovakia.
| | - Dominika Fabianova
- Institute of Chemical Sciences, Department of Organic Chemistry, Faculty of Science, P.J. Šafárik University, Košice, Slovakia.
| | - Andrej Mirossay
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Martina Bago Pilatova
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
| | - Martin Kello
- Department of Pharmacology, Faculty of Medicine, P.J. Šafárik University, Košice, Slovakia.
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Zhang J, Lin Y, Gao J, Pan Y, Hou G, Guo C, Gao F. Development and biological evaluation of 68Ga-labeled peptides for potential application in HER2-positive colorectal cancer. Bioorg Chem 2024; 151:107645. [PMID: 39059074 DOI: 10.1016/j.bioorg.2024.107645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/11/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024]
Abstract
Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world. Human epidermal growth factor receptor 2 (HER2) is a promising target for the diagnosis and treatment of CRC. In this study, we aimed to design, synthesize and label peptide-based positron emission tomography (PET) tracers targeting HER2-positive CRC, namely [68Ga]Ga-ES-01 and [68Ga]Ga-ES-02. The results show that [68Ga]Ga-ES-01 and [68Ga]Ga-ES-02 possessed hydrophilicity, rapid pharmacokinetic properties and excellent stabilities. [68Ga]Ga-ES-02 demonstrated higher binding affinity (Kd = 24.29 ± 4.95 nM) toward the HER2 in CRC. In HER2-positive HT-29 CRC xenograft mouse model, PET study showed specific tumor uptake after injection of [68Ga]Ga-ES-02 (SUV15min max = 0.87 ± 0.03; SUV30min max = 0.64 ± 0.02). In biodistribution study, the T/M ratios of 68Ga-ES-02 at 30 min after injection reached a maximum of 4.07 ± 0.34. In summary, we successfully synthesized and evaluated two novel peptide-based PET tracers. Our data demonstrate that [68Ga]Ga-ES-01/02 is capable of HER2-positive colorectal cancer, with [68Ga]Ga-ES-02 showing superior imaging effect, enhanced targeting, and increased specificity.
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Affiliation(s)
- Jinglin Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yixiang Lin
- Key Laboratory for Experimental Teratology of the Ministry of Education and Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Jingyue Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yuan Pan
- Key Laboratory for Experimental Teratology of the Ministry of Education and Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Guihua Hou
- Key Laboratory for Experimental Teratology of the Ministry of Education and Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Chun Guo
- Key Laboratory for Experimental Teratology of the Ministry of Education and Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
| | - Feng Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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Afolabi HA, Salleh SM, Zakaria Z, Seng CE, Nafi NM, Bin AbdulAziz AA, Wada Y, Irekeola AA, Al-Ml-hanna SB, Mussa A. Targeted variant prevalence of FBXW7 gene mutation in colorectal carcinoma propagation. The first systematic review and meta-analysis. Heliyon 2024; 10:e31471. [PMID: 38845996 PMCID: PMC11154211 DOI: 10.1016/j.heliyon.2024.e31471] [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: 09/08/2023] [Revised: 05/15/2024] [Accepted: 05/16/2024] [Indexed: 06/09/2024] Open
Abstract
FBXW7 is a tumour suppressor gene that functions as E3-ubiquitin-ligase, targeting numerous oncoproteins for degradation, i.e., Cyclin-E, c-Myc, and Notch. FBXW7 performs a pivotal role in regulating cell cycle progression. FBXW7 mutation is frequently implicated in various cancers. Methodology A systematic review and meta-analysis done on several studies using "Preferred Reporting Items for Systemmatic Reviews and Meta-Analysis (PRISMA)" criteria and registered with PROSPERO (registration-number-CRD42023388845). The preliminary search comprises 1182 articles; however, 58 studies were subsequently chosen after eliminating non-eligible studies. To explore the prevalence of FBXW7 mutation among colorectal cancer patients, data were analysed using "OpenMeta Analyst and comprehensive meta-analysis-3.0 (CMA-3.0)" software. Results This meta-analysis involves 13,974 respondents; most were males 7825/13,974, (56.0 %). Overall prevalence of FBXW7 mutations was 10.3 %, (95%CI: 8.6-12.4), I2 = 90.5 %, (P < 0.001). The occurrence of FBXW7 mutations was highest in Russia [19.0 %, (95%CI: 9.8-33.7)] and Taiwan [18.8 %, (95%CI: 8.7-35.9)], P-values< 0.05 while the least prevalence was reported in Netherland (4 %) and Italy (5 %), both P-values< 0.001. Overall prevalence of FBXW7 abberation was greatest amongst male gender: "53.9 %, (95%CI: 8.3-62.0 %)", Tumour location (colon): 59.8 %, (95%CI: 53.9-65), tumour site (left): 61.6 %, (95%CI: 53.8-68.9), Tumour-grade (Moderate): 65.9 %, (95%CI: 54.9-75.4 %), and Tumour late-stage: 67.9 %, (95%CI: 49.7-84.3 %), all P-values< 0.001. When stratified according to study-period, an increasing trend was noted from 2018 till present with the highest mutation rate recorded in 2022 (15.3 %). Conclusion Overall prevalence of FBXW7 mutations was 10.3 % with male gender, left side, and late-stage being most mutated, and these outcomes conform with severally published articles on FBXW7 mutation.
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Affiliation(s)
- Hafeez Abiola Afolabi
- Department of General Surgery, School of Medical Sciences, Hospital Universiti Sains Malaysia (HUSM), Health Campus, Universiti Sains Malaysia (USM), Kubang Kerian, Kelantan, 16150, Malaysia
| | - Salzihan Md Salleh
- Department of Pathology, School of Medical Sciences, Hospital Universiti Sains Malaysia (HUSM), Health Campus, Universiti Sains Malaysia (USM), Kubang Kerian, 16150, Kelantan, Malaysia
| | - Zaidi Zakaria
- Department of General Surgery, School of Medical Sciences, Hospital Universiti Sains Malaysia (HUSM), Health Campus, Universiti Sains Malaysia (USM), Kubang Kerian, Kelantan, 16150, Malaysia
| | - Ch'ng Ewe Seng
- Department of Pathology, Advanced Medical & Dental Institute, Universiti Sains Malaysia (USM), Kepala Batas, 13200, Malaysia
| | - Norasikin Mohd Nafi
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia (USM), Health Campus, Kubang Kerian, 16150, Malaysia
| | - Ahmad Aizat Bin AbdulAziz
- Department of Human Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia
| | - Yusuf Wada
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia
- Department of Zoology, Ahmadu Bello University, Zaria, Kaduna, Nigeria
| | - Ahmad Adebayo Irekeola
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia
| | - Sameer Badri Al-Ml-hanna
- Department of Exercise Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia
| | - Ali Mussa
- Department of Biology, Faculty of Education, Omdurman Islamic University, Omdurman, P.O. Box 382, Sudan
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia
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Travis G, McGowan EM, Simpson AM, Marsh DJ, Nassif NT. PTEN, PTENP1, microRNAs, and ceRNA Networks: Precision Targeting in Cancer Therapeutics. Cancers (Basel) 2023; 15:4954. [PMID: 37894321 PMCID: PMC10605164 DOI: 10.3390/cancers15204954] [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: 09/11/2023] [Revised: 10/06/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a well characterised tumour suppressor, playing a critical role in the maintenance of fundamental cellular processes including cell proliferation, migration, metabolism, and survival. Subtle decreases in cellular levels of PTEN result in the development and progression of cancer, hence there is tight regulation of the expression, activity, and cellular half-life of PTEN at the transcriptional, post-transcriptional, and post-translational levels. PTENP1, the processed pseudogene of PTEN, is an important transcriptional and post-transcriptional regulator of PTEN. PTENP1 expression produces sense and antisense transcripts modulating PTEN expression, in conjunction with miRNAs. Due to the high sequence similarity between PTEN and the PTENP1 sense transcript, the transcripts possess common miRNA binding sites with the potential for PTENP1 to compete for the binding, or 'sponging', of miRNAs that would otherwise target the PTEN transcript. PTENP1 therefore acts as a competitive endogenous RNA (ceRNA), competing with PTEN for the binding of specific miRNAs to alter the abundance of PTEN. Transcription from the antisense strand produces two functionally independent isoforms (PTENP1-AS-α and PTENP1-AS-β), which can regulate PTEN transcription. In this review, we provide an overview of the post-transcriptional regulation of PTEN through interaction with its pseudogene, the cellular miRNA milieu and operation of the ceRNA network. Furthermore, its importance in maintaining cellular integrity and how disruption of this PTEN-miRNA-PTENP1 axis may lead to cancer but also provide novel therapeutic opportunities, is discussed. Precision targeting of PTENP1-miRNA mediated regulation of PTEN may present as a viable alternative therapy.
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Affiliation(s)
- Glena Travis
- Cancer Biology, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (G.T.); (E.M.M.)
| | - Eileen M. McGowan
- Cancer Biology, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (G.T.); (E.M.M.)
- Central Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Ann M. Simpson
- Gene Therapy and Translational Molecular Analysis Laboratory, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Deborah J. Marsh
- Translational Oncology Group, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Najah T. Nassif
- Cancer Biology, Faculty of Science, School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia; (G.T.); (E.M.M.)
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Alsolme E, Alqahtani S, Fageeh M, Barakeh D, Sharma NK, Mangul S, Robinson HA, Fathaddin A, Hauser CAE, Abedalthagafi M. The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel. Diagnostics (Basel) 2023; 13:2993. [PMID: 37761360 PMCID: PMC10527739 DOI: 10.3390/diagnostics13182993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/20/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
PURPOSE Next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients. PATIENTS AND METHODS We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS in 107 Saudi Arabian patients without a family history of CRC. RESULTS Approximately 98% of patients had genetic alterations. Frequent mutations were observed in BRCA2 (79%), CHEK1 (78%), ATM (76%), PMS2 (76%), ATR (74%), and MYCL (73%). The APC gene was not included in the panel. Statistical analysis using the Cox proportional hazards model revealed an unusual positive association between poorly differentiated tumors and survival rates (p = 0.025). Although no significant univariate associations between specific mutations or overall mutation rate and overall survival were found, our preliminary analysis of the molecular markers for CRC in a predominantly Arab population can provide insights into the molecular pathways that play a significant role in the underlying disease progression. CONCLUSIONS These results may help optimize personalized therapy when drugs specific to a patient's mutation profile have already been developed.
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Affiliation(s)
- Ebtehal Alsolme
- Genomic Research Department, King Fahad Medical City, Riyadh 12231, Saudi Arabia; (E.A.); (D.B.)
| | - Saleh Alqahtani
- Royal Clinic and Hepatology Department, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia;
| | - Musa Fageeh
- Pathology Department, King Saud Medical City, Riyadh 12746, Saudi Arabia;
| | - Duna Barakeh
- Genomic Research Department, King Fahad Medical City, Riyadh 12231, Saudi Arabia; (E.A.); (D.B.)
| | - Nitesh K. Sharma
- The Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA 90007, USA; (N.K.S.); (S.M.)
| | - Serghei Mangul
- The Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA 90007, USA; (N.K.S.); (S.M.)
| | | | - Amany Fathaddin
- Department of Pathology, Collage of Medicine, King Saud University, Riyadh 11362, Saudi Arabia;
| | - Charlotte A. E. Hauser
- Laboratory for Nanomedicine, Biological & Environmental Science & Engineering (BESE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia;
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia
| | - Malak Abedalthagafi
- Department of Pathology and Laboratory Medicine, Emory School of Medicine, Atlanta, GA 30307, USA
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Afolabi HA, Salleh SM, Zakaria Z, Ch’ng ES, Mohd Nafi SN, Abdul Aziz AAB, Irekeola AA, Wada Y, Al-Mhanna SB. A GNAS Gene Mutation's Independent Expression in the Growth of Colorectal Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:cancers14225480. [PMID: 36428574 PMCID: PMC9688108 DOI: 10.3390/cancers14225480] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/10/2022] Open
Abstract
Globally, colorectal carcinoma CRC is the third most common cancer and the third most common reason for cancer-associated mortality in both genders. The GNAS mutations are significantly linked with poor prognosis and failed treatment outcomes in CRC. A systematic review and meta-analysis of multiple studies executed following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria and registered with PROSPERO (registration number: CRD42021256452). The initial search includes a total of 271 publications; however, only 30 studies that merit the eligibility criteria were eventually chosen. Data analysis via OpenMeta Analyst and comprehensive meta-analysis 3.0 (CMA 3.0) software were used to investigate the prevalence of GNAS gene mutation among CRC patients. The meta-analysis consisted of 10,689 participants with most being males 6068/10,689 (56.8%). Overall, prevalence of GNAS mutations was 4.8% (95% CI: 3.1−7.3) with I2 = 94.39% and (p < 0.001). In 11/30 studies, the frequency of GNAS gene mutations was majorly in codons R201C [40.7% (95% CI: 29.2−53.2%)] and in codon R201H [39.7% (95% CI = 27.1−53.8)]. Overall prevalence of GNAS mutations was highest among the male gender: 53.9% (95% CI: 48.2−59.5%: I2 = 94.00%, (p < 0.001), tumour location (colon): 50.5% (95% CI: 33.2−67.6%: I2 = 97.93%, (p < 0.001), tumour grade (Well): 57.5% (95% CI: 32.4−79.2%: I2 = 98.10%, (p < 0.001) and tumour late stage: 67.9% (95% CI: 49.7−84.3%: I2 = 98.%, (p < 0.001). When stratified according to study location, a higher prevalence was observed in Japan (26.8%) while Italy has the lowest (0.4%). Overall prevalence of GNAS gene mutations was 4.8% with codons R201C and R201H being the most mutated, and the results conformed with numerous published studies on GNAS mutation.
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Affiliation(s)
- Hafeez Abiola Afolabi
- Department of General Surgery, School of Medical Sciences, Hospital Universiti Sains Malaysia, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
| | - Salzihan Md Salleh
- Department of Pathology, School of Medical Sciences, Hospital Universiti Sains Malaysia (HUSM), Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia (USM), Health Campus, Kubang Kerian 16150, Malaysia
- Correspondence: or
| | - Zaidi Zakaria
- Department of General Surgery, School of Medical Sciences, Hospital Universiti Sains Malaysia, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
| | - Ewe Seng Ch’ng
- Advanced Medical and Dental Institute, Universiti Sains Malaysia USM, Kepala Batas 13200, Malaysia
| | - Siti Norasikin Mohd Nafi
- Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia (USM), Health Campus, Kubang Kerian 16150, Malaysia
| | - Ahmad Aizat Bin Abdul Aziz
- Department of Human Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
| | - Ahmad Adebayo Irekeola
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
| | - Yusuf Wada
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
| | - Sameer Badri Al-Mhanna
- Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kubang Kerian 16150, Malaysia
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Kastrisiou M, Zarkavelis G, Kougioumtzi A, Sakaloglou P, Kostoulas C, Georgiou I, Batistatou A, Pentheroudakis G, Magklara A. Development and Validation of a Targeted ‘Liquid’ NGS Panel for Treatment Customization in Patients with Metastatic Colorectal Cancer. Diagnostics (Basel) 2021; 11:diagnostics11122375. [PMID: 34943612 PMCID: PMC8700616 DOI: 10.3390/diagnostics11122375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/12/2021] [Accepted: 12/13/2021] [Indexed: 01/22/2023] Open
Abstract
The detection of actionable mutations in tumor tissue is a prerequisite for treatment customization in patients with metastatic colorectal cancer (mCRC). Analysis of circulating tumor DNA (ctDNA) for the identification of such mutations in patients’ plasma is an attractive alternative to invasive tissue biopsies. Despite having the high analytical sensitivity required for ctDNA analysis, digital polymerase chain reaction (dPCR) technologies can only detect a very limited number of hotspot mutations, whilst a broader mutation panel is currently needed for clinical decision making. Recent advances in next-generation sequencing (NGS) have led to high-sensitivity platforms that allow screening of multiple genes at a single assay. Our goal was to develop a small, cost- and time-effective NGS gene panel that could be easily integrated in the day-to-day clinical routine in the management of patients with mCRC. We designed a targeted panel comprising hotspots in six clinically relevant genes (KRAS, NRAS, MET, BRAF, ERBB2 and EGFR) and validated it in a total of 68 samples from 30 patients at diagnosis, first and second disease progression. Results from our NGS panel were compared against plasma testing with BEAMing dPCR regarding the RAS gene status. The overall percent of agreement was 83.6%, with a positive and negative percent agreement of 74.3% and 96.2%, respectively. Further comparison of plasma NGS with standard tissue testing used in the clinic showed an overall percent agreement of 86.7% for RAS status, with a positive and negative percent agreement of 81.2% and 92.8%, respectively. Thus, our study strongly supports the validity and efficiency of an affordable targeted NGS panel for the detection of clinically relevant mutations in patients with mCRC.
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Affiliation(s)
- Myrto Kastrisiou
- Department of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (M.K.); (A.K.)
- Department of Medical Oncology, University General Hospital of Ioannina, 45500 Ioannina, Greece;
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45444 Ioannina, Greece
| | - George Zarkavelis
- Department of Medical Oncology, University General Hospital of Ioannina, 45500 Ioannina, Greece;
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45444 Ioannina, Greece
| | - Anastasia Kougioumtzi
- Department of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (M.K.); (A.K.)
| | - Prodromos Sakaloglou
- Laboratory of Medical Genetics in Clinical Practice, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (P.S.); (C.K.); (I.G.)
| | - Charilaos Kostoulas
- Laboratory of Medical Genetics in Clinical Practice, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (P.S.); (C.K.); (I.G.)
| | - Ioannis Georgiou
- Laboratory of Medical Genetics in Clinical Practice, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (P.S.); (C.K.); (I.G.)
| | - Anna Batistatou
- Department of Pathology, Faculty of Medicine, University of Ioannina, 45500 Ioannina, Greece;
| | - George Pentheroudakis
- Department of Medical Oncology, University General Hospital of Ioannina, 45500 Ioannina, Greece;
- Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), 45444 Ioannina, Greece
- Correspondence: (G.P.); (A.M.)
| | - Angeliki Magklara
- Department of Clinical Chemistry, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece; (M.K.); (A.K.)
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, 45110 Ioannina, Greece
- Institute of Biosciences, University Research Center of Ioannina (URCI), 45110 Ioannina, Greece
- Correspondence: (G.P.); (A.M.)
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9
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Sanaei MJ, Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Shahrokh S, Zali MR, Bashash D. The PI3K/Akt/mTOR axis in colorectal cancer: Oncogenic alterations, non-coding RNAs, therapeutic opportunities, and the emerging role of nanoparticles. J Cell Physiol 2021; 237:1720-1752. [PMID: 34897682 DOI: 10.1002/jcp.30655] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/02/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the deadliest human malignancies worldwide. Several molecular pathways have been demonstrated to be involved in the initiation and development of CRC which among them, the overactivation of the phosphatidyl-inositol 3-kinase (PI3K)/Akt/mTOR axis is of importance. The current review aims to unravel the mechanisms by which the PI3K/Akt/mTOR pathway affects CRC progression; and also, to summarize the original data obtained from international research laboratories on the oncogenic alterations and polymorphisms affecting this pathway in CRC. Besides, we provide a special focus on the regulatory role of noncoding RNAs targeting the PI3K/Akt/mTOR pathway in this malignancy. Questions on how this axis is involved in the inhibition of apoptosis, in the induction of drug resistance, and the angiogenesis, epithelial to mesenchymal transition, and metastasis are also responded. We also discussed the PI3K/Akt pathway-associated prognostic and predictive biomarkers in CRC. In addition, we provide a general overview of PI3K/Akt/mTOR pathway inhibition whether by chemical-based drugs or by natural-based medications in the context of CRC, either as monotherapy or in combination with other therapeutic agents; however, those treatments might have life-threatening side effects and toxicities. To the best of our knowledge, the current review is one of the first ones highlighting the emerging roles of nanotechnology to overcome challenges related to CRC therapy in the hope that providing a promising platform for the treatment of CRC.
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Affiliation(s)
- Mohammad-Javad Sanaei
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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10
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Almuzzaini B, Alghamdi J, Alomani A, AlGhamdi S, Alsharm AA, Alshieban S, Sayed A, Alhejaily AG, Aljaser FS, Abudawood M, Almajed F, Samman A, Balwi MAA, Aziz MA. Identification of Novel Mutations in Colorectal Cancer Patients Using AmpliSeq Comprehensive Cancer Panel. J Pers Med 2021; 11:jpm11060535. [PMID: 34207827 PMCID: PMC8230213 DOI: 10.3390/jpm11060535] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/25/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023] Open
Abstract
Biomarker discovery would be an important tool in advancing and utilizing the concept of precision and personalized medicine in the clinic. Discovery of novel variants in local population provides confident targets for developing biomarkers for personalized medicine. We identified the need to generate high-quality sequencing data from local colorectal cancer patients and understand the pattern of occurrence of variants. In this report, we used archived samples from Saudi Arabia and used the AmpliSeq comprehensive cancer panel to identify novel somatic variants. We report a comprehensive analysis of next-generation sequencing results with a coverage of >300X. We identified 466 novel variants which were previously unreported in COSMIC and ICGC databases. We analyzed the genes associated with these variants in terms of their frequency of occurrence, probable pathogenicity, and clinicopathological features. Among pathogenic somatic variants, 174 were identified for the first time in the large intestine. APC, RET, and EGFR genes were most frequently mutated. A higher number of variants were identified in the left colon. Occurrence of variants in ERBB2 was significantly correlated with those of EGFR and ATR genes. Network analyses of the identified genes provide functional perspective of the identified genes and suggest affected pathways and probable biomarker candidates. This report lays the ground work for biomarker discovery and identification of driver gene mutations in local population.
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Affiliation(s)
- Bader Almuzzaini
- King Abdullah International Medical Research Center, Medical Genomics Research Department, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia;
- Correspondence: (B.A.); (M.A.A.); Tel.: +966-11-429-4533 (B.A.); +966-11-429-4582 (M.A.A.)
| | - Jahad Alghamdi
- King Abdullah International Medical Research Center, Saudi Biobank, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia; (J.A.); (A.S.)
| | - Alhanouf Alomani
- Department of Pathology, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 13318, Saudi Arabia;
| | - Saleh AlGhamdi
- Clinical Research Department, Research Center, King Fahad Medical City, Riyadh 11564, Saudi Arabia;
| | - Abdullah A. Alsharm
- Comprehensive Cancer Center, King Fahad Medical City, Riyadh 11564, Saudi Arabia;
| | - Saeed Alshieban
- King Abdul Aziz Medical City-National Guard Health Affairs (NGHA), King Abdullah International Medical Research Center, King Saud Bin Abdul Aziz University for Health Sciences (KSAU-HS), Riyadh 14611, Saudi Arabia;
| | - Ahood Sayed
- King Abdullah International Medical Research Center, Saudi Biobank, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia; (J.A.); (A.S.)
| | | | - Feda S. Aljaser
- Department of Clinical Laboratory Sciences, Chair of Medical and Molecular Genetics Research, College of Applied Medical Sciences, King Saud University Riyadh, Riyadh 11564, Saudi Arabia; (F.S.A.); (M.A.)
| | - Manal Abudawood
- Department of Clinical Laboratory Sciences, Chair of Medical and Molecular Genetics Research, College of Applied Medical Sciences, King Saud University Riyadh, Riyadh 11564, Saudi Arabia; (F.S.A.); (M.A.)
| | - Faisal Almajed
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11481, Saudi Arabia;
| | - Abdulhadi Samman
- Department of Pathology, Faculty of Medicine, University of Jeddah, Jeddah 23218, Saudi Arabia;
| | - Mohammed A. Al Balwi
- King Abdullah International Medical Research Center, Medical Genomics Research Department, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia;
| | - Mohammad Azhar Aziz
- King Abdullah International Medical Research Center, Colorectal Cancer Research Program, Department of Cellular Therapy and Cancer Research, Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia
- Correspondence: (B.A.); (M.A.A.); Tel.: +966-11-429-4533 (B.A.); +966-11-429-4582 (M.A.A.)
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11
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Epstein RJ, Tian LJ, Gu YF. 2b or Not 2b: How Opposing FGF Receptor Splice Variants Are Blocking Progress in Precision Oncology. JOURNAL OF ONCOLOGY 2021; 2021:9955456. [PMID: 34007277 PMCID: PMC8110382 DOI: 10.1155/2021/9955456] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 04/21/2021] [Indexed: 01/16/2023]
Abstract
More than ten thousand peer-reviewed studies have assessed the role of fibroblast growth factors (FGFs) and their receptors (FGFRs) in cancer, but few patients have yet benefited from drugs targeting this molecular family. Strategizing how best to use FGFR-targeted drugs is complicated by multiple variables, including RNA splicing events that alter the affinity of ligands for FGFRs and hence change the outcomes of stromal-epithelial interactions. The effects of splicing are most relevant to FGFR2; expression of the FGFR2b splice isoform can restore apoptotic sensitivity to cancer cells, whereas switching to FGFR2c may drive tumor progression by triggering epithelial-mesenchymal transition. The differentiating and regulatory actions of wild-type FGFR2b contrast with the proliferative actions of FGFR1 and FGFR3, and may be converted to mitogenicity either by splice switching or by silencing of tumor suppressor genes such as CDH1 or PTEN. Exclusive use of small-molecule pan-FGFR inhibitors may thus cause nonselective blockade of FGFR2 isoforms with opposing actions, undermining the rationale of FGFR2 drug targeting. This splice-dependent ability of FGFR2 to switch between tumor-suppressing and -driving functions highlights an unmet oncologic need for isoform-specific drug targeting, e.g., by antibody inhibition of ligand-FGFR2c binding, as well as for more nuanced molecular pathology prediction of FGFR2 actions in different stromal-tumor contexts.
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Affiliation(s)
- Richard J. Epstein
- New Hope Cancer Center, Beijing United Hospital, 9-11 Jiangtai West Rd, Chaoyang, Beijing 100015, China
- Garvan Institute of Medical Research and UNSW Clinical School, 84 Victoria St, Darlinghurst 2010 Sydney, Australia
| | - Li Jun Tian
- New Hope Cancer Center, Beijing United Hospital, 9-11 Jiangtai West Rd, Chaoyang, Beijing 100015, China
| | - Yan Fei Gu
- New Hope Cancer Center, Beijing United Hospital, 9-11 Jiangtai West Rd, Chaoyang, Beijing 100015, China
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12
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Hasbal-Celikok G, Aksoy-Sagirli P, Altiparmak-Ulbegi G, Can A. Identification of AKT1/β-catenin mutations conferring cetuximab and chemotherapeutic drug resistance in colorectal cancer treatment. Oncol Lett 2021; 21:209. [PMID: 33574948 DOI: 10.3892/ol.2021.12470] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 11/19/2020] [Indexed: 12/24/2022] Open
Abstract
In anticancer therapy, the effectiveness of therapeutics is limited by mutations causing drug resistance. KRAS mutations are the only determinant for cetuximab resistance in patients with colorectal cancer (CRC). However, cetuximab treatment has not been fully successful in the majority of patients with wild-type (WT) KRAS. Therefore, it is important to determine new predictive mutations in CRC treatment. In the present study, the association between AKT1/β-catenin (CTNNB1) mutations with the drug resistance to cetuximab and other chemotherapeutics used in the CRC treatment was investigated by using site-directed mutagenesis, transfection, western blotting and cell proliferation inhibition assay. Cetuximab resistance was higher in the presence of AKT1 E17K, E49K and L52R mutations, as well as CTNNB1 T41A, S45F and S33P mutations compared with that of respective WT proteins. AKT1/CTNNB1 mutations were also associated with oxaliplatin, irinotecan, SN-38 and 5-fluorouracil resistance. Furthermore, mutant cell viability in oxaliplatin treatment was more effectively inhibited compared with that of the other chemotherapeutic drugs. In conclusion, AKT1/CTNNB1 mutations may be used as an important predictive biomarker in CRC treatment.
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Affiliation(s)
- Gozde Hasbal-Celikok
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, Fatih, Istanbul 34116, Turkey
| | - Pinar Aksoy-Sagirli
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, Fatih, Istanbul 34116, Turkey
| | - Gulsum Altiparmak-Ulbegi
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, Fatih, Istanbul 34116, Turkey
| | - Ayse Can
- Department of Biochemistry, Faculty of Pharmacy, Istanbul University, Fatih, Istanbul 34116, Turkey
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13
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Tabibzadeh A, Tameshkel FS, Moradi Y, Soltani S, Moradi-Lakeh M, Ashrafi GH, Motamed N, Zamani F, Motevalian SA, Panahi M, Esghaei M, Ajdarkosh H, Mousavi-Jarrahi A, Niya MHK. Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis. Sci Rep 2020; 10:18713. [PMID: 33127962 PMCID: PMC7599243 DOI: 10.1038/s41598-020-73770-1] [Citation(s) in RCA: 10] [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: 02/05/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023] Open
Abstract
The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3-8%), 12% (95% CI: 8-18%), 17% (95% CI: 14-20%), and 20% (95% CI: 5-41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14-33%) and 20% (95% CI, 17-24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.
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Affiliation(s)
- Alireza Tabibzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Safarnezhad Tameshkel
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Yousef Moradi
- Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Saber Soltani
- Department of Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Maziar Moradi-Lakeh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
- Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - G Hossein Ashrafi
- Cancer Theme SEC Faculty, Kingston University, Penrhyn Road, London, KT1 2EE, UK
| | - Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Abbas Motevalian
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Panahi
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Esghaei
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
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14
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Liu Y, Cao J, Zhu YN, Ma Y, Murtaza G, Li Y, Wang JH, Pu YS. C1222C Deletion in Exon 8 of ABL1 Is Involved in Carcinogenesis and Cell Cycle Control of Colorectal Cancer Through IRS1/PI3K/Akt Pathway. Front Oncol 2020; 10:1385. [PMID: 32850446 PMCID: PMC7433659 DOI: 10.3389/fonc.2020.01385] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 06/30/2020] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. ABL1 (c-Abl) is a non-receptor tyrosine kinase, whose role, and molecular mechanism in CRC remain largely unclear. The aim of this study was to elucidate the role of ABL1 to obtain information on colon cancer gene mutation. We analyzed the tissue samples obtained from patients with CRC, CRC cell lines, and the immunodeficient mice. The proliferation, cell cycle, and apoptosis of CRC cells were examined. IPA software was used to analyze the molecules involved in CRC after ABL1 RNA interference. We found ABL1 was highly expressed in CRC tissues and cells. This high expression was associated with the TNM stage of CRC patients. In exon 8 of the ABL1 gene, we identified a novel mutation of C1222C deletion, which was related to the CRC stage. Depletion of ABL1 resulted in the inhibition of proliferation and escalation of apoptosis in two CRC cell lines, SW480, and HCT-116. Our in vivo study also demonstrated that depletion of ABL1 reduced CRC tumor progression. The results of the ingenuity pathway analysis indicated that the expression of 732 genes was upregulated and that of 691 genes was downregulated in mice transplanted with ABL1-downregulated CRC cells, among which we confirmed that depletion of ABL1 inhibited TGF-β1 via IRS1/PI3K/AKT pathway in CRC progression. These findings demonstrated that ABL1 plays an important role and that it can be a potential molecular target for CRC therapy.
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Affiliation(s)
- Yi Liu
- Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Jian Cao
- Department of Pharmacy, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Ya-Ning Zhu
- Department of Pharmacy, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Yu Ma
- Department of Pathology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Ghulam Murtaza
- Department of Pharmacy, COMSATS University Islamabad, Lahore Campus, Lahore, Pakistan
| | - Yu Li
- Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Jian-Hua Wang
- The Second Department of General Surgery, Shaanxi Provincial People's Hospital, Xi'an, China
| | - Yan-Song Pu
- The Second Department of General Surgery, Shaanxi Provincial People's Hospital, Xi'an, China
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15
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Foster JM, Patel A, Zhang C, Shostrom V, Brown K, Cushman-Vokoun AM. Investigating the utility of extended mutation analysis in gastrointestinal peritoneal metastasis. J Surg Oncol 2020; 122:1106-1113. [PMID: 32662065 DOI: 10.1002/jso.26114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 06/28/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES Outcomes for gastrointestinal peritoneal metastases (GI-PM) are worse compared to systemic metastases, with a paucity of data exploring extended mutation profiling. An exploratory mutation analysis in GI-PMs was performed as a "proof of concept" of potential predictive values of profiling in GI-PM and rates of actionable mutations. METHODS The study included 40 GI-PM patients: 14 low-grade mucinous carcinoma peritonei and 26 HG-PM (12 colons, 10 appendix, 4 small bowels). Demographics, histologies, peritoneal cancer indexes, cytoreduction scores, and survival data were collected. NGS 50-gene mutation profiling was performed on 38 specimens. The association of mutations with survival was evaluated in high-grade PM. RESULTS KRAS, TP53, and SMAD4 mutations were observed in 61%, 29%, and 8% of cases across all tumor histologies. In 66% cases >1 mutations occurred, associated with decreased survival in HG-PM: 32 vs 73 months, P = .03. TP53 or SMAD4 mutations were associated with decreased survival in HG-PM: 22 vs 48 months, P = .02. Actionable mutations were detected in 70%. CONCLUSION Actionable mutations were detected at high rates. GI-PMs have similar mutational profiles and TP53, SMAD4, and/or >1 mutation were associate with decreased survival in HG-PM. This data supports the concept of the extended mutation profiling utility in GI-PM warranting further investigation.
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Affiliation(s)
- Jason M Foster
- Department of Surgery, Division of Surgical Oncology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Asish Patel
- Department of Surgery, Division of Surgical Oncology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Chunmeng Zhang
- Department of Surgery, Division of Surgical Oncology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Valerie Shostrom
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska
| | - Krista Brown
- Department of Surgery, Division of Surgical Oncology, University of Nebraska Medical Center, Omaha, Nebraska
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16
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Kondelin J, Salokas K, Saarinen L, Ovaska K, Rauanheimo H, Plaketti RM, Hamberg J, Liu X, Yadav L, Gylfe AE, Cajuso T, Hänninen UA, Palin K, Ristolainen H, Katainen R, Kaasinen E, Tanskanen T, Aavikko M, Taipale M, Taipale J, Renkonen-Sinisalo L, Lepistö A, Koskensalo S, Böhm J, Mecklin JP, Ongen H, Dermitzakis ET, Kilpivaara O, Vahteristo P, Turunen M, Hautaniemi S, Tuupanen S, Karhu A, Välimäki N, Varjosalo M, Pitkänen E, Aaltonen LA. Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer. EMBO Mol Med 2019; 10:emmm.201708552. [PMID: 30108113 PMCID: PMC6402450 DOI: 10.15252/emmm.201708552] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite‐stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit‐targeted area from 24 exome‐sequenced sporadic MSI CRCs and respective normals, and 12 whole‐genome‐sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well‐established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular.
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Affiliation(s)
- Johanna Kondelin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Kari Salokas
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland.,Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Lilli Saarinen
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Kristian Ovaska
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Heli Rauanheimo
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Roosa-Maria Plaketti
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Jiri Hamberg
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Xiaonan Liu
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland.,Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Leena Yadav
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland.,Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Alexandra E Gylfe
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Tatiana Cajuso
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Ulrika A Hänninen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Kimmo Palin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Heikki Ristolainen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Riku Katainen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Eevi Kaasinen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Tomas Tanskanen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Mervi Aavikko
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Minna Taipale
- Division of Functional Genomics, Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institutet, Stockholm, Sweden
| | - Jussi Taipale
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.,Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.,Science for Life Center, Huddinge, Sweden
| | - Laura Renkonen-Sinisalo
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland
| | - Anna Lepistö
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland
| | - Selja Koskensalo
- The HUCH Gastrointestinal Clinic, Helsinki University Central Hospital, Helsinki, Finland
| | - Jan Böhm
- Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland
| | - Jukka-Pekka Mecklin
- Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland.,Department Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Halit Ongen
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.,Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Swiss Institute of Bioinformatics, Geneva, Switzerland
| | - Emmanouil T Dermitzakis
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.,Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland.,Swiss Institute of Bioinformatics, Geneva, Switzerland
| | - Outi Kilpivaara
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Pia Vahteristo
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Mikko Turunen
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Sampsa Hautaniemi
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Sari Tuupanen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Auli Karhu
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Niko Välimäki
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Markku Varjosalo
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland.,Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Esa Pitkänen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Lauri A Aaltonen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland .,Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
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17
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Álvarez-Garcia V, Tawil Y, Wise HM, Leslie NR. Mechanisms of PTEN loss in cancer: It's all about diversity. Semin Cancer Biol 2019; 59:66-79. [PMID: 30738865 DOI: 10.1016/j.semcancer.2019.02.001] [Citation(s) in RCA: 266] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/22/2019] [Accepted: 02/05/2019] [Indexed: 01/04/2023]
Abstract
PTEN is a phosphatase which metabolises PIP3, the lipid product of PI 3-Kinase, directly opposing the activation of the oncogenic PI3K/AKT/mTOR signalling network. Accordingly, loss of function of the PTEN tumour suppressor is one of the most common events observed in many types of cancer. Although the mechanisms by which PTEN function is disrupted are diverse, the most frequently observed events are deletion of a single gene copy of PTEN and gene silencing, usually observed in tumours with little or no PTEN protein detectable by immunohistochemistry. Accordingly, with the exceptions of glioblastoma and endometrial cancer, mutations of the PTEN coding sequence are uncommon (<10%) in most types of cancer. Here we review the data relating to PTEN loss in seven common tumour types and discuss mechanisms of PTEN regulation, some of which appear to contribute to reduced PTEN protein levels in cancers.
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Affiliation(s)
- Virginia Álvarez-Garcia
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK
| | - Yasmine Tawil
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK
| | - Helen M Wise
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK
| | - Nicholas R Leslie
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, Edinburgh, EH14 4AS, UK.
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18
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van Lanschot MCJ, Carvalho B, Rausch C, Snaebjornsson P, van Engeland M, Kuipers EJ, Stoker J, Tutein Nolthenius CJ, Dekker E, Meijer GA. Molecular profiling of longitudinally observed small colorectal polyps: A cohort study. EBioMedicine 2019; 39:292-300. [PMID: 30555044 PMCID: PMC6354708 DOI: 10.1016/j.ebiom.2018.12.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 12/06/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Knowledge of the natural history of colorectal adenomas is limited because these lesions are removed upon detection. The few studies in which small adenomas have been left in situ for a limited period of time, have shown that most lesions remain stable or even completely regress. Specific DNA copy number changes ('cancer associated events' or CAEs) are associated with progression of adenomas to cancer. In this study we evaluated whether molecular features of progression correlated with growth of small polyps. METHODS Small (6-9 mm) colorectal precursor lesions detected on CT-colonography (CTC) were left in situ and re-evaluated with CTC after three years. Based on volumetric change, polyps were classified as either grown, stable or regressed. Surveillance CTC was followed by colonoscopy, during which all lesions were resected. Using DNA isolated from FFPE polyp tissues, low-coverage whole genome sequencing was performed to determine DNA copy number profiles, as well as target enrichment mutation analysis and CpG island methylation phenotype (CIMP) analysis. Expression of DNA mismatch repair (MMR) proteins was determined by immunohistochemistry. Samples were marked as MMR proficient if all MMR proteins were expressed. FINDINGS Out of 68 polyps resected at colonoscopy, for 65 (96%) material was available. Of these, 31 (48%) had grown, 27 (41%) remained stable and 7 (11%) regressed. Polyps with at least one CAE had higher growth rates compared to polyps without CAEs (difference 91% growth (95% CI 13-169), p = .023). CAEs were absent in lesions that had partially regressed. Mutations occurred in 94% of the polyps, with higher growth rates being associated with polyps having ≥2 mutations compared to lesions with only 0-1 mutations (difference 99% growth (95% CI 9-189), p = .032). All samples were MMR proficient. No relation between growth and CIMP was observed. INTERPRETATION Molecular alterations associated with colorectal cancer, correlated with growth of small polyps and were absent in polyps that regressed. Therefore, this longitudinal study provides in vivo support in the human setting for the functional role of these molecular alterations, that have mostly been identified by cross sectional observations in tissue samples of colorectal adenomas and cancers. FUND: Alpe d'Huzes- Dutch Cancer Society (project number NKI2013-6338).
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Affiliation(s)
- M C J van Lanschot
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Centre Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - B Carvalho
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - C Rausch
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - P Snaebjornsson
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - M van Engeland
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - E J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, the Netherlands
| | - J Stoker
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - C J Tutein Nolthenius
- Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - E Dekker
- Cancer Centre Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - G A Meijer
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
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19
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Loree JM, Bailey AM, Johnson AM, Yu Y, Wu W, Bristow CA, Davis JS, Shaw KR, Broaddus R, Banks KC, Lanman RB, Meric-Bernstam F, Overman MJ, Kopetz S, Raghav K. Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer. J Natl Cancer Inst 2018; 110:1409-1417. [PMID: 29718453 PMCID: PMC6292791 DOI: 10.1093/jnci/djy067] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 02/10/2018] [Accepted: 03/16/2018] [Indexed: 01/14/2023] Open
Abstract
Background Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC. Methods We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided. Results ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival. Conclusions MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.
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Affiliation(s)
- Jonathan M Loree
- Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Ann M Bailey
- Sheikh Khalifa Bin Zayed Al Nahyan Institute of Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Amber M Johnson
- Sheikh Khalifa Bin Zayed Al Nahyan Institute of Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Yao Yu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Wenhui Wu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Christopher A Bristow
- Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jennifer S Davis
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kenna R Shaw
- Sheikh Khalifa Bin Zayed Al Nahyan Institute of Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Russell Broaddus
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | - Funda Meric-Bernstam
- Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael J Overman
- Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Scott Kopetz
- Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kanwal Raghav
- Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
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20
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Schweiger T, Liebmann-Reindl S, Glueck O, Starlinger P, Laengle J, Birner P, Klepetko W, Pils D, Streubel B, Hoetzenecker K. Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery. J Thorac Dis 2018; 10:6147-6157. [PMID: 30622786 DOI: 10.21037/jtd.2018.10.72] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Pulmonary metastasectomy is one of the cornerstones in the treatment of oligometastatic colorectal cancer (CRC). However, the selection of patients who benefit from a surgical resection is difficult. Mutational profiling has become an essential part of diagnosis and treatment of malignant disease. Despite this, comprehensive data on the mutational profile of CRC and its clinical impact in the context of pulmonary metastasectomy is sparse. We therefore aimed to provide a complete mutational status of CRC pulmonary metastases (PM) and corresponding primary tumors by targeted next-generation sequencing (tNGS), and correlate sequencing data with clinical outcome variables. Methods Case-matched, formalin-fixed paraffin embedded surgical specimens of lung metastases (n=47) and matched primary CRC (n=24) were sequenced using the TruSeq Amplicon Cancer Panel (Illumina platform). Penalized Cox regression models were applied to identify mutations with prognostic impact. Results Mutations were found most frequently in APC, TP53 and KRAS, in both PM and matched primary tumors. Concordance between primary tumors and PM was 83.5%. Adaptive elastic-net regularized Cox regression models identified mutations being prognostic for time to pulmonary recurrence (EGFR, GNAQ, KIT, MET, and PTPN11) and for overall survival (OS) (PDGFRA, SMARCB1, and TP53). Conclusions Our findings suggest that CRC PM harbor a variety of conserved and de novo mutations. We could identify a mutational profile predicting clinical outcome after pulmonary metastasectomy. Moreover, our data provide a rationale for future targeted therapies of patients with CRC lung metastases.
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Affiliation(s)
- Thomas Schweiger
- Division of Thoracic Surgery, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Sandra Liebmann-Reindl
- Core Facility Genomics, Comprehensive Cancer Center, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.,Department of Pathology, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Olaf Glueck
- Division of Thoracic Surgery, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Patrick Starlinger
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Johannes Laengle
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Peter Birner
- Department of Pathology, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Walter Klepetko
- Division of Thoracic Surgery, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Dietmar Pils
- Division of General Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.,Institute of Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Berthold Streubel
- Core Facility Genomics, Comprehensive Cancer Center, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.,Department of Pathology, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Konrad Hoetzenecker
- Division of Thoracic Surgery, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria
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21
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Mirza-Aghazadeh-Attari M, Darband SG, Kaviani M, Mihanfar A, Aghazadeh Attari J, Yousefi B, Majidinia M. DNA damage response and repair in colorectal cancer: Defects, regulation and therapeutic implications. DNA Repair (Amst) 2018; 69:34-52. [PMID: 30055507 DOI: 10.1016/j.dnarep.2018.07.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 07/15/2018] [Accepted: 07/15/2018] [Indexed: 12/11/2022]
Abstract
DNA damage response, a key factor involved in maintaining genome integrity and stability, consists of several kinase-dependent signaling pathways, which sense and transduce DNA damage signal. The severity of damage appears to determine DNA damage responses, which can include cell cycle arrest, damage repair and apoptosis. A number of recent studies have demonstrated that defection in signaling through this network is thought to be an underlying mechanism behind the development and progression of various types of human malignancies, including colorectal cancer. In this review, colorectal cancer and its molecular pathology as well as DNA damage response is briefly introduced. Finally, the involvement of key components of this network in the initiation/progression, prognosis, response to treatment and development of drug resistance is comprehensively discussed.
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Affiliation(s)
- Mohammad Mirza-Aghazadeh-Attari
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saber Ghazizadeh Darband
- Danesh Pey Hadi Co., Health Technology Development Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Mojtaba Kaviani
- School of Nutrition and Dietetics, Acadia University, Wolfville, Nova Scotia, Canada
| | - Ainaz Mihanfar
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran.
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22
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Ross JS, Fakih M, Ali SM, Elvin JA, Schrock AB, Suh J, Vergilio J, Ramkissoon S, Severson E, Daniel S, Fabrizio D, Frampton G, Sun J, Miller VA, Stephens PJ, Gay LM. Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3. Cancer 2018; 124:1358-1373. [PMID: 29338072 PMCID: PMC5900732 DOI: 10.1002/cncr.31125] [Citation(s) in RCA: 152] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/28/2017] [Accepted: 10/06/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND In contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2-targeted therapies. METHODS In this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer-related genes, tumor mutational burden, and microsatellite instability. This cohort included both colonic (7599 cases; 85.5%) and rectal (1288 cases; 14.5%) adenocarcinomas. RESULTS A total of 569 mCRCs were positive for ERBB2 (429 cases; 4.8%) and/or ERBB3 (148 cases; 1.7%) and featured ERBB amplification, short variant alterations, or a combination of the 2. High tumor mutational burden (≥20 mutations/Mb) was significantly more common in ERBB-mutated samples, and ERBB3-mutated CRCs were significantly more likely to have high microsatellite instability (P<.002). Alterations affecting KRAS (27.3%) were significantly underrepresented in ERBB2-amplified samples compared with wild-type CRC samples (51.8%), and ERBB2- or ERBB3-mutated samples (49.0% and 60.8%, respectively) (P<.01). Other significant differences in mutation frequency were observed for genes in the PI3K/MTOR and mismatch repair pathways. CONCLUSIONS Although observed less often than in breast or upper gastrointestinal carcinomas, indications for which anti-HER2 therapies are approved, the percentage of CRC with ERBB genomic alterations is significant. Importantly, 32% of ERBB2-positive CRCs harbor short variant alterations that are undetectable by routine immunohistochemistry or fluorescence in situ hybridization testing. The success of anti-HER2 therapies in ongoing clinical trials is a promising development for patients with CRC. Cancer 2018;124:1358-73. © 2018 Foundation Medicine, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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Affiliation(s)
- Jeffrey S. Ross
- Foundation Medicine IncCambridgeMassachusetts
- Department of PathologyAlbany Medical CenterAlbanyNew York
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research City of HopeDuarteCalifornia
| | | | | | | | - James Suh
- Foundation Medicine IncCambridgeMassachusetts
| | | | | | | | | | | | | | - James Sun
- Foundation Medicine IncCambridgeMassachusetts
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23
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Ishikawa T. Next-generation sequencing traces human induced pluripotent stem cell lines clonally generated from heterogeneous cancer tissue. World J Stem Cells 2017; 9:77-88. [PMID: 28596815 PMCID: PMC5440771 DOI: 10.4252/wjsc.v9.i5.77] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 04/03/2017] [Accepted: 05/05/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate genotype variation among induced pluripotent stem cell (iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing.
METHODS Human iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer (OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using next-generation sequencing and bioinformatics analysis using the human reference genome hg19. Non-synonymous single-nucleotide variants (SNVs) (missense, nonsense, and read-through) were identified within the target region of 612 genes related to cancer and the human kinome. All SNVs were annotated using dbSNP135, CCDS, RefSeq, GENCODE, and 1000 Genomes. The SNVs of the iPSC lines were compared with the genotypes of the cancerous and non-cancerous tissues. The putative genotypes were validated using allelic depth and genotype quality. For final confirmation, mutated genotypes were manually curated using the Integrative Genomics Viewer.
RESULTS In eight of the ten iPSC lines, one or two non-synonymous SNVs in EIF2AK2, TTN, ULK4, TSSK1B, FLT4, STK19, STK31, TRRAP, WNK1, PLK1 or PIK3R5 were identified as novel SNVs and were not identical to the genotypes found in the cancer and non-cancerous tissues. This result suggests that the SNVs were de novo or pre-existing mutations that originated from minor populations, such as multifocal pre-cancer (stem) cells or pre-metastatic cancer cells from multiple, different clonal evolutions, present within the heterogeneous cancer tissue. The genotypes of all ten iPSC lines were different from the mutated ERBB2 and MKNK2 genotypes of the cancer tissues and were identical to those of the non-cancerous tissues and that found in the human reference genome hg19. Furthermore, two of the ten iPSC lines did not have any confirmed mutated genotypes, despite being derived from cancerous tissue. These results suggest that the traceability and preference of the starting single cells being derived from pre-cancer (stem) cells, stroma cells such as cancer-associated fibroblasts, and immune cells that co-existed in the tissues along with the mature cancer cells.
CONCLUSION The genotypes of iPSC lines derived from heterogeneous cancer tissues can provide information on the type of starting cell that the iPSC line was generated from.
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24
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Sarshekeh AM, Advani S, Overman MJ, Manyam G, Kee BK, Fogelman DR, Dasari A, Raghav K, Vilar E, Manuel S, Shureiqi I, Wolff RA, Patel KP, Luthra R, Shaw K, Eng C, Maru DM, Routbort MJ, Meric-Bernstam F, Kopetz S. Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer. PLoS One 2017; 12:e0173345. [PMID: 28267766 PMCID: PMC5340382 DOI: 10.1371/journal.pone.0173345] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 02/20/2017] [Indexed: 12/15/2022] Open
Abstract
SMAD4 is an essential mediator in the transforming growth factor-β pathway. Sporadic mutations of SMAD4 are present in 2.1-20.0% of colorectal cancers (CRCs) but data are limited. In this study, we aimed to evaluate clinicopathologic characteristics, prognosis, and clinical outcome associated with this mutation in CRC cases. Data for patients with metastatic or unresectable CRC who underwent genotyping for SMAD4 mutation and received treatment at The University of Texas MD Anderson Cancer Center from 2000 to 2014 were reviewed. Their tumors were sequenced using a hotspot panel predicted to cover 80% of the reported SMAD4 mutations, and further targeted resequencing that included full-length SMAD4 was performed on mutated tumors using a HiSeq sequencing system. Using The Cancer Genome Atlas data on CRC, the characteristics of SMAD4 and transforming growth factor-β pathway mutations were evaluated according to different consensus molecular subtypes of CRC. Among 734 patients with CRC, 90 (12%) had SMAD4 mutations according to hotspot testing. SMAD4 mutation was associated with colon cancer more so than with rectal cancer (odds ratio 2.85; p<0.001), female sex (odds ratio 1.71; p = 0.02), and shorter overall survival than in wild-type SMAD4 cases (median, 29 months versus 56 months; hazard ratio 2.08; p<0.001 [log-rank test]). SMAD4 mutation was not associated with age, stage at presentation, colonic location, distant metastasis, or tumor grade. A subset of patients with metastatic CRC (n = 44) wild-type for KRAS, NRAS, and BRAF who received anti-epidermal growth factor receptor therapy with mutated SMAD4 (n = 13) had shorter progression-free survival duration than did patients wild-type for SMAD4 (n = 31) (median, 111 days versus 180 days; p = 0.003 [log-rank test]). Full-length sequencing confirmed that missense mutations at R361 and P356 in the MH2 domain were the most common SMAD4 alterations. In The Cancer Genome Atlas data, SMAD4 mutation frequently occurred with KRAS, NRAS, and BRAF mutations and was more common in patients with the consensus molecular subtype 3 of CRC than in those with the other 3 subtypes. This is one of the largest retrospective studies to date characterizing SMAD4 mutations in CRC patients and demonstrates the prognostic role and lack of response of CRC to anti-epidermal growth factor receptor therapy. Further studies are required to validate these findings and the role of SMAD4 mutation in CRC.
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Affiliation(s)
- Amir Mehrvarz Sarshekeh
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Shailesh Advani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Michael J. Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Ganiraju Manyam
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Bryan K. Kee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - David R. Fogelman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Eduardo Vilar
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Shanequa Manuel
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Imad Shureiqi
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Robert A. Wolff
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Keyur P. Patel
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Raja Luthra
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Kenna Shaw
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Cathy Eng
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Dipen M. Maru
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Mark J. Routbort
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Funda Meric-Bernstam
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
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