|
1
|
Klekowski J, Chabowski M, Krzystek-Korpacka M, Fleszar M. The Utility of Lipidomic Analysis in Colorectal Cancer Diagnosis and Prognosis-A Systematic Review of Recent Literature. Int J Mol Sci 2024; 25:7722. [PMID: 39062964 PMCID: PMC11277303 DOI: 10.3390/ijms25147722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/07/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Colorectal cancer (CRC) is among the most prevalent and lethal malignancies. Lipidomic investigations have revealed numerous disruptions in lipid profiles across various cancers. Studies on CRC exhibit potential for identifying novel diagnostic or prognostic indicators through lipidomic signatures. This review examines recent literature regarding lipidomic markers for CRC. PubMed database was searched for eligible articles concerning lipidomic biomarkers of CRC. After selection, 36 articles were included in the review. Several studies endeavor to establish sets of lipid biomarkers that demonstrate promising potential to diagnose CRC based on blood samples. Phosphatidylcholine, phosphatidylethanolamine, ceramides, and triacylglycerols (TAGs) appear to offer the highest diagnostic accuracy. In tissues, lysophospholipids, ceramides, and TAGs were among the most altered lipids, while unsaturated fatty acids also emerged as potential biomarkers. In-depth analysis requires both cell culture and animal studies. CRC involves multiple lipid metabolism alterations. Although numerous lipid species have been suggested as potential diagnostic markers, the establishment of standardized methods and the conduct of large-scale studies are necessary to facilitate their clinical application.
Collapse
Affiliation(s)
- Jakub Klekowski
- Department of Nursing and Obstetrics, Division of Anesthesiological and Surgical Nursing, Faculty of Health Science, Wroclaw Medical University, 50-367 Wroclaw, Poland;
- Department of Surgery, 4th Military Clinical Hospital, 50-981 Wroclaw, Poland
| | - Mariusz Chabowski
- Department of Surgery, 4th Military Clinical Hospital, 50-981 Wroclaw, Poland
- Department of Clinical Surgical Sciences, Faculty of Medicine, Wroclaw University of Science and Technology, 50-556 Wroclaw, Poland
| | - Małgorzata Krzystek-Korpacka
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (M.K.-K.); (M.F.)
| | - Mariusz Fleszar
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (M.K.-K.); (M.F.)
- Omics Research Center, Wroclaw Medical University, 50-368 Wroclaw, Poland
| |
Collapse
|
|
2
|
Imai T, Naruse M, Ochiai M, Matsumoto K, Ikeda S, Kani M, Kato Y, Hirayama A, Soga T, Hori Y, Yokoi A, Ochiai A. Different types of reactions to E7386 among colorectal cancer patient‑derived organoids and corresponding CAFs. Oncol Lett 2022; 24:221. [PMID: 35707761 PMCID: PMC9178669 DOI: 10.3892/ol.2022.13342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/27/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Toshio Imai
- Central Animal Division, National Cancer Center Research Institute, Tokyo 104‑0045, Japan
| | - Mie Naruse
- Central Animal Division, National Cancer Center Research Institute, Tokyo 104‑0045, Japan
| | - Masako Ochiai
- Central Animal Division, National Cancer Center Research Institute, Tokyo 104‑0045, Japan
| | - Kenji Matsumoto
- Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo 157‑8535, Japan
| | - Satsuki Ikeda
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997‑0035, Japan
| | - Manami Kani
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997‑0035, Japan
| | - Yuyu Kato
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997‑0035, Japan
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997‑0035, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997‑0035, Japan
| | - Yusaku Hori
- Oncology Business Group, Eisai Co., Ltd., Tokyo 112‑8088, Japan
| | - Akira Yokoi
- Oncology Business Group, Eisai Co., Ltd., Tokyo 112‑8088, Japan
| | - Atsushi Ochiai
- Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo 104‑0045, Japan
| |
Collapse
|
|
3
|
Youssef ASED, Abdel-Fattah MA, Lotfy MM, Nassar A, Abouelhoda M, Touny AO, Hassan ZK, Mohey Eldin M, Bahnassy AA, Khaled H, Zekri ARN. Multigene Panel Sequencing Reveals Cancer-Specific and Common Somatic Mutations in Colorectal Cancer Patients: An Egyptian Experience. Curr Issues Mol Biol 2022; 44:1332-1352. [PMID: 35723313 PMCID: PMC8947625 DOI: 10.3390/cimb44030090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 02/22/2022] [Accepted: 02/25/2022] [Indexed: 12/11/2022] Open
Abstract
This study aims at identifying common pathogenic somatic mutations at different stages of colorectal carcinogenesis in Egyptian patients. Our cohort included colonoscopic biopsies collected from 120 patients: 20 biopsies from patients with inflammatory bowel disease, 38 from colonic polyp patients, and 62 from patients with colorectal cancer. On top of this, the cohort included 20 biopsies from patients with non-specific mild to moderated colitis. Targeted DNA sequencing using a customized gene panel of 96 colorectal related genes running on the Ion Torrent NGS technology was used to process the samples. Our results revealed that 69% of all cases harbored at least one somatic mutation. Fifty-seven genes were found to carry 232 somatic non-synonymous variants. The most frequently pathogenic somatic mutations were localized in TP53, APC, KRAS, and PIK3CA. In total, 16 somatic mutations were detected in the CRC group and in either the IBD or CP group. In addition, our data showed that 51% of total somatic variants were CRC-specific variants. The average number of CRC-specific variants per sample is 2.4. The top genes carrying CRC-specific mutations are APC, TP53, PIK3CA, FBXW7, ATM, and SMAD4. It seems obvious that TP53 and APC genes were the most affected genes with somatic mutations in all groups. Of interest, 85% and 28% of the APC and TP53 deleterious somatic mutations were located in Exon 14 and Exon 3, respectively. Besides, 37% and 28% of the total somatic mutations identified in APC and TP53 were CRC-specific variants, respectively. Moreover, we identified that, in 29 somatic mutations in 21 genes, their association with CRC patients was unprecedented. Ten detected variants were likely to be novel: six in PIK3CA and four variants in FBXW7. The detected P53, Wnt/βcatenin, Angiogenesis, EGFR, TGF-β and Interleukin signaling pathways were the most altered pathways in 22%, 16%, 12%, 10%, 9% and 9% of the CRC patients, respectively. These results would contribute to a better understanding of the colorectal cancer and in introducing personalized therapies for Egyptian CRC patients.
Collapse
Affiliation(s)
- Amira Salah El-Din Youssef
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | | | - Mai M. Lotfy
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | - Auhood Nassar
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | | | - Ahmed O. Touny
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Zeinab K. Hassan
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| | - Mohammed Mohey Eldin
- Tropical Medicine Department, El Kasr Al-Aini, Cairo University, Cairo 11562, Egypt;
| | - Abeer A. Bahnassy
- Molecular Pathology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Hussein Khaled
- Medical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Abdel Rahman N. Zekri
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt; (M.M.L.); (A.N.); (Z.K.H.)
| |
Collapse
|
|
4
|
Hussen BM, Abdullah ST, Salihi A, Sabir DK, Sidiq KR, Rasul MF, Hidayat HJ, Ghafouri-Fard S, Taheri M, Jamali E. The emerging roles of NGS in clinical oncology and personalized medicine. Pathol Res Pract 2022; 230:153760. [PMID: 35033746 DOI: 10.1016/j.prp.2022.153760] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/29/2021] [Accepted: 01/06/2022] [Indexed: 02/07/2023]
Abstract
Next-generation sequencing (NGS) has been increasingly popular in genomics studies over the last decade, as new sequencing technology has been created and improved. Recently, NGS started to be used in clinical oncology to improve cancer therapy through diverse modalities ranging from finding novel and rare cancer mutations, discovering cancer mutation carriers to reaching specific therapeutic approaches known as personalized medicine (PM). PM has the potential to minimize medical expenses by shifting the current traditional medical approach of treating cancer and other diseases to an individualized preventive and predictive approach. Currently, NGS can speed up in the early diagnosis of diseases and discover pharmacogenetic markers that help in personalizing therapies. Despite the tremendous growth in our understanding of genetics, NGS holds the added advantage of providing more comprehensive picture of cancer landscape and uncovering cancer development pathways. In this review, we provided a complete overview of potential NGS applications in scientific and clinical oncology, with a particular emphasis on pharmacogenomics in the direction of precision medicine treatment options.
Collapse
Affiliation(s)
- Bashdar Mahmud Hussen
- Department Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq; Center of Research and Strategic Studies, Lebanese French University, Kurdistan Region, Erbil, Iraq
| | - Sara Tharwat Abdullah
- Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Abbas Salihi
- Center of Research and Strategic Studies, Lebanese French University, Kurdistan Region, Erbil, Iraq; Department of Biology, College of Science, Salahaddin University, Kurdistan Region, Erbil, Iraq
| | - Dana Khdr Sabir
- Department of Medical Laboratory Sciences, Charmo University, Kurdistan Region, Iraq
| | - Karzan R Sidiq
- Department of Biology, College of Education, University of Sulaimani, Sulaimani 334, Kurdistan, Iraq
| | - Mohammed Fatih Rasul
- Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Kurdistan Region, Erbil, Iraq
| | - Hazha Jamal Hidayat
- Department of Biology, College of Education, Salahaddin University, Kurdistan Region, Erbil, Iraq
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany; Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Elena Jamali
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
5
|
Hancock KJ, Hsu W, Klimberg VS. The Clinical Versatility of Next-Generation Sequencing in Colorectal Cancer. AMERICAN JOURNAL OF BIOMEDICAL SCIENCE & RESEARCH 2020; 7:548-550. [PMID: 32924015 DOI: 10.34297/ajbsr.2020.07.001220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Next-Generation Sequencing is an evolving technology employed in the field of cancer biology. This mini review is intended as a brief overview of NGS for the clinical utility in colorectal cancer. The pathogenesis and treatment of colorectal cancer will continue to evolve as NGS is applied to more patient samples, correlating tumor biology and outcomes.
Collapse
Affiliation(s)
- Kevin J Hancock
- Department of Surgery, University of Texas Medical Branch, USA
| | - Willie Hsu
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, USA
| | - V Suzanne Klimberg
- Department of Surgery, University of Texas Medical Branch, USA.,Adjunct Professor, MD Anderson Cancer Center, USA
| |
Collapse
|
|
6
|
Lv Z, Wu K, Qin X, Yuan J, Yan M, Zhang J, Wang L, Ji T, Cao W, Chen W. A Novel Tumor Suppressor SPINK5 Serves as an Independent Prognostic Predictor for Patients with Head and Neck Squamous Cell Carcinoma. Cancer Manag Res 2020; 12:4855-4869. [PMID: 32606974 PMCID: PMC7320891 DOI: 10.2147/cmar.s236266] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 04/25/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND In our previous study, serine protease inhibitor Kazal-type 5 (SPINK5), which encodes the product of serine protease inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI) was found to be down-regulated in head and neck squamous cell carcinoma (HNSCC) using oligonucleotide microarrays. However, the function and clinical implications of SPINK5/LEKTI remain obscure in HNSCC. METHODS The endogenous expression level of SPINK5/LEKTI was further verified in 9 HNSCC cell lines and HNSCCs by means of reverse transcription-polymerase chain reaction, real-time PCR, Western blotting and immunohistochemistry. The biological function of SPINK5/LEKTI was investigated in vitro and in vivo experiments. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to determine the correlation between SPINK5/LEKTI expression and clinical outcome. RESULTS Down-regulation expression of SPINK5/LEKTI was found in six out of nine HNSCC cell lines and in 85.7% HNSCC specimens (P<0.0001). Upon silencing of SPINK5/LEKTI, the cell proliferation, plate colony formation and cell invasion of WU-HN6 cells were significantly increased, while exogenous overexpression of SPINK5/LEKTI, the proliferation, plate colony and invasion of WU-HN13 and HN30 cells were remarkably inhibited with the arrest of G1 cell cycle (P=0.0001, P=0.003, respectively). HNSCC patients with lower LEKTI levels had significantly inferior overall survival compared to those patients with higher LEKTI (P=0.0017) by Kaplan-Meier survival analysis. Univariate and multivariate Cox proportional hazards regression model analysis revealed that LEKTI expression was an independent prognostic predictor for HNSCC patients (HR=0.114, 95% CI:0.044-0.292, P<0.001). CONCLUSION Our results demonstrate that SPINK5/LEKTI might be a tumor suppressor in HNSCCs and serve as an independent prognostic predictor for HNSCC patients.
Collapse
Affiliation(s)
- Zhongjing Lv
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- Department of Stomatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, People’s Republic of China
| | - Kun Wu
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, People’s Republic of China
| | - Xing Qin
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, People’s Republic of China
| | - Jian Yuan
- Department of Stomatology, Affiliated Hospital of Xuzhou Medical University, Xuzhou City, Jiangsu Province, People’s Republic of China
| | - Ming Yan
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, People’s Republic of China
| | - Jianjun Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, People’s Republic of China
| | - Lizhen Wang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- Department of Oral Pathology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Tong Ji
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, People’s Republic of China
| | - Wei Cao
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, People’s Republic of China
| | - Wantao Chen
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
- Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, Shanghai, People’s Republic of China
| |
Collapse
|
|
7
|
In-Depth Characterization of Mass Spectrometry-Based Proteomic Profiles Revealed Novel Signature Proteins Associated with Liver Metastatic Colorectal Cancers. Anal Cell Pathol (Amst) 2019; 2019:7653230. [PMID: 31781478 PMCID: PMC6875276 DOI: 10.1155/2019/7653230] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/18/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023] Open
Abstract
Liver metastasis is the most common form of metastatic colorectal cancers during the course of the disease. The global change in protein abundance in liver metastatic colorectal cancers and its role in metastasis establishment have not been comprehensively analyzed. In the present study, fresh-frozen tissue samples including normal colon/localized/liver metastatic CRCs from each recruited patient were analyzed by quantitative proteomics using a multiplexed TMT labeling strategy. Around 5000 protein groups were quantified from all samples. The proteomic profile of localized/metastatic CRCs varied greatly from that of normal colon tissues; differential proteins were mainly from extracellular regions and participate in immune activities, which is crucial for the chronic inflammation signaling pathways in the tumor microenvironment. Further statistical analysis revealed 47 proteins exhibiting statistical significance between localized and metastatic CRCs, of which FILI1P1 and PLG were identified for the first time in proteomic data, which were highly associated with liver metastasis in CRCs.
Collapse
|
|
8
|
Liang Y, Jiang L, Zhong X, Hochwald SN, Wang Y, Huang L, Nie Q, Huang H, Xu JF. Discovery of Aberrant Alteration of Genome in Colorectal Cancer by Exome Sequencing. Am J Med Sci 2019; 358:340-349. [PMID: 31445671 DOI: 10.1016/j.amjms.2019.07.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 07/27/2019] [Accepted: 07/31/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND This study analyzed multiple parameters including somatic single nucleotide variations (SNVs), Insertion/Deletions, significantly mutated genes (SMGs), copy number variations and frequently altered pathways aims to discover novel aberrances in the tumorigenesis of colorectal cancer (CRC). MATERIALS AND METHODS Exome sequencing was performed on an Illumina platform to identify novel potential somatic variances in 34 paired tumor and adjacent normal tissues from 17 CRC patients. Results were compared with databases (dbSNP138, 1000 genomes SNP, Hapmap, Catalogue of Somatic Mutation of Cancer and ESP6500) and analyzed. MuSic software was used to identify SMGs. RESULTS In total, 1,637 somatic SNVs in 17 analyzed tumors were identified. Only 7 SNVs were shared by more than 1 tumor, suggesting that over 99% of the analyzed SNVs were independent events. Mutation of KRAS p. G12D and ZNF717 p. L39V were the most common SNVs. Moreover, 10 SMGs namely KRAS, TP53, SMAD4, ZNF717, FBXW7, APC, ZNF493, CDR1, the Armadillo repeat containing 4 (ARMC4) and sulfate-modifying factor 2 (SUMF2) were found. Among those, ZNF717, ZNF493, CDR1, ARMC4 and SUMF2 were novel frequent genes in CRC. For copy number variations analysis, gains in 10q25.3, 1p31.1, 1q44, 10q23.33, 11p15.4 and 20q13.33, and loss of 3q21.3 and 3q29 were frequent aberrations identified in our results. CONCLUSIONS We frequently found novel genes ZNF717, ZNF493, CDR1, ARMC4 and SUMF2 and gains in 10q25.3, which may be functional mutation in CRC. The high-frequency private events such as SNVs confirm the highly heterogeneous mutations found in CRCs. The mutated genes sites in different patients may vary significantly, which may also be more challenging for clinical treatment.
Collapse
Affiliation(s)
- Yuanzi Liang
- Department of Clinical Immunology, Institute of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong, China
| | | | - Xiaogang Zhong
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Steven N Hochwald
- Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York
| | - Yongsi Wang
- Division of Genome Sequencing, Huayin Medical Laboratory, Guangzhou, Guangdong, China
| | - Lihe Huang
- Department of Laboratory Medicine, Debao County Hospital, Baise, Guangxi, China
| | - Qiumiao Nie
- Wilking Biotechnology Co., Ltd, Nanning, Guangxi, China
| | - Huayi Huang
- Department of Laboratory Medicine and; Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York.
| | - Jun-Fa Xu
- Department of Clinical Immunology, Institute of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, Guangdong, China.
| |
Collapse
|
|
9
|
Oliveira DM, Laudanna C, Migliozzi S, Zoppoli P, Santamaria G, Grillone K, Elia L, Mignogna C, Biamonte F, Sacco R, Corcione F, Viglietto G, Malanga D, Rizzuto A. Identification of different mutational profiles in cancers arising in specific colon segments by next generation sequencing. Oncotarget 2018; 9:23960-23974. [PMID: 29844865 PMCID: PMC5963617 DOI: 10.18632/oncotarget.25251] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 04/06/2018] [Indexed: 02/07/2023] Open
Abstract
The objective of this study was to investigate the mutational profiles of cancers arising in different colon segments. To this aim, we have analyzed 37 colon cancer samples by use of the Ion AmpliSeq™ Comprehensive Cancer Panel. Overall, we have found 307 mutated genes, most of which already implicated in the development of colon cancer. Among these, 15 genes were mutated in tumors originating in all six colon segments and were defined "common genes" (i.e. APC, PIK3CA, TP53) whereas 13 genes were preferentially mutated in tumors originating only in specific colon segments and were defined "site-associated genes" (i.e. BLNK, PTPRD). In addition, the presence of mutations in 10 of the 307 identified mutated genes (NBN, SMUG1, ERBB2, PTPRT, EPHB1, ALK, PTPRD, AURKB, KDR and GPR124) were found to be of clinical relevance. Among clinically relevant genes, NBN and SMUG1 were identified as independent prognostic factors that predicted poor survival in colon cancer patients. In conclusion, the findings reported here indicate that tumors arising in different colon segments present differences in the type and/or frequency of genetic variants, with two of them being independent prognostic factors that predict poor survival in colon cancer patients.
Collapse
Affiliation(s)
- Duarte Mendes Oliveira
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Carmelo Laudanna
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Simona Migliozzi
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Pietro Zoppoli
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Gianluca Santamaria
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Katia Grillone
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Laura Elia
- Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
| | - Chiara Mignogna
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Flavia Biamonte
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Rosario Sacco
- Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
| | | | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Donatella Malanga
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Antonia Rizzuto
- Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy
| |
Collapse
|
|
10
|
Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K, Miyoshi N, Takahashi H, Nishida N, Haraguchi N, Sakai D, Kudo T, Hata T, Matsuda C, Mizushima T, Satoh T, Doki Y, Mori M, Ishii H. Oncogene c-Myc promotes epitranscriptome m 6A reader YTHDF1 expression in colorectal cancer. Oncotarget 2018; 9:7476-7486. [PMID: 29484125 PMCID: PMC5800917 DOI: 10.18632/oncotarget.23554] [Citation(s) in RCA: 181] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 10/28/2017] [Indexed: 12/20/2022] Open
Abstract
Recent studies that have emerged on the diversity of RNA modification in tumors suggest their eligibility as bona fide targets in diagnosis and drug discovery. N6-methyladenosine (m6A) was first reported and is most common in epitranscriptome modification of various RNAs. The YT521-B homology (YTH) domain family are representative m6A-binding proteins, but how the YTH domain family is involved in cancer remains to be clearly understood. Given that clinical sequence data in colorectal cancer indicate that overexpression of YTHDF1 is outstanding among other family members, we studied the role of Ythdf1 and the transcriptional control of YTHDF1. Immunostaining of Ythdf1 showed that its expression was associated with various malignant tumor behaviors, such as depth, lymph node metastasis, and poorer cancer stages. The study of patient survival indicated that patients with high Ythdf1 expression had significantly poorer overall survival. The results indicated that Ythdf1 expression is an independent prognostic factor of patients. The in vitro study showed that the knockdown of YTHDF1 resulted in the suppression of cancer proliferation and sensitization to the exposure of anticancer drugs such as fluorouracil and oxaliplatin. Importantly, the study upstream of the YTHDF1 gene indicated that an oncogenic transcription factor c-Myc was associated with YTHDF1 in both expression and chromatin immunoprecipitation data. Moreover, the knockdown experiments of c-Myc showed the inhibition of YTHDF1, supporting a notion of c-Myc-driven YTHDF1 axis significance. These data suggest that m6A reader Ythdf1 plays a significant role in colorectal cancer progression.
Collapse
Affiliation(s)
- Yujiro Nishizawa
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Ayumu Asai
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Jun Koseki
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Naohiro Nishida
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Naotsugu Haraguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Daisuke Sakai
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Toshihiro Kudo
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Taishi Hata
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Chu Matsuda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Therapeutics for Inflammatory Bowel Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| |
Collapse
|
|
11
|
Miyamoto Y, Zhang W, Lenz HJ. Molecular Landscape and Treatment Options for Patients with Metastatic Colorectal Cancer. Indian J Surg Oncol 2017; 8:580-590. [PMID: 29203992 PMCID: PMC5705494 DOI: 10.1007/s13193-016-0543-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 07/14/2016] [Indexed: 12/13/2022] Open
Abstract
Over the last 20 years, median survival for patients with metastatic colorectal cancer (CRC) has remarkably improved from about 12 to over 30 months, mainly because of the development of new agents and patient selection using predictive biomarkers. However, the identification of the most effective treatment for an individual patient is still a challenge. Molecular profiling of CRC has made great progress, but it is limited by tumor heterogeneity and absence of driver mutation. However, RAS, BRAF, and microsatellite instability are validated biomarker recommended by NCCN and ESMO. In this review, we discuss recent advances and future developments.
Collapse
Affiliation(s)
- Yuji Miyamoto
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Shanon A. Carpenter Laboratory, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033 USA
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Shanon A. Carpenter Laboratory, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033 USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Shanon A. Carpenter Laboratory, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033 USA
| |
Collapse
|
|
12
|
Xiao Y, Yurievich UA, Yosypovych SV. Long noncoding RNA XIST is a prognostic factor in colorectal cancer and inhibits 5-fluorouracil-induced cell cytotoxicity through promoting thymidylate synthase expression. Oncotarget 2017; 8:83171-83182. [PMID: 29137332 PMCID: PMC5669958 DOI: 10.18632/oncotarget.20487] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 07/25/2017] [Indexed: 01/17/2023] Open
Abstract
A major reason for the failure of advanced colorectal cancer (CRC) treatment is the occurrence of chemoresistance to 5-fluorouracil (5FU)-based treatment. Recent studies have shown that long non-coding RNAs (lncRNAs) are critical regulators in chemoresistance. By using the next generation HiSeq sequencing assay, we identified lncRNAs showing differential expression levels in 5FU resistant and non-resistant CRC patients. RT-qPCR was then performed for validation in tissues and serum samples, and lncRNA XIST was verified to be up-regulated in non-responding patients and have considerable diagnostic potential to identify responding patients from non-responding patients. In addition, increased serum XIST level was associated with poor response and lower survival rate in CRC patients receiving 5FU-based treatment. Subsequently, the 5FU resistant (5FU-R) cell lines were established, and lncRNA XIST was significantly up-regulated HT29 5FU-R and HCT116 5FU-R cells. Furthermore, knockdown of XIST reversed 5FU resistance while enhanced XIST could restrained the 5FU-induced cell cytotoxcity in both CRC cell lines. Western blotting and immunofluorescence analysis indicated that XIST promoted the expression of thymidylate synthase, a critical 5FU-targetd enzyme. In conclusion, our integrated approach demonstrates that increased expression of lncRNA XIST3 in CRC confers a potent poor therapeutic efficacy, and that lncRNA XIST participated in 5FU resistance through promoting the expression of thymidylate synthase. Thus, specific silence oflncRNA XIST could be a future direction to develop a novel therapeutic strategy to overcome 5FU resistance of CRC patients.
Collapse
Affiliation(s)
- Yang Xiao
- Department of Surgery and Transplantology, P. L. Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine
| | - Usenko Alexander Yurievich
- Department of Surgery and Transplantology, P. L. Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine
| | | |
Collapse
|
|
13
|
Das V, Kalita J, Pal M. Predictive and prognostic biomarkers in colorectal cancer: A systematic review of recent advances and challenges. Biomed Pharmacother 2016; 87:8-19. [PMID: 28040600 DOI: 10.1016/j.biopha.2016.12.064] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 12/15/2016] [Accepted: 12/15/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading cause of cancer deaths worldwide. Since CRC is largely asymptomatic until alarm features develop to advanced stages, the implementation of the screening programme is very much essential to reduce cancer incidence and mortality rates. CRC occurs predominantly from accumulation of genetic and epigenetic changes in colon epithelial cells, which later gets transformed into adenocarcinomas. SCOPE OF REVIEW The current challenges of screening paradigm and diagnostic ranges are from semi-invasive methods like colonoscopy to non-invasive stool-based test, have resulted in over-diagnosis and over-treatment of CRC. Hence, new screening initiatives and deep studies are required for early diagnosis of CRC. In this regard, we not only summarise current predictive and prognostic biomarkers with their potential for diagnostic and therapeutic applications, but also describe current limitations, future perspectives and challenges associated with the progression of CRC. MAJOR CONCLUSIONS Currently many potential biomarkers have already been successfully translated into clinical practice eg. Fecal haemoglobin, Carcinoembryonic antigen (CEA) and CA19.9, although these are not highly promising diagnostic target for personalized medicine. So there is a critical need for reliable, minimally invasive, highly sensitive and specific genetic markers of an individualised and optimised patient treatment at the earliest disease stage possible. GENERAL SIGNIFICANCE Identification of a new biomarker, or a set of biomarkers to the development of a valid, and clinical sensible assay that can be served as an alternative tool for early diagnosis of CRC and open up promising new targets in therapeutic intervention strategies.
Collapse
Affiliation(s)
- Vishal Das
- Biotechnology Division, CSIR-North East Institute of Science and Technology, Jorhat, Assam 785006, India
| | - Jatin Kalita
- Biotechnology Division, CSIR-North East Institute of Science and Technology, Jorhat, Assam 785006, India
| | - Mintu Pal
- Biotechnology Division, CSIR-North East Institute of Science and Technology, Jorhat, Assam 785006, India.
| |
Collapse
|
|
14
|
Papadopoulou E, Metaxa-Mariatou V, Tsaousis G, Tsoulos N, Tsirigoti A, Efstathiadou C, Apessos A, Agiannitopoulos K, Pepe G, Bourkoula E, Nasioulas G. Molecular predictive markers in tumors of the gastrointestinal tract. World J Gastrointest Oncol 2016; 8:772-785. [PMID: 27895815 PMCID: PMC5108979 DOI: 10.4251/wjgo.v8.i11.772] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 07/11/2016] [Accepted: 08/31/2016] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal malignancies are among the leading causes of cancer-related deaths worldwide. Like all human malignancies they are characterized by accumulation of mutations which lead to inactivation of tumor suppressor genes or activation of oncogenes. Advances in Molecular Biology techniques have allowed for more accurate analysis of tumors’ genetic profiling using new breakthrough technologies such as next generation sequencing (NGS), leading to the development of targeted therapeutical approaches based upon biomarker-selection. During the last 10 years tremendous advances in the development of targeted therapies for patients with advanced cancer have been made, thus various targeted agents, associated with predictive biomarkers, have been developed or are in development for the treatment of patients with gastrointestinal cancer patients. This review summarizes the advances in the field of molecular biomarkers in tumors of the gastrointestinal tract, with focus on the available NGS platforms that enable comprehensive tumor molecular profile analysis.
Collapse
|
|
15
|
Kim TM, An CH, Rhee JK, Jung SH, Lee SH, Baek IP, Kim MS, Lee SH, Chung YJ. Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma. Oncotarget 2016; 6:27725-35. [PMID: 26336987 PMCID: PMC4695021 DOI: 10.18632/oncotarget.4834] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 07/27/2015] [Indexed: 12/19/2022] Open
Abstract
Although the colorectal adenoma-to-carcinoma sequence represents a classical cancer progression model, the evolution of the mutational landscape underlying this model is not fully understood. In this study, we analyzed eight synchronous pairs of colorectal high-grade adenomas and carcinomas, four microsatellite-unstable (MSU) and four -stable (MSS) pairs, using whole-exome sequencing. In the MSU adenoma-carcinoma pairs, we observed no subclonal mutations in adenomas that became fixed in paired carcinomas, suggesting a ‘parallel’ evolution of synchronous adenoma-to-carcinoma, rather than a ‘stepwise’ evolution. The abundance of indel (in MSU and MSS pairs) and microsatellite instability (in MSU pairs) was noted in the later adenoma- or carcinoma-specific mutations, indicating that the mutational processes and functional constraints operative in early and late colorectal carcinogenesis are different. All MSU cases exhibited clonal, truncating mutations in ACVR2A, TGFBR2, and DNA mismatch repair genes, but none were present in APC or KRAS. In three MSS pairs, both APC and KRAS mutations were identified as both early and clonal events, often accompanying clonal copy number changes. An MSS case uniquely exhibited clonal ERBB2 amplification, followed by APC and TP53 mutations as carcinoma-specific events. Along with the previously unrecognized clonal origins of synchronous colorectal adenoma-carcinoma pairs, our study revealed that the preferred sequence of mutational events during colorectal carcinogenesis can be context-dependent.
Collapse
Affiliation(s)
- Tae-Min Kim
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Chang Hyeok An
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Je-Keun Rhee
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Seung-Hyun Jung
- Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - In-Pyo Baek
- Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Min Sung Kim
- Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sug Hyung Lee
- Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Yeun-Jun Chung
- Department of Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, South Korea.,Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| |
Collapse
|
|
16
|
Jesinghaus M, Pfarr N, Endris V, Kloor M, Volckmar AL, Brandt R, Herpel E, Muckenhuber A, Lasitschka F, Schirmacher P, Penzel R, Weichert W, Stenzinger A. Genotyping of colorectal cancer for cancer precision medicine: Results from the IPH Center for Molecular Pathology. Genes Chromosomes Cancer 2016; 55:505-21. [PMID: 26917275 DOI: 10.1002/gcc.22352] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Revised: 02/02/2016] [Accepted: 02/05/2016] [Indexed: 12/19/2022] Open
Abstract
Cancer precision medicine has opened up new avenues for the treatment of colorectal cancer (CRC). To fully realize its potential, high-throughput sequencing platforms that allow genotyping beyond KRAS need to be implemented and require performance assessment. We comprehensively analyzed first-year data of 202 consecutive formalin-fixed paraffin embedded (FFPE) CRC samples for which prospective genotyping at our institution was requested. Deep targeted genotyping was done using a semiconductor-based sequencing platform and a self-designed panel of 30 CRC-related genes. Additionally, microsatellite status (MS) was determined. Ninety-seven percent of tumor samples were suitable for sequencing and in 88% MS could be assessed. The minimal drop-out rates of 6 and 25 cases, respectively were due to too low amounts or heavy degradation of DNA. Of 557 nonsynonymous mutations, 90 (16%) have not been described in COSMIC at the time of data query. Forty-three cases (22%) had double- or triple mutations affecting a single gene. Sixty-four percent had genetic alterations influencing oncological therapy. Eight percent of patients (MSI phenotype: 6%; mutated POLE: 2%) were potentially eligible for treatment with immune checkpoint inhibitors. Of 56% of KRASwt CRC that potentially qualified for anti-EGFR treatment, 30% presented with mutations in BRAF/NRAS. Mutated PIK3CA was detected in 21%. In conclusion, we here present real-life routine diagnostics data that not only demonstrate the robustness and feasibility of deep targeted sequencing and MS-analysis of FFPE CRC samples but also contribute to the understanding of CRC genetics. Most importantly, in more than half of the patients our approach enabled the selection of the best treatment currently available. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Moritz Jesinghaus
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.,Institute of Pathology, Technical University Munich (TUM), Munich, 81675, Germany
| | - Nicole Pfarr
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.,Institute of Pathology, Technical University Munich (TUM), Munich, 81675, Germany
| | - Volker Endris
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Matthias Kloor
- Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Anna-Lena Volckmar
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Regine Brandt
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Esther Herpel
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.,NCT Tissue Bank, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | | | - Felix Lasitschka
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Roland Penzel
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany
| | - Wilko Weichert
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.,Institute of Pathology, Technical University Munich (TUM), Munich, 81675, Germany.,National Center for Tumor Diseases (NCT), Heidelberg, Germany.,Member of the German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, 69120, Germany.,National Center for Tumor Diseases (NCT), Heidelberg, Germany.,National Center for Tumor Diseases-Heidelberg School of Oncology (NCT-HSO), Heidelberg, Germany
| |
Collapse
|
|
17
|
Simbolo M, Mafficini A, Agostini M, Pedrazzani C, Bedin C, Urso ED, Nitti D, Turri G, Scardoni M, Fassan M, Scarpa A. Next-generation sequencing for genetic testing of familial colorectal cancer syndromes. Hered Cancer Clin Pract 2015; 13:18. [PMID: 26300997 PMCID: PMC4546256 DOI: 10.1186/s13053-015-0039-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 08/12/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Genetic screening in families with high risk to develop colorectal cancer (CRC) prevents incurable disease and permits personalized therapeutic and follow-up strategies. The advancement of next-generation sequencing (NGS) technologies has revolutionized the throughput of DNA sequencing. METHODS A series of 16 probands for either familial adenomatous polyposis (FAP; 8 cases) or hereditary nonpolyposis colorectal cancer (HNPCC; 8 cases) were investigated for intragenic mutations in five CRC familial syndromes-associated genes (APC, MUTYH, MLH1, MSH2, MSH6) applying both a custom multigene Ion AmpliSeq NGS panel and conventional Sanger sequencing. RESULTS Fourteen pathogenic variants were detected in 13/16 FAP/HNPCC probands (81.3 %); one FAP proband presented two co-existing pathogenic variants, one in APC and one in MUTYH. Thirteen of these 14 pathogenic variants were detected by both NGS and Sanger, while one MSH2 mutation (L280FfsX3) was identified only by Sanger sequencing. This is due to a limitation of the NGS approach in resolving sequences close or within homopolymeric stretches of DNA. To evaluate the performance of our NGS custom panel we assessed its capability to resolve the DNA sequences corresponding to 2225 pathogenic variants reported in the COSMIC database for APC, MUTYH, MLH1, MSH2, MSH6. Our NGS custom panel resolves the sequences where 2108 (94.7 %) of these variants occur. The remaining 117 mutations reside inside or in close proximity to homopolymer stretches; of these 27 (1.2 %) are imprecisely identified by the software but can be resolved by visual inspection of the region, while the remaining 90 variants (4.0 %) are blind spots. In summary, our custom panel would miss 4 % (90/2225) of pathogenic variants that would need a small set of Sanger sequencing reactions to be solved. CONCLUSIONS The multiplex NGS approach has the advantage of analyzing multiple genes in multiple samples simultaneously, requiring only a reduced number of Sanger sequences to resolve homopolymeric DNA regions not adequately assessed by NGS. The implementation of NGS approaches in routine diagnostics of familial CRC is cost-effective and significantly reduces diagnostic turnaround times.
Collapse
Affiliation(s)
- Michele Simbolo
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
| | - Andrea Mafficini
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
| | - Marco Agostini
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Nano Inspired Biomedicine, Institute of Pediatric Research, Città della Speranza, Padua, Italy
| | - Corrado Pedrazzani
- Department of Surgery, General Surgery A, University of Verona, Verona, Italy
| | - Chiara Bedin
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
- Nano Inspired Biomedicine, Institute of Pediatric Research, Città della Speranza, Padua, Italy
| | - Emanuele D. Urso
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Donato Nitti
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Giona Turri
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Maria Scardoni
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Matteo Fassan
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- ARC-Net Research Centre, Department of Pathology & Diagnostics, University of Verona, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, Verona, Italy
| | - Aldo Scarpa
- ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy
- Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
- ARC-Net Research Centre, Department of Pathology & Diagnostics, University of Verona, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, Verona, Italy
| |
Collapse
|
|
18
|
Baek IP, Jeong YB, Jung SH, Chung YJ. MAP: Mutation Arranger for Defining Phenotype-Related Single-Nucleotide Variant. Genomics Inform 2015; 12:289-92. [PMID: 25705172 PMCID: PMC4330268 DOI: 10.5808/gi.2014.12.4.289] [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: 10/16/2014] [Revised: 11/16/2014] [Accepted: 11/20/2014] [Indexed: 11/20/2022] Open
Abstract
Next-generation sequencing (NGS) is widely used to identify the causative mutations underlying diverse human diseases, including cancers, which can be useful for discovering the diagnostic and therapeutic targets. Currently, a number of single-nucleotide variant (SNV)-calling algorithms are available; however, there is no tool for visualizing the recurrent and phenotype-specific mutations for general researchers. In this study, in order to support defining the recurrent mutations or phenotype-specific mutations from NGS data of a group of cancers with diverse phenotypes, we aimed to develop a user-friendly tool, named mutation arranger for defining phenotype-related SNV (MAP). MAP is a user-friendly program with multiple functions that supports the determination of recurrent or phenotype-specific mutations and provides graphic illustration images to the users. Its operation environment, the Microsoft Windows environment, enables more researchers who cannot operate Linux to define clinically meaningful mutations with NGS data from cancer cohorts.
Collapse
Affiliation(s)
- In-Pyo Baek
- Department of Microbiology, Integrated Research Center for Genome Polymorphism (IRCGP), The Catholic University of Korea College of Medicine, Seoul 137-701, Korea
| | | | - Seung-Hyun Jung
- Department of Microbiology, Integrated Research Center for Genome Polymorphism (IRCGP), The Catholic University of Korea College of Medicine, Seoul 137-701, Korea
| | - Yeun-Jun Chung
- Department of Microbiology, Integrated Research Center for Genome Polymorphism (IRCGP), The Catholic University of Korea College of Medicine, Seoul 137-701, Korea
| |
Collapse
|
|
19
|
Akkad J, Bochum S, Martens UM. Personalized treatment for colorectal cancer: novel developments and putative therapeutic strategies. Langenbecks Arch Surg 2015; 400:129-43. [DOI: 10.1007/s00423-015-1276-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 01/23/2015] [Indexed: 01/14/2023]
|
|
20
|
Isolation of oxygenase genes for indigo-forming activity from an artificially polluted soil metagenome by functional screening using Pseudomonas putida strains as hosts. Appl Microbiol Biotechnol 2015; 99:4453-70. [DOI: 10.1007/s00253-014-6322-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 12/08/2014] [Accepted: 12/12/2014] [Indexed: 10/24/2022]
|
|
21
|
Esplin ED, Snyder MP. Genomic era diagnosis and management of hereditary and sporadic colon cancer. World J Clin Oncol 2014; 5:1036-1047. [PMID: 25493239 PMCID: PMC4259930 DOI: 10.5306/wjco.v5.i5.1036] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 03/21/2014] [Accepted: 05/16/2014] [Indexed: 02/06/2023] Open
Abstract
The morbidity and mortality attributable to heritable and sporadic carcinomas of the colon are substantial and affect children and adults alike. Despite current colonoscopy screening recommendations colorectal adenocarcinoma (CRC) still accounts for almost 140000 cancer cases yearly. Familial adenomatous polyposis (FAP) is a colon cancer predisposition due to alterations in the adenomatous polyposis coli gene, which is mutated in most CRC. Since the beginning of the genomic era next-generation sequencing analyses of CRC continue to improve our understanding of the genetics of tumorigenesis and promise to expand our ability to identify and treat this disease. Advances in genome sequence analysis have facilitated the molecular diagnosis of individuals with FAP, which enables initiation of appropriate monitoring and timely intervention. Genome sequencing also has potential clinical impact for individuals with sporadic forms of CRC, providing means for molecular diagnosis of CRC tumor type, data guiding selection of tumor targeted therapies, and pharmacogenomic profiles specifying patient specific drug tolerances. There is even a potential role for genomic sequencing in surveillance for recurrence, and early detection, of CRC. We review strategies for diagnostic assessment and management of FAP and sporadic CRC in the current genomic era, with emphasis on the current, and potential for future, impact of genome sequencing on the clinical care of these conditions.
Collapse
|
|
22
|
Vicente CM, Lima MA, Yates EA, Nader HB, Toma L. Enhanced tumorigenic potential of colorectal cancer cells by extracellular sulfatases. Mol Cancer Res 2014; 13:510-23. [PMID: 25477293 DOI: 10.1158/1541-7786.mcr-14-0372] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
UNLABELLED Heparan sulfate endosulfatase-1 and -2 (SULF1 and SULF2) are two important extracellular 6-O-endosulfatases that remove 6-O sulfate groups of N-glucosamine along heparan sulfate (HS) proteoglycan chains often found in the extracellular matrix. The HS sulfation pattern influences signaling events at the cell surface, which are critical for interactions with growth factors and their receptors. SULFs are overexpressed in several types of human tumors, but their role in cancer is still unclear because their molecular mechanism has not been fully explored and understood. To further investigate the functions of these sulfatases in tumorigenesis, stable overexpression models of these genes were generated in the colorectal cancer cells, Caco-2 and HCT-116. Importantly, mimicking overexpression of these sulfatases resulted in increased viability and proliferation, and augmented cell migration. These effects were reverted by shRNA-mediated knockdown of SULF1 or SULF2 and by the addition of unfractionated heparin. Detailed structural analysis of HS from cells overexpressing SULFs showed reduction in the trisulfated disaccharide UA(2S)-GlcNS(6S) and corresponding increase in UA(2S)-GlcNS disaccharide, as well as an unexpected rise in less common disaccharides containing GlcNAc(6S) residues. Moreover, cancer cells transfected with SULFs demonstrated increased Wnt signaling. In summary, SULF1 or SULF2 overexpression contributes to colorectal cancer cell proliferation, migration, and invasion. IMPLICATIONS This study reveals that sulfatases have oncogenic effects in colon cancer cells, suggesting an important role for these enzymes in cancer progression.
Collapse
Affiliation(s)
- Carolina M Vicente
- Disciplina de Biologia Molecular, Departamento de Bioquímica, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil
| | - Marcelo A Lima
- Disciplina de Biologia Molecular, Departamento de Bioquímica, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil. Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Edwin A Yates
- Disciplina de Biologia Molecular, Departamento de Bioquímica, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil. Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Helena B Nader
- Disciplina de Biologia Molecular, Departamento de Bioquímica, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil
| | - Leny Toma
- Disciplina de Biologia Molecular, Departamento de Bioquímica, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil.
| |
Collapse
|
|
23
|
San Lucas FA, Fowler J, Chang K, Kopetz S, Vilar E, Scheet P. Cancer in silico drug discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes. Mol Cancer Ther 2014; 13:3230-40. [PMID: 25349306 PMCID: PMC4341901 DOI: 10.1158/1535-7163.mct-14-0260] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Large-scale cancer datasets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and technology differences between CMap and TCGA experiments, such analyses are challenging to conduct and reproduce. We present Cancer in silico Drug Discovery (CiDD; scheet.org/software), a computational drug discovery platform that addresses these challenges. CiDD integrates data from TCGA, CMap, and Cancer Cell Line Encyclopedia (CCLE) to perform computational drug discovery experiments, generating hypotheses for the following three general problems: (i) determining whether specific clinical phenotypes or molecular characteristics are associated with unique gene expression signatures; (ii) finding candidate drugs to repress these expression signatures; and (iii) identifying cell lines that resemble the tumors being studied for subsequent in vitro experiments. The primary input to CiDD is a clinical or molecular characteristic. The output is a biologically annotated list of candidate drugs and a list of cell lines for in vitro experimentation. We applied CiDD to identify candidate drugs to treat colorectal cancers harboring mutations in BRAF. CiDD identified EGFR and proteasome inhibitors, while proposing five cell lines for in vitro testing. CiDD facilitates phenotype-driven, systematic drug discovery based on clinical and molecular data from TCGA.
Collapse
Affiliation(s)
- F Anthony San Lucas
- The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Jerry Fowler
- Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Kyle Chang
- The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Scott Kopetz
- The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas. Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | - Eduardo Vilar
- The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas. Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
| | - Paul Scheet
- The Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
| |
Collapse
|
|
24
|
Sapari NS, Elahi E, Wu M, Loh M, Ng HK, Han X, Yap HL, Klemm TP, Pang B, Benoukraf T, Teo YY, Iacopetta B, Lee SC, Soong R. Feasibility of low-throughput next generation sequencing for germline DNA screening. Clin Chem 2014; 60:1549-57. [PMID: 25338684 DOI: 10.1373/clinchem.2014.227728] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Next generation sequencing (NGS) promises many benefits for clinical diagnostics. However, current barriers to its adoption include suboptimal amenability for low clinical throughputs and uncertainty over data accuracy and analytical procedures. We assessed the feasibility and performance of low-throughput NGS for detecting germline mutations for Lynch syndrome (LS). METHODS Sequencing depth, time, and cost of 6 formats on the MiSeq and Personal Genome Machine platforms at 1-12 samples/run were calculated. Analytical performance was assessed from 3 runs of 3 DNA samples annotated for 7500 nucleotides by BeadChip arrays. The clinical performance of low-throughput NGS and 9 analytical processes were assessed through blinded analysis of DNA samples from 12 LS cases confirmed by Sanger sequencing, and 3 control cases. RESULTS The feasibility analysis revealed different formats were optimal at different throughputs. Detection was reproducible for 2619/2635 (99.39%) replicate variants, and sensitivity and specificity to array annotation were 99.42% and 99.99% respectively. Eleven of 16 inconsistently detected variants could be specifically identified by having allele frequencies ≤ 0.15, strand biases >-35, or genotype quality scores ≤ 80. Positive selection for variants in the Human Genome Mutation Database (colorectal cancer, nonpolyposis) and variants with ≤ 5% frequency in the Asian population gave the best clinical performance (92% sensitivity, 67% specificity). CONCLUSIONS Low-throughput NGS can be a cost-efficient and reliable approach for screening germline variants; however, its clinical utility is subject to the quality of annotation of clinically relevant variants.
Collapse
Affiliation(s)
- Nur Sabrina Sapari
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Eiram Elahi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Mengchu Wu
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Marie Loh
- Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
| | - Hong Kiat Ng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Xiao Han
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Hui Ling Yap
- Department of Haematology Oncology, National University Cancer Institute, National University Health System, Singapore
| | | | - Brendan Pang
- Department of Pathology, National University Health System, Singapore
| | - Touati Benoukraf
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Yik Ying Teo
- School of Public Health, National University Health System, Singapore
| | - Barry Iacopetta
- School of Surgery, The University of Western Australia, Perth, Australia
| | - Soo Chin Lee
- Department of Haematology Oncology, National University Cancer Institute, National University Health System, Singapore
| | - Richie Soong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pathology, National University Health System, Singapore;
| |
Collapse
|
|
25
|
Ciombor KK, Haraldsdottir S, Goldberg RM. How Can Next-Generation Sequencing (Genomics) Help Us in Treating Colorectal Cancer? CURRENT COLORECTAL CANCER REPORTS 2014; 10:372-379. [PMID: 25395895 DOI: 10.1007/s11888-014-0244-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Next generation sequencing methods have exponentially increased the amount of genomic information available to scientists and clinicians. This review will explain the evolution of tumor gene sequencing and identify its potential to accelerate therapeutic progress by using colorectal cancer to illustrate the benefits of this type of analysis. A milestone in sequencing occurred when The Cancer Genome Atlas investigators characterized the genomes of 276 colorectal cancer samples, with the resulting information expected to provide future clinical applications and help to guide the treatment of colorectal cancer. Data regarding colorectal cancer mutational frequencies, prognostic and predictive biomarker usefulness, and signaling pathway alterations are emerging from various next generation sequencing platforms. Next generation sequencing methods are also enhancing our understanding of the causes and consequences of both the chromosomal instability and microsatellite instability pathways, as well as expanding our knowledge of the origins of familial colorectal cancer. Limitations to next generation sequencing methods include the need for storage and analysis of massive quantities of data, as well as assurance that the data is of the highest possible quality. However, this genomic technology carries with it the potential to revolutionize our treatment of colorectal cancer patients through better understanding of the underlying disease biology and subsequent development and application of therapeutic approaches targeting the genetic abnormalities specific to individual malignancies.
Collapse
Affiliation(s)
- Kristen K Ciombor
- Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Sigurdis Haraldsdottir
- Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Richard M Goldberg
- Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| |
Collapse
|
|
26
|
Rasool S, Rasool V, Naqvi T, Ganai BA, Shah BA. Genetic unraveling of colorectal cancer. Tumour Biol 2014; 35:5067-82. [PMID: 24573608 DOI: 10.1007/s13277-014-1713-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Accepted: 01/29/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is a common disease in both men and women (being the third most common cancer in men and the second most common among women) and thus represents an important and serious public health issue, especially in the western world. Although it is a well-established fact that cancers of the large intestine produce symptoms relatively earlier at a stage that can be easily cured by resection, a large number of people lose their lives to this deadly disease each year. Recent times have seen an important change in the incidence of colorectal cancer in different parts of the world. The etiology of colorectal cancer is multifactorial and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. Exhaustive efforts have been made out in the direction of unraveling the role of various environmental factors, gene mutations, and polymorphisms worldwide (as well as in Kashmir-"a valley of gastrointestinal cancers") that have got a role to play in the development of this disease so that antitumor drugs could be developed against this cancer, first, and, finally, the responsiveness or resistance to these agents could be understood for combating this global issue.
Collapse
Affiliation(s)
- Sabha Rasool
- Department of Biochemistry, University of Kashmir, Hazratbal, Srinagar, 190006, Kashmir, India
| | | | | | | | | |
Collapse
|