|
1
|
Tawil S, Khaddage-Soboh N. Cancer research in Lebanon: Scope of the most recent publications of an academic institution (Review). Oncol Lett 2024; 28:350. [PMID: 38872861 PMCID: PMC11170263 DOI: 10.3892/ol.2024.14484] [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: 11/28/2022] [Accepted: 06/09/2023] [Indexed: 06/15/2024] Open
Abstract
Cancer may be considered one of the most interesting areas of study, and although oncology research has grown markedly over the last decade, there is as yet no known cure for cancer. The objective of the present review is to examine various approaches to cancer research from a single institution, summarize their key conclusions and offer recommendations for future evaluations. The review examined 72 cancer-associated studies that were published within six years from 2017 to 2022. Published works in the subject fields of 'cancer' or 'oncology' and 'research' that were indexed in Scopus and Web of Science were retrieved and sorted according to article title, author names, author count, citation count and key words. After screening, a total of 28 in vitro/animal studies and 46 patient-associated published studies were obtained. A large proportion of these studies comprised literature reviews (20/72), while 20 studies were observational in nature. The 72 publications included 23 in which various types of cancer were examined, while the remaining studies focused on specific types of cancer, including lung, breast, colon and brain cancer. These studies aimed to investigate the incidence, prevalence, treatment and prevention mechanisms associated with cancer. Despite the existence of extensive cancer research, scientists seldom contemplate an ultimate cure for cancer. However, it is crucial to continuously pursue research on cancer prevention and treatment in order to enhance the effectiveness and minimize potential side effects of cancer therapy.
Collapse
Affiliation(s)
- Samah Tawil
- School of Medicine, Lebanese American University, Beirut 1102 2801, Lebanon
| | - Nada Khaddage-Soboh
- Adnan Kassar School of Business, Lebanese American University, Beirut 1102 2801, Lebanon
| |
Collapse
|
|
2
|
Jarak I, Isabel Santos A, Helena Pinto A, Domingues C, Silva I, Melo R, Veiga F, Figueiras A. Colorectal cancer cell exosome and cytoplasmic membrane for homotypic delivery of therapeutic molecules. Int J Pharm 2023; 646:123456. [PMID: 37778515 DOI: 10.1016/j.ijpharm.2023.123456] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/03/2023]
Abstract
Colorectal cancer (CRC) is one of the most common causes of death in the world. The multi-drug resistance, especially in metastatic colorectal cancer, drives the development of new strategies that secure a positive outcome and reduce undesirable side effects. Nanotechnology has made an impact in addressing some pharmacokinetic and safety issues related to administration of free therapeutic agents. However, demands of managing complex biointerfacing require equally complex methods for introducing stimuli-responsive or targeting elements. In order to procure a more efficient solution to the overcoming of biological barriers, the physiological functions of cancer cell plasma and exosomal membranes provided the source of highly functionalized coatings. Biomimetic nanovehicles based on colorectal cancer (CRC) membranes imparted enhanced biological compatibility, immune escape and protection to diverse classes of therapeutic molecules. When loaded with therapeutic load or used as a coating for other therapeutic nanovehicles, they provide highly efficient and selective cell targeting and uptake. This review presents a detailed overview of the recent application of homotypic biomimetic nanovehicles in the management of CRC. We also address some of the current possibilities and challenges associated with the CRC membrane biomimetics.
Collapse
Affiliation(s)
- Ivana Jarak
- Univ Coimbra, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, Coimbra, Portugal; Univ Porto, Instituto de Investigação e Inovação em Saúde, Porto, Portugal
| | - Ana Isabel Santos
- Univ Coimbra, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, Coimbra, Portugal
| | - Ana Helena Pinto
- Univ Coimbra, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, Coimbra, Portugal
| | - Cátia Domingues
- Univ Coimbra, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, Coimbra, Portugal; Univ Coimbra, REQUIMTE/LAQV, Group of Pharmaceutical Technology, Coimbra, Portugal; Univ Coimbra, Institute for Clinical and Biomedical Research (iCBR) Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal
| | - Inês Silva
- Univ Coimbra, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, Coimbra, Portugal
| | - Raquel Melo
- Univ Coimbra, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, Coimbra, Portugal
| | - Francisco Veiga
- Univ Coimbra, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, Coimbra, Portugal; Univ Coimbra, REQUIMTE/LAQV, Group of Pharmaceutical Technology, Coimbra, Portugal
| | - Ana Figueiras
- Univ Coimbra, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, Coimbra, Portugal; Univ Coimbra, REQUIMTE/LAQV, Group of Pharmaceutical Technology, Coimbra, Portugal.
| |
Collapse
|
|
3
|
Olkinuora AP, Peltomäki PT, Aaltonen LA, Rajamäki K. From APC to the genetics of hereditary and familial colon cancer syndromes. Hum Mol Genet 2021; 30:R206-R224. [PMID: 34329396 PMCID: PMC8490010 DOI: 10.1093/hmg/ddab208] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 11/12/2022] Open
Abstract
Hereditary colorectal cancer (CRC) syndromes attributable to high penetrance mutations represent 9-26% of young-onset CRC cases. The clinical significance of many of these mutations is understood well enough to be used in diagnostics and as an aid in patient care. However, despite the advances made in the field, a significant proportion of familial and early-onset cases remains molecularly uncharacterized and extensive work is still needed to fully understand the genetic nature of CRC susceptibility. With the emergence of next-generation sequencing and associated methods, several predisposition loci have been unraveled, but validation is incomplete. Individuals with cancer-predisposing mutations are currently enrolled in life-long surveillance, but with the development of new treatments, such as cancer vaccinations, this might change in the not so distant future for at least some individuals. For individuals without a known cause for their disease susceptibility, prevention and therapy options are less precise. Herein, we review the progress achieved in the last three decades with a focus on how CRC predisposition genes were discovered. Furthermore, we discuss the clinical implications of these discoveries and anticipate what to expect in the next decade.
Collapse
Affiliation(s)
- Alisa P Olkinuora
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
| | - Päivi T Peltomäki
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
| | - Lauri A Aaltonen
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland
| | - Kristiina Rajamäki
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland
| |
Collapse
|
|
4
|
Ability of known colorectal cancer susceptibility SNPs to predict colorectal cancer risk: A cohort study within the UK Biobank. PLoS One 2021; 16:e0251469. [PMID: 34525106 PMCID: PMC8443076 DOI: 10.1371/journal.pone.0251469] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 09/02/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer risk stratification is crucial to improve screening and risk-reducing recommendations, and consequently do better than a one-size-fits-all screening regimen. Current screening guidelines in the UK, USA and Australia focus solely on family history and age for risk prediction, even though the vast majority of the population do not have any family history. We investigated adding a polygenic risk score based on 45 single-nucleotide polymorphisms to a family history model (combined model) to quantify how it improves the stratification and discriminatory performance of 10-year risk and full lifetime risk using a prospective population-based cohort within the UK Biobank. For both 10-year and full lifetime risk, the combined model had a wider risk distribution compared with family history alone, resulting in improved risk stratification of nearly 2-fold between the top and bottom risk quintiles of the full lifetime risk model. Importantly, the combined model can identify people (n = 72,019) who do not have family history of colorectal cancer but have a predicted risk that is equivalent to having at least one affected first-degree relative (n = 44,950). We also confirmed previous findings by showing that the combined full lifetime risk model significantly improves discriminatory accuracy compared with a simple family history model 0.673 (95% CI 0.664–0.682) versus 0.666 (95% CI 0.657–0.675), p = 0.0065. Therefore, a combined polygenic risk score and first-degree family history model could be used to improve risk stratified population screening programs.
Collapse
|
|
5
|
He CY, Chen LZ, Wang ZX, Sun LP, Peng JJ, Wu MQ, Wang TM, Li YQ, Yang XH, Zhou DL, Ye ZL, Ma JJ, Li XZ, Zhang PF, Ju HQ, Mo HY, Zhang ZC, Zeng ZL, Shao JY, Jia WH, Cai SJ, Yuan Y, Xu RH. Performance of common genetic variants in risk prediction for colorectal cancer in Chinese: A two-stage and multicenter study. Genomics 2021; 113:867-873. [PMID: 33545268 DOI: 10.1016/j.ygeno.2021.01.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 01/21/2021] [Accepted: 01/31/2021] [Indexed: 11/25/2022]
Abstract
The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.
Collapse
Affiliation(s)
- Cai-Yun He
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Le-Zong Chen
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Zi-Xian Wang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Li-Ping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China
| | - Jun-Jie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Min-Qing Wu
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Tong-Min Wang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Ya-Qi Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xin-Hua Yang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Da-Lei Zhou
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Zu-Lu Ye
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Jiang-Jun Ma
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Xi-Zhao Li
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Pei-Fen Zhang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Huai-Qiang Ju
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Hai-Yu Mo
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Zi-Chen Zhang
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Zhao-Lei Zeng
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jian-Yong Shao
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - Wei-Hua Jia
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
| | - San-Jun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang 110001, China.
| | - Rui-Hua Xu
- Sun Yat-sen University Cancer Center, Sun Yat-sen University, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
| |
Collapse
|
|
6
|
Debesa-Tur G, Pérez-Brocal V, Ruiz-Ruiz S, Castillejo A, Latorre A, Soto JL, Moya A. Metagenomic analysis of formalin-fixed paraffin-embedded tumor and normal mucosa reveals differences in the microbiome of colorectal cancer patients. Sci Rep 2021; 11:391. [PMID: 33432015 PMCID: PMC7801721 DOI: 10.1038/s41598-020-79874-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 12/14/2020] [Indexed: 02/06/2023] Open
Abstract
An increased risk of developing colorectal cancer (CRC) and other types of tumor is associated to Lynch syndrome (LS), an inherited condition caused by germline mutations in mismatch repair genes. We selected a cohort of LS patients that had developed CRC and had undergone surgical resection. Formalin-fixed paraffin embedded (FFPE) tissue blocks from matched colorectal and normal mucosa were used for genomic DNA extraction with a commercial kit and sequenced by high-throughput sequencing. A metagenomic approach enabled the taxonomic and functional identification of the microbial community and associated genes detected in the specimens. Slightly lower taxonomic diversity was observed in the tumor compared to the non-tumor tissue. Furthermore, the most remarkable differences between tumors and healthy tissue was the significant increase in the genus Fusobacterium in the former, in particular the species F. nucleatum, as well as Camplylobacter or Bacteroides fragilis, in accordance with previous studies of CRC. However, unlike prior studies, the present work is not based on directed detection by qPCR but instead uses a metagenomic approach to retrieve the whole bacterial community, and addresses the additional difficulty of using long-term stored FFPE samples.
Collapse
Affiliation(s)
- Gabriela Debesa-Tur
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Área de Genómica y Salud, Valencia, Spain
- Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Vicente Pérez-Brocal
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Área de Genómica y Salud, Valencia, Spain
- Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Susana Ruiz-Ruiz
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Área de Genómica y Salud, Valencia, Spain
- Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Adela Castillejo
- Unidad de Genética Molecular, Hospital General Universitario de Elche, Alicante, Spain
- Departamento de Salud Elche, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Elche, Spain
| | - Amparo Latorre
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Área de Genómica y Salud, Valencia, Spain
- Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- Instituto de Biología Integrativa de Sistemas (I2Sysbio), Universitat de València and Consejo Superior de Investigaciones Científicas (CSIC), Paterna, Valencia, Spain
| | - José Luis Soto
- Unidad de Genética Molecular, Hospital General Universitario de Elche, Alicante, Spain
- Departamento de Salud Elche, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Elche, Spain
| | - Andrés Moya
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Área de Genómica y Salud, Valencia, Spain.
- Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
- Instituto de Biología Integrativa de Sistemas (I2Sysbio), Universitat de València and Consejo Superior de Investigaciones Científicas (CSIC), Paterna, Valencia, Spain.
| |
Collapse
|
|
7
|
Colistro V, Mut P, Hidalgo PC, Carracedo A, Quintela I, Rojas-Martínez A, Sans M. Differential admixture in Latin American populations and its impact on the study of colorectal cancer. Genet Mol Biol 2020; 43:e20200143. [PMID: 33306774 PMCID: PMC7783724 DOI: 10.1590/1678-4685-gmb-2020-0143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 09/14/2020] [Indexed: 11/22/2022] Open
Abstract
Genome-wide association studies focused on searching genes responsible for
several diseases. Admixture mapping studies proposed a more efficient
alternative capable of detecting polymorphisms contributing with a small effect
on the disease risk. This method focuses on the higher values of linkage
disequilibrium in admixed populations. To test this, we analyzed 10 genomic
regions previously defined as related with colorectal cancer among nine
populations and studied the variation pattern of haplotypic structures and
heterozygosity values on seven categories of SNPs. Both analyses showed
differences among chromosomal regions and studied populations. Admixed
Latin-American samples generally show intermediate values. Heterozygosity of the
SNPs grouped in categories varies more in each gene than in each population.
African related populations have more blocks per chromosomal region, coherently
with their antiquity. In sum, some similarities were found among Latin American
populations, but each chromosomal region showed a particular behavior, despite
the fact that the study refers to genes and regions related with one particular
complex disease. This study strongly suggests the necessity of developing
statistical methods to deal with di- or tri-hybrid populations, as well as to
carefully analyze the different historic and demographic scenarios, and the
different characteristics of particular chromosomal regions and evolutionary
forces.
Collapse
Affiliation(s)
- Valentina Colistro
- Universidad de la República, Facultad de Medicina, Departamento de Métodos Cuantitativos, Montevideo, Uruguay
| | - Patricia Mut
- Universidad de la República, Facultad de Humanidades y Ciencias de la Educación, Departamento de Antropología Biológica, Montevideo, Uruguay
| | - Pedro C Hidalgo
- Universidad de la República, Centro Universitario de Tacuarembó, Polo de Desarrollo Universitario Diversidad Genética Humana, Tacuarembó, Uruguay
| | - Angel Carracedo
- Universidad de Santiago de Compostela, Centro Nacional de Genotipado (CEGEN), Spain.,Universidade de Santiago de Compostela, CIBER de Enfermedades Raras (CIBERER)-Instituto de Salud Carlos III, Grupo de Medicina Xenómica, Santiago de Compostela, Spain
| | - Inés Quintela
- Universidad de Santiago de Compostela, Centro Nacional de Genotipado (CEGEN), Spain
| | | | - Mónica Sans
- Universidad de la República, Facultad de Humanidades y Ciencias de la Educación, Departamento de Antropología Biológica, Montevideo, Uruguay
| |
Collapse
|
|
8
|
Wang C, Wang Y, Hughes KS, Parmigiani G, Braun D. Penetrance of Colorectal Cancer Among Mismatch Repair Gene Mutation Carriers: A Meta-Analysis. JNCI Cancer Spectr 2020; 4:pkaa027. [PMID: 32923933 PMCID: PMC7476651 DOI: 10.1093/jncics/pkaa027] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Lynch syndrome, the most common colorectal cancer (CRC) syndrome, is caused by germline mismatch repair (MMR) genes. Precise estimates of age-specific risks are crucial for sound counseling of individuals managing a genetic predisposition to cancer, but published risk estimates vary. The objective of this work is to provide gene-, sex-, and age-specific risk estimates of CRC for MMR mutation carriers that comprehensively reflect the best available data. METHODS We conducted a meta-analysis to combine risk information from multiple studies on Lynch syndrome-associated CRC. We used a likelihood-based approach to integrate reported measures of CRC risk and deconvolved aggregated information to estimate gene- and sex-specific risk. RESULTS Our comprehensive search identified 10 studies (8 on MLH1, 9 on MSH2, and 3 on MSH6). We estimated the cumulative risk of CRC by age and sex in heterozygous mutation carriers. At age 70 years, for male and female carriers, respectively, risks for MLH1 were 43.9% (95% confidence interval [CI] = 39.6% to 46.6%) and 37.3% (95% CI = 32.2% to 40.2%), for MSH2 were 53.9% (95% CI = 49.0% to 56.3%) and 38.6% (95% CI = 34.1% to 42.0%), and for MSH6 were 12.0% (95% CI = 2.4% to 24.6%) and 12.3% (95% CI = 3.5% to 23.2%). CONCLUSIONS Our results provide up-to-date and comprehensive age-specific CRC risk estimates for counseling and risk prediction tools. These will have a direct clinical impact by improving prevention and management strategies for both individuals who are MMR mutation carriers and those considering testing.
Collapse
Affiliation(s)
- Cathy Wang
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Yan Wang
- Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA
- Department of Breast Surgery, Shanghai Cancer Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Kevin S Hughes
- Division of Surgical Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Giovanni Parmigiani
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Danielle Braun
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| |
Collapse
|
|
9
|
Schubert SA, Morreau H, de Miranda NFCC, van Wezel T. The missing heritability of familial colorectal cancer. Mutagenesis 2020; 35:221-231. [PMID: 31605533 PMCID: PMC7352099 DOI: 10.1093/mutage/gez027] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/05/2019] [Indexed: 02/06/2023] Open
Abstract
Pinpointing heritability factors is fundamental for the prevention and early detection of cancer. Up to one-quarter of colorectal cancers (CRCs) occur in the context of familial aggregation of this disease, suggesting a strong genetic component. Currently, only less than half of the heritability of CRC can be attributed to hereditary syndromes or common risk loci. Part of the missing heritability of this disease may be explained by the inheritance of elusive high-risk variants, polygenic inheritance, somatic mosaicism, as well as shared environmental factors, among others. A great deal of the missing heritability in CRC is expected to be addressed in the coming years with the increased application of cutting-edge next-generation sequencing technologies, routine multigene panel testing and tumour-focussed germline predisposition screening approaches. On the other hand, it will be important to define the contribution of environmental factors to familial aggregation of CRC incidence. This review provides an overview of the known genetic causes of familial CRC and aims at providing clues that explain the missing heritability of this disease.
Collapse
Affiliation(s)
- Stephanie A Schubert
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Hans Morreau
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Noel F C C de Miranda
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Tom van Wezel
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| |
Collapse
|
|
10
|
Qazi AS, Akbar S, Saeed RF, Bhatti MZ. Translational Research in Oncology. 'ESSENTIALS OF CANCER GENOMIC, COMPUTATIONAL APPROACHES AND PRECISION MEDICINE 2020:261-311. [DOI: 10.1007/978-981-15-1067-0_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
11
|
Summers MG, Maughan TS, Kaplan R, Law PJ, Houlston RS, Escott-Price V, Cheadle JP. Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants. Eur J Cancer 2020; 124:56-63. [PMID: 31734605 DOI: 10.1016/j.ejca.2019.09.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 09/20/2019] [Accepted: 09/28/2019] [Indexed: 12/29/2022]
Abstract
PURPOSE Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship. EXPERIMENTAL DESIGN For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN-B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10-4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival. RESULTS Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21-1.71, P = 5.0 × 10-5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13-1.34, P = 1.9 × 10-6). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42-0.87, P = 6.6 × 10-3). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses. CONCLUSIONS The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.
Collapse
Affiliation(s)
- Matthew G Summers
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Timothy S Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Richard Kaplan
- MRC Clinical Trials Unit, Aviation House, 125 Kingsway, London, WC2B 6NH, UK
| | - Philip J Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Richard S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Valentina Escott-Price
- Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Jeremy P Cheadle
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
| |
Collapse
|
|
12
|
Thutkawkorapin J, Lindblom A, Tham E. Exome sequencing in 51 early onset non-familial CRC cases. Mol Genet Genomic Med 2019; 7:e605. [PMID: 30809968 PMCID: PMC6503031 DOI: 10.1002/mgg3.605] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 12/22/2018] [Accepted: 01/16/2019] [Indexed: 12/12/2022] Open
Abstract
Background Colorectal cancer (CRC) cases with an age of onset <40 years suggests a germline genetic cause. In total, 51 simplex cases were included to test the hypothesis of CRC as a mendelian trait caused by either heterozygous autosomal dominant or bi‐allelic autosomal recessive pathogenic variants. Methods The cohort was whole exome sequenced (WES) at 100× coverage. Both a dominant‐ and recessive model were used for searching predisposing genetic factors. In addition, we assayed recessive variants of potential moderate risk that were enriched in our young‐onset CRC cohort. Variants were filtered using a candidate cancer gene list or by selecting variants more likely to be pathogenic based on variant type (e.g., loss‐of‐function) or allele frequency. Results We identified one pathogenic variant in PTEN in a patient subsequently confirmed to have a hereditary hamartoma tumor syndrome (Cowden syndrome) and one patient with a pathogenic heterozygous variant in PMS2 that was originally not identified by WES due to low quality reads resulting from pseudogenes. In addition, we identified three heterozygous candidate missense variants in known cancer susceptibility genes (BMPR1A,BRIP1, and SRC), three truncating variants in possibly novel cancer genes (CLSPN,SEC24B, SSH2) and four candidate missense variants in ACACA, NR2C2, INPP4A, and DIDO1. We also identify five possible autosomal recessive candidate genes: ATP10B,PKHD1,UGGT2,MYH13,TFF3. Conclusion Two clear pathogenic variants were identified in patients that had not been identified clinically. Thus, the chance of detecting a hereditary cancer syndrome in patients with CRC at young age but without family history is 2/51 (4%) and therefore the clinical benefit of genetic testing in this patient group is low. Of note, using stringent filtering, we have identified a total of ten candidate heterozygous variants and five possibly biallelic autosomal recessive candidate genes that warrant further study.
Collapse
Affiliation(s)
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Emma Tham
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
13
|
Tanikawa C, Kamatani Y, Takahashi A, Momozawa Y, Leveque K, Nagayama S, Mimori K, Mori M, Ishii H, Inazawa J, Yasuda J, Tsuboi A, Shimizu A, Sasaki M, Yamaji T, Sawada N, Iwasaki M, Tsugane S, Naito M, Wakai K, Koyama T, Takezaki T, Yuji K, Murakami Y, Nakamura Y, Kubo M, Matsuda K. GWAS identifies two novel colorectal cancer loci at 16q24.1 and 20q13.12. Carcinogenesis 2019; 39:652-660. [PMID: 29471430 DOI: 10.1093/carcin/bgy026] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 02/13/2018] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is the fourth leading cause of cancer mortality worldwide. Genome-wide association studies (GWAS) identified more than 50 CRC loci. However, most of the previous studies were conducted in European population, and host genetic factors among Japanese population are largely remained to be identified. To identify novel loci in the Japanese population, here, we performed a large-scale GWAS using 6692 cases and 27 178 controls followed by a replication analysis using more than 11 000 case-control samples. We found the significant association of 10 loci (P < 5 × 10-8), including 2 novel loci on 16q24.1 (IRF8-FOXF1, rs847208, P = 3.15 × 10-9 and odds ratio = 1.107 with 95% confidence interval (CI) of 1.071-1.145) and 20q13.12 (TOX2, rs6065668, P = 4.47 × 10-11 and odds ratio = 0.897 with 95% CI of 0.868-0.926). Moreover, 35 previously reported single nucleotide polymorphisms (SNPs) in 24 regions were validated in the Japanese population (P < 0.05) with the same risk allele as in the previous studies. SNP rs6065668 was significantly associated with TOX2 expression in the sigmoid colon. In addition, nucleotide substitutions in the regulatory region of TOX2 were predicted to alter the binding of several transcription factors, including KLF5. Our findings elucidate the important role of genetic variations in the development of CRC in the Japanese population.
Collapse
Affiliation(s)
- Chizu Tanikawa
- Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Yoichiro Kamatani
- Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan
| | - Atsushi Takahashi
- Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan.,Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Yukihide Momozawa
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan
| | - Karine Leveque
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.,Oncology Master Progam, University Claude Bernard, Lyon I, Lyon, France
| | - Satoshi Nagayama
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Koshi Mimori
- Department of Surgery and Molecular Oncology, Medical Institute of Bioregulation, Kyushu University, Oita, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery and Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hideshi Ishii
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Johji Inazawa
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Jun Yasuda
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Akito Tsuboi
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Atsushi Shimizu
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan
| | - Makoto Sasaki
- Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan
| | - Taiki Yamaji
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Norie Sawada
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Motoki Iwasaki
- Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Shoichiro Tsugane
- Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Mariko Naito
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Kenji Wakai
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Teruhide Koyama
- Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiro Takezaki
- Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Koichiro Yuji
- Project Division of International Advanced Medical Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoshinori Murakami
- Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yusuke Nakamura
- Department of Medicine, The University of Chicago, IL, USA.,Department of Surgery, The University of Chicago, IL, USA.,Center for Personalized Therapeutics, The University of Chicago, IL, USA
| | - Michiaki Kubo
- Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Kanagawa, Japan
| | - Koichi Matsuda
- Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.,Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
14
|
Kong J, Liu Z, Cai F, Xu X, Liul J. Relationship between the Asp1104His polymorphism of the nucleotide excision repair gene ERCC5 and treatment sensitivity to oxaliplatin in patients with advanced colorectal cancer in China. Clinics (Sao Paulo) 2018; 73:e455. [PMID: 30517302 PMCID: PMC6251253 DOI: 10.6061/clinics/2017/e455] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 05/25/2018] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVES To study the relationship between the Asp1104His polymorphism of the nucleotide excision repair gene ERCC5 and treatment sensitivity to oxaliplatin in patients with advanced colorectal cancer (CRC) in China. METHODS A group of 226 patients in the Department of Gastrointestinal Oncology at Zhejiang Xiaoshan Hospital from July 2011∼December 2016 and a control group of 226 normal healthy individuals were involved in this study. All patients were first diagnosed with advanced CRC and were treated with oxaliplatin-based chemotherapy. The genotype of ERCC5 at the site of amino acid 1104 was determined by a TaqMan probe-based real-time PCR approach. RESULTS There were no differences in age or gender between the groups, but the percentages of smokers and individuals with a family history of cancer were significantly higher in the patient group than in the control group. Analysis of the G/C polymorphism frequency among the patients and the healthy controls showed that the frequencies of the CC genotype and the CC+GC genotype were significantly related to CRC, but no significant difference in these frequencies was found between genders. The analysis of the relationship between the 5-year survival rate and different genotypes showed that in the total patient group, regardless of gender, the 5-year survival rate was significantly associated with the Asp1104His polymorphism of ERCC5. CONCLUSIONS The Asp1104His polymorphism of ERCC5 was associated with the risk and 5-year survival rate of CRC as well as treatment sensitivity to oxaliplatin.
Collapse
Affiliation(s)
- Jiangying Kong
- />Clinical Laboratory Department, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang 311202, China
| | - Zhuo Liu
- />Clinical Laboratory Department, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang 311202, China
| | - Feng Cai
- />Clinical Laboratory Department, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang 311202, China
| | - Xiaocheng Xu
- />Clinical Laboratory Department, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang 311202, China
| | - Jun Liul
- />Clinical Laboratory Department, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang 311202, China
- *Corresponding author. E-mail:
| |
Collapse
|
|
15
|
Jenkins MA, Ait Ouakrim D, Boussioutas A, Hopper JL, Ee HC, Emery JD, Macrae FA, Chetcuti A, Wuellner L, St John DJB. Revised Australian national guidelines for colorectal cancer screening: family history. Med J Aust 2018; 209:455-460. [DOI: 10.5694/mja18.00142] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 06/06/2018] [Indexed: 12/24/2022]
Affiliation(s)
| | | | | | | | - Hooi C Ee
- Sir Charles Gardiner Hospital, Perth, WA
| | | | | | | | | | | |
Collapse
|
|
16
|
Hatfield E, Green JS, Woods MO, Warden G, Parfrey PS. Impact of colonoscopic screening in Familial Colorectal Cancer Type X. Mol Genet Genomic Med 2018; 6:1021-1030. [PMID: 30300963 PMCID: PMC6305669 DOI: 10.1002/mgg3.478] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 08/21/2018] [Accepted: 08/24/2018] [Indexed: 12/22/2022] Open
Abstract
Background Hereditary Non‐Polyposis Colorectal cancer is caused by Lynch Syndrome (LS; an autosomal dominant condition) or by Familial Colorectal Cancer Type‐X (FCCTX; a condition of high family risk that fulfills Amsterdam criteria). The lifetime risk of developing colorectal cancer (CRC) in FCCTX family members is high and CRC occurs later than in LS. Methods To determine the impact of primary prevention colonoscopic screening in asymptomatic first‐degree relatives of incident CRC cases in 20 families with FCCTX, we compared cancer incidence and survival in 79 males and 83 females, assumed to be at 50% risk of inheriting a genetic CRC susceptibility factor, who entered screening to an unscreened control group from the families, matched for age at entry into screening and for sex. Results In males, median age at entry into screening was 44.8 years, median follow‐up 12.4 years, 12% developed CRC, and 46% died after 30 years of follow‐up. Compared to the unscreened group, relative risk of CRC was 0.27 (95% confidence intervals (CI) 0.10–0.71). In screened females, comparable results were 44.5 years at entry, 11.2 years of follow‐up, 7.1% developed CRC, and 7.2% died after 30 years of follow‐up. The relative risk of CRC compared to the unscreened group was 0.19 (95% CI 0.07–0.48). Conclusion Primary prevention screening colonoscopy in asymptomatic family members significantly decreased the risk of CRC in FCCTX.
Collapse
Affiliation(s)
- Elizabeth Hatfield
- Clinical Epidemiology Unit, Memorial University, St. John's, Newfoundland, Canada
| | - Jane S Green
- Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Michael O Woods
- Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Geoff Warden
- Clinical Epidemiology Unit, Memorial University, St. John's, Newfoundland, Canada
| | - Patrick S Parfrey
- Clinical Epidemiology Unit, Memorial University, St. John's, Newfoundland, Canada
| |
Collapse
|
|
17
|
Yu G, Liao J, Wu J, Ding J, Zhang L. The proliferation of colorectal cancer cells is suppressed by silencing of EIF3H. Biosci Biotechnol Biochem 2018; 82:1694-1701. [PMID: 30022709 DOI: 10.1080/09168451.2018.1484271] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
ABSTRACT
Colorectal cancer is one of the most common causes of cancer-related deaths worldwide. Eukaryotic translation initiation factor 3, subunit H (EIF3H) is a subunit of EIF3, which is involved in mRNA recruitment and ribosomal complex disassembly and is known to be a driver of cell proliferation and survival in cancer. To investigate its function in colorectal cancer, the Oncomine database was used to evaluate the expression of EIF3H in human colorectal cancer and normal tissues. Then, we constructed a Lentivirus shorthair EIF3H vector (Lv-shEIF3H) to silence EIF3H expression in the colorectal cancer cell lines HCT116 and SW1116. We observed impaired cell growth and colony formation in these silenced cell lines. In addition, we showed that EIF3H knock-down led to cell apoptosis. In conclusion, EIF3H plays key roles in the apoptosis in colorectal cancer cells, which suggests EIF3H as a potential diagnostic biomarker in colorectal cancer.
Collapse
Affiliation(s)
- Genhua Yu
- Department of Radiotherapy, Huzhou Central Hospital, Zhejiang, China
| | - Jiaqun Liao
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Junlan Wu
- Department of Oncology, Shanghai Armed Police Corps Hospital, Shanghai, China
| | - Jun Ding
- Department of colorectal surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lin Zhang
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
18
|
Li W, Zhao LZ, Ma DW, Wang DZ, Shi L, Wang HL, Dong M, Zhang SY, Cao L, Zhang WH, Zhang XP, Zhang QH, Yu L, Qin H, Wang XM, Chen SLS. Predicting the risk for colorectal cancer with personal characteristics and fecal immunochemical test. Medicine (Baltimore) 2018; 97:e0529. [PMID: 29718843 PMCID: PMC6392567 DOI: 10.1097/md.0000000000010529] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
We aimed to predict colorectal cancer (CRC) based on the demographic features and clinical correlates of personal symptoms and signs from Tianjin community-based CRC screening data.A total of 891,199 residents who were aged 60 to 74 and were screened in 2012 were enrolled. The Lasso logistic regression model was used to identify the predictors for CRC. Predictive validity was assessed by the receiver operating characteristic (ROC) curve. Bootstrapping method was also performed to validate this prediction model.CRC was best predicted by a model that included age, sex, education level, occupations, diarrhea, constipation, colon mucosa and bleeding, gallbladder disease, a stressful life event, family history of CRC, and a positive fecal immunochemical test (FIT). The area under curve (AUC) for the questionnaire with a FIT was 84% (95% CI: 82%-86%), followed by 76% (95% CI: 74%-79%) for a FIT alone, and 73% (95% CI: 71%-76%) for the questionnaire alone. With 500 bootstrap replications, the estimated optimism (<0.005) shows good discrimination in validation of prediction model.A risk prediction model for CRC based on a series of symptoms and signs related to enteric diseases in combination with a FIT was developed from first round of screening. The results of the current study are useful for increasing the awareness of high-risk subjects and for individual-risk-guided invitations or strategies to achieve mass screening for CRC.
Collapse
Affiliation(s)
- Wen Li
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Li-Zhong Zhao
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Dong-Wang Ma
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - De-Zheng Wang
- Non-Communicable Disease Control and Prevention, Tianjin Centers for Disease Control and Prevention
| | - Lei Shi
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Hong-Lei Wang
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Mo Dong
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Shu-Yi Zhang
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Lei Cao
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Wei-Hua Zhang
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Xi-Peng Zhang
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Qing-Huai Zhang
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Lin Yu
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Hai Qin
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Union Medical Center
| | - Xi-Mo Wang
- Department of Epidemiology, Tianjin Colorectal and Anal Disease Research Institute
- Department of Gastroenterology, Tianjin Nankai Hospital, Tianjin, P.R. China
| | - Sam Li-Sheng Chen
- School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taiwan
| |
Collapse
|
|
19
|
Chen E, Xu X, Liu T. Hereditary Nonpolyposis Colorectal Cancer and Cancer Syndromes: Recent Basic and Clinical Discoveries. JOURNAL OF ONCOLOGY 2018; 2018:3979135. [PMID: 29849630 PMCID: PMC5937448 DOI: 10.1155/2018/3979135] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 03/12/2018] [Accepted: 03/20/2018] [Indexed: 12/14/2022]
Abstract
Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer, suggesting that CRCs may result from a heritable component. Despite the availability of current gene-identification techniques, only 5% of all CRCs emerge from well-identifiable inherited causes for predisposition, including polyposis and nonpolyposis syndromes. Hereditary nonpolyposis colorectal cancer represents a large proportion of cases, and robustly affected patients are at increased risk for early onset, synchronous, and metachronous colorectal malignancies and extracolonic malignancies. HNPCC encompasses several cancer syndromes, such as Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X, which have remarkable clinical presentations and overlapping genetic profiles that make clinical diagnosis a challenging task. Therefore, distinguishing between the HNPCC disorders is crucial for physicians as an approach to tailor different recommendations for patients and their at-risk family members according to the risks for colonic and extracolonic cancer associated with each syndrome. Identification of these potential patients through epidemiological characteristics and new genetic testing can estimate the individual risk, which informs appropriate cancer screening, surveillance, and/or treatment strategies. In the past three years, many appealing and important advances have been made in our understanding of the relationship between HNPCC and CRC-associated syndromes. The knowledge from the genetic profile of cancer syndromes and unique genotype-phenotype profiles in the different syndromes has changed our cognition. Therefore, this review presents and discusses HNPCC and several common nonpolyposis syndromes with respect to molecular phenotype, histopathologic features, and clinical presentation.
Collapse
Affiliation(s)
- Erbao Chen
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaojing Xu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
20
|
Olver I. Bowel cancer screening for women at midlife. Climacteric 2018; 21:243-248. [PMID: 29609509 DOI: 10.1080/13697137.2018.1455823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
In Australia one in 15 women will be diagnosed with colorectal cancer in their lifetime because of the high incidences of lifestyle risk factors. The risk could be reduced by taking aspirin. Evidence-based Clinical Practice Guidelines for the prevention, early detection and management of colorectal cancer produced by Cancer Council Australia and approved by the National Health and Medical Research Council recommended that 'population screening in Australia, directed at those at average risk of colorectal cancer and without relevant symptoms, is immunochemical fecal occult blood testing every 2 years, starting at age 50 years and continuing to age 74 years.' Women at high risk because of family history will need more intense screening. At the current 40% participation rate, it is estimated that biennial screening with fecal immunohistochemical tests (FIT) reduces colorectal cancer incidence by 23% and mortality by 36%. The major adverse effects of screening are the psychological impact of a positive FIT that does not prove to be cancer, or adenomas on colonoscopy (47.7%), and the rare side-effects of colonoscopy of hemorrhage, bleeding or even death. A range of factors that could increase a woman's participation rate includes advice to screen from her general practitioner and more information about the nature of the screening tests.
Collapse
Affiliation(s)
- I Olver
- a Sansom Institute for Health Research , University of South Australia , Adelaide , Australia
| |
Collapse
|
|
21
|
Risk of eighteen genome-wide association study-identified genetic variants for colorectal cancer and colorectal adenoma in Han Chinese. Oncotarget 2018; 7:77651-77663. [PMID: 27769063 PMCID: PMC5363611 DOI: 10.18632/oncotarget.12750] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2015] [Accepted: 10/01/2016] [Indexed: 01/20/2023] Open
Abstract
Background Recent genome-wide association studies (GWAS) identified eighteen single-nucleotide polymorphisms (SNPs) to be significantly associated with the risk of colorectal cancer (CRC). However, overall results of the following replications are inconsistent and little is known about whether these associations also exit in colorectal adenomas (CRA). Methods The SNP genotyping was performed using a Sequenom MassARRAY to investigate the association of these eighteen SNPs with colorectal neoplasm in a case-control study consisted of 1049 colorectal cancers, 283 adenomas, and 1030 controls. Results Two of these SNPs, rs10505477 and rs719725, showed evidence of an association in both CRC and CRA in our study population. Besides, seven SNPs (rs10808555, rs7014346, rs7837328, rs704017, rs11196172, rs4779584, and rs7229639) were significantly associated with CRC, and another one SNP rs11903757 was over-represented in CRA compared with controls. The strongest association was provided by rs11196172 (OR = 2.02, 95% CI = 1.66 - 2.46, P < 0.0001) and rs11903757 (OR = 1.96, 95% CI = 1.28 - 3.00, P = 0.0026). Conclusion These results suggest that some previously reported SNP associations also have impact on CRC and CRA predispositions in the Han Chinese population. A part of genetic risk to CRC is possibly mediated by susceptibility to adenomas.
Collapse
|
|
22
|
Thutkawkorapin J, Mahdessian H, Barber T, Picelli S, von Holst S, Lundin J, Valle L, Kontham V, Liu T, Nilsson D, Jiao X, Lindblom A. Two novel colorectal cancer risk loci in the region on chromosome 9q22.32. Oncotarget 2018. [PMID: 29541405 PMCID: PMC5834248 DOI: 10.18632/oncotarget.24340] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Highly penetrant cancer syndromes account for less than 5% of all cases with familial colorectal cancer (CRC), and other genetic contribution explains the majority of the genetic contribution to CRC. A CRC susceptibility locus on chromosome 9q has been suggested. In this study, families where risk of CRC was linked to the region, were used to search for predisposing mutations in all genes in the region. No disease-causing mutation was found. Next, haplotype association studies were performed in the region, comparing Swedish CRC cases (2664) and controls (4782). Two overlapping haplotypes were suggested. One 10-SNP haplotype was indicated in familial CRC (OR 1.4, p = 0.00005) and one 25-SNP haplotype was indicated in sporadic CRC (OR 2.2, p = 0.0000012). The allele frequencies of the 10-SNP and the 25-SNP haplotypes were 13.7% and 2.5% respectively and both included one RNA, RP11-332M4.1 and RP11-l80l4.2, in the non-overlapping regions. The sporadic 25-SNP haplotype could not be studied further, but the familial 10-SNP haplotype was analyzed in 61 additional CRC families, and 6 of them were informative for all markers and had the risk haplotype. Targeted sequencing of the 10-SNP region in the linked families identified one variant in RP11-332M4.1, suggestive to confer the increased CRC risk on this haplotype. Our results support the presence of two loci at 9q22.32, each with one RNA as the putative cause of increased CRC risk. These RNAs could exert their effect through the same, or different, genes/pathways, possibly through the regulation of neighboring genes, such as PTCH1, FANCC, DKFZP434H0512, ERCC6L2 or the processed transcript LINC00046.
Collapse
Affiliation(s)
- Jessada Thutkawkorapin
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Hovsep Mahdessian
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Tom Barber
- The Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
| | - Simone Picelli
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Susanna von Holst
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Johanna Lundin
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Barcelona 08908, Spain
| | - Vinaykumar Kontham
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Tao Liu
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Daniel Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Xiang Jiao
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-17176, Sweden
| |
Collapse
|
|
23
|
Mushtaq M, Ali RH, Kashuba V, Klein G, Kashuba E. S18 family of mitochondrial ribosomal proteins: evolutionary history and Gly132 polymorphism in colon carcinoma. Oncotarget 2018; 7:55649-55662. [PMID: 27489352 PMCID: PMC5342443 DOI: 10.18632/oncotarget.10957] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 07/10/2016] [Indexed: 01/12/2023] Open
Abstract
S18 family of mitochondrial ribosomal proteins (MRPS18, S18) consists of three members, S18-1 to -3. Earlier, we found that overexpression of S18-2 protein resulted in immortalization and eventual transformation of primary rat fibroblasts. The S18-1 and -3 have not exhibited such abilities. To understand the differences in protein properties, the evolutionary history of S18 family was analyzed. The S18-3, followed by S18-1 and S18-2 emerged as a result of ancient gene duplication in the root of eukaryotic species tree, followed by two metazoan-specific gene duplications. However, the most conserved metazoan S18 homolog is the S18-1; it shares the most sequence similarity with S18 proteins of bacteria and of other eukaryotic clades. Evolutionarily conserved residues of S18 proteins were analyzed in various cancers. S18-2 is mutated at a higher rate, compared with S18-1 and -3 proteins. Moreover, the evolutionarily conserved residue, Gly132 of S18-2, shows genetic polymorphism in colon adenocarcinomas that was confirmed by direct DNA sequencing.Concluding, S18 family represents the yet unexplored important mitochondrial ribosomal proteins.
Collapse
Affiliation(s)
- Muhammad Mushtaq
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, S-17177, Sweden
| | - Raja Hashim Ali
- KTH Royal Institute of Technology, Science for Life Laboratory, School of Computer Science and Communication, Solna, SE-17 177, Sweden
| | - Vladimir Kashuba
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, S-17177, Sweden.,Institute of Molecular Biology and Genetics of NASU, Kyiv, 03680, Ukraine
| | - George Klein
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, S-17177, Sweden
| | - Elena Kashuba
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, S-17177, Sweden.,R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NASU, Kyiv, 03022, Ukraine
| |
Collapse
|
|
24
|
Abe M, Ito H, Oze I, Nomura M, Ogawa Y, Matsuo K. The more from East-Asian, the better: risk prediction of colorectal cancer risk by GWAS-identified SNPs among Japanese. J Cancer Res Clin Oncol 2017; 143:2481-2492. [PMID: 28849422 DOI: 10.1007/s00432-017-2505-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Accepted: 08/16/2017] [Indexed: 12/24/2022]
Abstract
BACKGROUND Little is known about the difference of genetic predisposition for CRC between ethnicities; however, many genetic traits common to colorectal cancer have been identified. This study investigated whether more SNPs identified in GWAS in East Asian population could improve the risk prediction of Japanese and explored possible application of genetic risk groups as an instrument of the risk communication. METHODS 558 Patients histologically verified colorectal cancer and 1116 first-visit outpatients were included for derivation study, and 547 cases and 547 controls were for replication study. Among each population, we evaluated prediction models for the risk of CRC that combined the genetic risk group based on SNPs from GWASs in European-population and a similarly developed model adding SNPs from GWASs in East Asian-population. We examined whether adding East Asian-specific SNPs would improve the discrimination. RESULTS Six SNPs (rs6983267, rs4779584, rs4444235, rs9929218, rs10936599, rs16969681) from 23 SNPs by European-based GWAS and five SNPs (rs704017, rs11196172, rs10774214, rs647161, rs2423279) among ten SNPs by Asian-based GWAS were selected in CRC risk prediction model. Compared with a 6-SNP-based model, an 11-SNP model including Asian GWAS-SNPs showed improved discrimination capacity in Receiver operator characteristic analysis. A model with 11 SNPs resulted in statistically significant improvement in both derivation (P = 0.0039) and replication studies (P = 0.0018) compared with six SNP model. We estimated cumulative risk of CRC by using genetic risk group based on 11 SNPs and found that the cumulative risk at age 80 is approximately 13% in the high-risk group while 6% in the low-risk group. CONCLUSION We constructed a more efficient CRC risk prediction model with 11 SNPs including newly identified East Asian-based GWAS SNPs (rs704017, rs11196172, rs10774214, rs647161, rs2423279). Risk grouping based on 11 SNPs depicted lifetime difference of CRC risk. This might be useful for effective individualized prevention for East Asian.
Collapse
Affiliation(s)
- Makiko Abe
- Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, 812-8582, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, 812-8582, Japan
| | - Hidemi Ito
- Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
- Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan
| | - Isao Oze
- Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
| | - Masatoshi Nomura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, 812-8582, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka, 812-8582, Japan
- Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Keitaro Matsuo
- Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.
- Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan.
| |
Collapse
|
|
25
|
Raskin L, Guo Y, Du L, Clendenning M, Rosty C, Colon Cancer Family Registry (CCFR), Lindor NM, Gruber SB, Buchanan DD. Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort. Oncotarget 2017; 8:93450-93463. [PMID: 29212164 PMCID: PMC5706810 DOI: 10.18632/oncotarget.18596] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 04/19/2017] [Indexed: 01/07/2023] Open
Abstract
The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation sequencing (NGS) can be prohibitively expensive for studies requiring large samples sizes. The aim of the study was to identify rare single nucleotide variants and small indels in 40 established or candidate CRC susceptibility genes in 1,046 familial CRC cases (including both MSS and MSI-H tumor subtypes) and 1,006 unrelated controls from the Colon Cancer Family Registry Cohort using a robust and cost-effective DNA pooling NGS strategy. We identified 264 variants in 38 genes that were observed only in cases, comprising either very rare (minor allele frequency <0.001) or not previously reported (n=90, 34%) in reference databases, including six stop-gain, three frameshift, and 255 non-synonymous variants predicted to be damaging. We found novel germline mutations in established CRC genes MLH1, APC, and POLE, and likely pathogenic variants in cancer susceptibility genes BAP1, CDH1, CHEK2, ENG, and MSH3. For the candidate CRC genes, we identified likely pathogenic variants in the helicase domain of POLQ and in the LRIG1, SH2B3, and NOS1 genes and present their clinicopathological characteristics. Using a DNA pooling NGS strategy, we identified novel germline mutations in established CRC susceptibility genes in familial CRC cases. Further studies are required to support the role of POLQ, LRIG1, SH2B3 and NOS1 as CRC susceptibility genes.
Collapse
Affiliation(s)
- Leon Raskin
- Division of Epidemiology, School of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN, USA
| | - Yan Guo
- Center for Quantitative Sciences, Vanderbilt University Medical Center and Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN, USA
| | - Liping Du
- Center for Quantitative Sciences, Vanderbilt University Medical Center and Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN, USA
| | - Mark Clendenning
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
| | - Christophe Rosty
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
- Envoi Specialist Pathologists, Herston, Queensland, Australia
- University of Queensland, School of Medicine, Herston, Queensland, Australia
| | - Colon Cancer Family Registry (CCFR)
- Division of Epidemiology, School of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN, USA
- Center for Quantitative Sciences, Vanderbilt University Medical Center and Vanderbilt Ingram Comprehensive Cancer Center, Nashville, TN, USA
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
- Envoi Specialist Pathologists, Herston, Queensland, Australia
- University of Queensland, School of Medicine, Herston, Queensland, Australia
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA
- USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
- Genetic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Noralane M. Lindor
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA
| | - Stephen B. Gruber
- USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
- University of Queensland, School of Medicine, Herston, Queensland, Australia
- Genetic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| |
Collapse
|
|
26
|
Sud A, Kinnersley B, Houlston RS. Genome-wide association studies of cancer: current insights and future perspectives. Nat Rev Cancer 2017; 17:692-704. [PMID: 29026206 DOI: 10.1038/nrc.2017.82] [Citation(s) in RCA: 259] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Genome-wide association studies (GWAS) provide an agnostic approach for investigating the genetic basis of complex diseases. In oncology, GWAS of nearly all common malignancies have been performed, and over 450 genetic variants associated with increased risks have been identified. As well as revealing novel pathways important in carcinogenesis, these studies have shown that common genetic variation contributes substantially to the heritable risk of many common cancers. The clinical application of GWAS is starting to provide opportunities for drug discovery and repositioning as well as for cancer prevention. However, deciphering the functional and biological basis of associations is challenging and is in part a barrier to fully unlocking the potential of GWAS.
Collapse
Affiliation(s)
- Amit Sud
- Division of Genetics and Epidemiology, The Institute of Cancer Research
| | - Ben Kinnersley
- Division of Genetics and Epidemiology, The Institute of Cancer Research
| | - Richard S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London SM2 5NG, UK
| |
Collapse
|
|
27
|
Schubert SA, Ruano D, Elsayed FA, Boot A, Crobach S, Sarasqueta AF, Wolffenbuttel B, van der Klauw MM, Oosting J, Tops CM, van Eijk R, Vasen HFA, Vossen RHAM, Nielsen M, Castellví-Bel S, Ruiz-Ponte C, Tomlinson I, Dunlop MG, Vodicka P, Wijnen JT, Hes FJ, Morreau H, de Miranda NFCC, Sijmons RH, van Wezel T. Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia. Br J Cancer 2017; 117:1215-1223. [PMID: 28742792 PMCID: PMC5589990 DOI: 10.1038/bjc.2017.240] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 05/31/2017] [Accepted: 06/30/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders. METHODS Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level. RESULTS Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2-42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues. CONCLUSIONS Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.
Collapse
Affiliation(s)
- Stephanie A Schubert
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Dina Ruano
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Fadwa A Elsayed
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Arnoud Boot
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Stijn Crobach
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Arantza Farina Sarasqueta
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Bruce Wolffenbuttel
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands
| | - Melanie M van der Klauw
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands
| | - Jan Oosting
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Carli M Tops
- Department of Clinical Genetics, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Ronald van Eijk
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Hans FA Vasen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Rolf HAM Vossen
- Department of Human Genetics, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Maartje Nielsen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Sergi Castellví-Bel
- Department of Gastroenterology, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Catalonia 08036, Spain
| | - Clara Ruiz-Ponte
- Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica-USC, Instituto de Investigación Sanitaria de Santiago (IDIS), Centro de Investigación en Red de Enfermedades Raras (CIBERER), Santiago de Compostela 15706, Spain
| | - Ian Tomlinson
- Oxford Centre for Cancer Gene Research, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Malcolm G Dunlop
- Colon Cancer Genetics Group, MRC Human Genetics Unit, The University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
| | - Pavel Vodicka
- Institute of Experimental Medicine, Institute of Biology and Medical Genetics, Prague 142 00, Czech Republic
| | - Juul T Wijnen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Frederik J Hes
- Department of Clinical Genetics, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Hans Morreau
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Noel FCC de Miranda
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| | - Rolf H Sijmons
- Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen 9700 RB, The Netherlands
| | - Tom van Wezel
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden 2300 RC, The Netherlands
| |
Collapse
|
|
28
|
Graff RE, Möller S, Passarelli MN, Witte JS, Skytthe A, Christensen K, Tan Q, Adami HO, Czene K, Harris JR, Pukkala E, Kaprio J, Giovannucci E, Mucci LA, Hjelmborg JB. Familial Risk and Heritability of Colorectal Cancer in the Nordic Twin Study of Cancer. Clin Gastroenterol Hepatol 2017; 15:1256-1264. [PMID: 28130150 PMCID: PMC5522647 DOI: 10.1016/j.cgh.2016.12.041] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Revised: 12/05/2016] [Accepted: 12/29/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We analyzed data from twins to determine how much the familial risk of colorectal cancer can be attributed to genetic factors vs environment. We also examined whether heritability is distinct for colon vs rectal cancer, given evidence of distinct etiologies. METHODS Our data set included 39,990 monozygotic and 61,443 same-sex dizygotic twins from the Nordic Twin Study of Cancer. We compared each cancer's risk in twins of affected co-twins relative to the cohort risk (familial risk ratio [FRR]). We then estimated the proportion of variation in risk that could be attributed to genetic factors (heritability). RESULTS From earliest registration in 1943 through 2010, there were 1861 individuals diagnosed with colon cancer and 1268 diagnosed with rectal cancer. Monozygotic twins of affected co-twins had an FRR for colorectal cancer of 3.1 (95% confidence interval [CI], 2.4-3.8) relative to the cohort risk. Dizygotic twins of affected co-twins had an FRR for colorectal cancer of 2.2 (95% CI, 1.7-2.7). We estimated that 40% (95% CI, 33%-48%) of the variation in colorectal cancer risk could be attributed to genetic factors; unique environment only accounted for the remaining liability. For colon cancer, the FRR was 3.3 (95% CI, 2.1-4.5) for monozygotic twins and 2.6 (95% CI, 1.7-3.5) for dizygotic twins. For rectal cancer, comparable estimates were 3.3 (95% CI, 1.5-5.1) for monozygotic twins and 2.6 (95% CI, 1.2-4.0) for dizygotic twins. Heritability estimates for colon and rectal cancer were 16% (95% CI, 0-46%) and 15% (95% CI, 0-50%), common environment estimates were 15% (95% CI, 0-38%) and 11% (95% CI, 0-38%), and unique environment estimates were 68% (95% CI, 57%-79%) and 75% (95% CI, 61%-88%), respectively. CONCLUSIONS Interindividual genetic differences could account for 40% of the variation in susceptibility to colorectal cancer; risk for colon and rectal cancers might have less of a genetic component than risk for colorectal cancer. Siblings, and particularly monozygotic co-twins, of individuals with colon or rectal cancer should consider personalized screening.
Collapse
Affiliation(s)
- Rebecca E. Graff
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA,Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - Sören Möller
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark,The Danish Twin Registry, University of Southern Denmark, Denmark
| | - Michael N. Passarelli
- Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA
| | - John S. Witte
- Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA,Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA,Department of Urology, University of California San Francisco, San Francisco, CA, USA,Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Axel Skytthe
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark,The Danish Twin Registry, University of Southern Denmark, Denmark
| | - Kaare Christensen
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark,The Danish Twin Registry, University of Southern Denmark, Denmark
| | - Qihua Tan
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark,The Danish Twin Registry, University of Southern Denmark, Denmark
| | - Hans-Olov Adami
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jennifer R. Harris
- Department of Genetics and Bioinformatics, Norwegian Institute of Public Health, Oslo, Norway
| | - Eero Pukkala
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland,School of Health Sciences, University of Tampere, Tampere, Finland
| | - Jaakko Kaprio
- University of Helsinki, Department of Public Health, Helsinki, Finland,National Institute for Health and Welfare, Department of Health, Helsinki, Finland,University of Helsinki, Institute for Molecular Medicine (FIMM), Helsinki, Finland
| | - Edward Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA,Department of Nutrition, Harvard School of Public Health, Boston, MA, USA,Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Lorelei A. Mucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA,Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA,Centre for Public Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Jacob B. Hjelmborg
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark,The Danish Twin Registry, University of Southern Denmark, Denmark
| |
Collapse
|
|
29
|
Recent Discoveries in the Genetics of Familial Colorectal Cancer and Polyposis. Clin Gastroenterol Hepatol 2017; 15:809-819. [PMID: 27712984 DOI: 10.1016/j.cgh.2016.09.148] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 09/26/2016] [Accepted: 09/27/2016] [Indexed: 02/07/2023]
Abstract
The development of genome-wide massively parallel sequencing, ie, whole-genome and whole-exome sequencing, and copy number approaches has raised high expectations for the identification of novel hereditary colorectal cancer genes. Although relatively successful for genes causing adenomatous polyposis syndromes, both autosomal dominant and recessive, the identification of genes associated with hereditary non-polyposis colorectal cancer has proven extremely challenging, mainly because of the absence of major high-penetrance genes and the difficulty in demonstrating the functional impact of the identified variants and their causal association with tumor development. Indeed, most, if not all, novel candidate non-polyposis colorectal cancer genes identified so far lack corroborative data in independent studies. Here we review the novel hereditary colorectal cancer genes and syndromes identified and the candidate genes proposed in recent years as well as discuss the challenges we face.
Collapse
|
|
30
|
Sheng S, Chen Y, Shen Z. Correlation between polymorphism of vitamin D receptor TaqI and susceptibility to colorectal cancer: A meta-analysis. Medicine (Baltimore) 2017; 96:e7242. [PMID: 28658114 PMCID: PMC5500036 DOI: 10.1097/md.0000000000007242] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 05/18/2017] [Accepted: 05/19/2017] [Indexed: 12/31/2022] Open
Abstract
The meta-analysis aimed to investigate the correlation between the polymorphism of the vitamin D receptor (VDR) TaqI and susceptibility of colorectal cancer.Studies were extracted from the electronic databases of PubMed and Embase. The balance of heredity was estimated by the Hardy-Weinberg equilibrium test, and heterogeneity was assessed by Cochran Q statistics and I test. Four assessed models, namely additive (t vs T), dominant (Tt + tt vs TT), recessive (tt vs Tt + TT), and codominant (Tt vs TT and tt vs TT), were used to evaluate the correlations and the effective results were measured as odds ratio (OR) with 95% confidence interval (CI).A total of 14 studies, including 4632 patients and 5086 controls, were enrolled in this meta-analysis. With no significant heterogeneities observed among the 4 models, the fixed-effect model was used to examine the pooled effect value. There were no significant differences among t vs T (OR = 1.01; 95% CI, 0.94-1.09; P = .70), Tt + tt vs TT (OR = 1.05; 95% CI, 0.96-1.15; P = .32), tt vs Tt + TT (OR = 1.01; 95% CI, 0.87-1.17; P = .92), Tt vs TT (OR = 1.03; 95% CI, 0.93-1.13; P = .62), and tt vs TT (OR = 1.00; 95% CI, 0.85-1.17; P = .98) with respect to increasing CRC frequency.No evidence showed that TaqI polymorphisms were significantly associated with susceptibility to CRC.
Collapse
|
|
31
|
Modulation of Colorectal Cancer Risk by Polymorphisms in 51Gln/His, 64Ile/Val, and 148Asp/Glu of APEX Gene; 23Gly/Ala of XPA Gene; and 689Ser/Arg of ERCC4 Gene. Gastroenterol Res Pract 2017; 2017:3840243. [PMID: 28386271 PMCID: PMC5366231 DOI: 10.1155/2017/3840243] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 12/01/2016] [Accepted: 12/07/2016] [Indexed: 12/14/2022] Open
Abstract
Polymorphisms in DNA repair genes may affect the activity of the BER (base excision repair) and NER (nucleotide excision repair) systems. Using DNA isolated from blood taken from patients (n = 312) and a control group (n = 320) with CRC, we have analyzed the polymorphisms of selected DNA repair genes and we have demonstrated that genotypes 51Gln/His and 148Asp/Glu of APEX gene and 23Gly/Ala of XPA gene may increase the risk of colorectal cancer. At the same time analyzing the gene-gene interactions, we suggest the thesis that the main factor to be considered when analyzing the impact of polymorphisms on the risk of malignant transformation should be intergenic interactions. Moreover, we are suggesting that some polymorphisms may have impact not only on the malignant transformation but also on the stage of the tumor.
Collapse
|
|
32
|
Win AK, Jenkins MA, Dowty JG, Antoniou AC, Lee A, Giles GG, Buchanan DD, Clendenning M, Rosty C, Ahnen DJ, Thibodeau SN, Casey G, Gallinger S, Le Marchand L, Haile RW, Potter JD, Zheng Y, Lindor NM, Newcomb PA, Hopper JL, MacInnis RJ. Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 2017; 26:404-412. [PMID: 27799157 PMCID: PMC5336409 DOI: 10.1158/1055-9965.epi-16-0693] [Citation(s) in RCA: 335] [Impact Index Per Article: 41.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 10/19/2016] [Accepted: 10/26/2016] [Indexed: 12/26/2022] Open
Abstract
Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known.Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component.Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404-12. ©2016 AACR.
Collapse
Affiliation(s)
- Aung Ko Win
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - James G Dowty
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Antonis C Antoniou
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Andrew Lee
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Daniel D Buchanan
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Mark Clendenning
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Christophe Rosty
- Queensland Institute of Medical Research, Brisbane, Queensland, Australia
| | - Dennis J Ahnen
- University of Colorado School of Medicine, Denver, Colorado
| | - Stephen N Thibodeau
- Molecular Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Graham Casey
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | | | - Robert W Haile
- Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, California
| | - John D Potter
- School of Public Health, University of Washington, Seattle, Washington
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Centre for Public Health Research, Massey University, Wellington, New Zealand
| | - Yingye Zheng
- School of Public Health, University of Washington, Seattle, Washington
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Noralane M Lindor
- Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona
| | - Polly A Newcomb
- School of Public Health, University of Washington, Seattle, Washington
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Robert J MacInnis
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia
| |
Collapse
|
|
33
|
Park C, Kim JI, Hong SN, Jung HM, Kim TJ, Lee S, Kim SJ, Kim HC, Kim DH, Cho B, Park JH, Sung J, Lee DS, Kang M, Son HJ, Kim YH. A copy number variation in PKD1L2 is associated with colorectal cancer predisposition in korean population. Int J Cancer 2016; 140:86-94. [PMID: 27605020 DOI: 10.1002/ijc.30421] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 08/15/2016] [Indexed: 12/30/2022]
Abstract
Recently reported genome-wide association studies have identified more than 20 common low-penetrance colorectal cancer (CRC) susceptibility loci. Recent studies have reported that copy number variations (CNVs) are considered important human genomic variants related to cancer, while the contribution of CNVs remains unclear. We performed array comparative genomic hybridization (aCGH) in 36 CRC patients and 47 controls. Using breakpoint PCR, we confirmed the breakpoint of the PKD1L2 deletion region. High frequency of PKD1L2 CNV was observed in CRC cases. We validated the association between PKD1L2 variation and CRC risk in 1,874 cases and 2,088 controls (OR = 1.44, 95% CI = 1.04-1.98, p = 0.028). Additionally, PKD1L2 CNV is associated with increased CRC risk in patients younger than 50 years (OR = 2.14, 95% CI 1.39-3.30, p = 5.8 × 10-4 ). In subgroup analysis according to body mass index (BMI), we found that the CN loss of PKD1L2 with BMI above or equal to 25 exhibited a significant increase in CRC risk (OR = 2.29, 95% CI 1.29-4.05, p = 0.005). PKD1L2 CNV with BMI above or equal to 25 and age below 50 is associated with a remarkably increased risk of colorectal cancer (OR = 5.24, 95% CI 2.36-11.64, p= 4.8 × 10-5 ). Moreover, we found that PKD1L2 variation in obese patients (BMI ≥ 25) was associated with poor survival rate (p = 0.026). Our results suggest that the common PKD1L2 CNV is associated with CRC, and PKD1L2 CNV with high BMI and/or age below 50 exhibited a significant increased risk of CRC. In obese patients, PKD1L2 variation was associated with poor survival.
Collapse
Affiliation(s)
- Changho Park
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.,Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.,Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.,Medical Research Center, Genomic Medicine Institute (GMI), Seoul National University, Seoul, Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Noh Hong
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hey Mi Jung
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Jun Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seungbok Lee
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.,Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.,Medical Research Center, Genomic Medicine Institute (GMI), Seoul National University, Seoul, Korea
| | - Seong Jin Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Duk-Hwan Kim
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Belong Cho
- Department of Family Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jin-Ho Park
- Department of Family Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Joohon Sung
- Complex Disease and Genome Epidemiology Branch, Department of Epidemiology, School of Public Health, Seoul National University, Seoul, Korea
| | - Dong-Sung Lee
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.,Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.,Medical Research Center, Genomic Medicine Institute (GMI), Seoul National University, Seoul, Korea
| | - Mingon Kang
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Jung Son
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| |
Collapse
|
|
34
|
Radice P, Pharoah PDP, Peterlongo P. Personalized testing based on polygenic risk score is promising for more efficient population-based screening programs for common oncological diseases. Ann Oncol 2016; 27:369-70. [PMID: 26782956 DOI: 10.1093/annonc/mdw003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Affiliation(s)
- P Radice
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - P D P Pharoah
- Department of Public Health and Primary Care, Department of Oncology, University of Cambridge, Cambridge, UK
| | - P Peterlongo
- IFOM, The FIRC Institute of Molecular Oncology, Milan, Italy
| |
Collapse
|
|
35
|
Frampton MJE, Law P, Litchfield K, Morris EJ, Kerr D, Turnbull C, Tomlinson IP, Houlston RS. Implications of polygenic risk for personalised colorectal cancer screening. Ann Oncol 2016; 27:429-34. [PMID: 26578737 DOI: 10.1093/annonc/mdv540] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 10/19/2015] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND We modelled the utility of applying a personalised screening approach for colorectal cancer (CRC) when compared with standard age-based screening. In this personalised screening approach, eligibility is determined by absolute risk which is calculated from age and polygenic risk score (PRS), where the PRS is relative risk attributable to common genetic variation. In contrast, eligibility in age-based screening is determined only by age. DESIGN We calculated absolute risks of CRC from UK population age structure, incidence and mortality rate data, and a PRS distribution which we derived for the 37 known CRC susceptibility variants. We compared the number of CRC cases potentially detectable by personalised and age-based screening. Using Genome-Wide Complex Trait Analysis to calculate the heritability attributable to common variation, we repeated the analysis assuming all common CRC risk variants were known. RESULTS Based on the known CRC variants, individuals with a PRS in the top 1% have a 2.9-fold increased CRC risk over the population median. Compared with age-based screening (aged 60: 10-year absolute risk 1.96% in men, 1.19% in women, as per the UK NHS National Bowel Screening Programme), personalised screening of individuals aged 55-69 at the same risk would lead to 16% fewer men and 17% fewer women being eligible for screening with 10% and 8%, respectively, fewer screen-detected cases. If all susceptibility variants were known, individuals with a PRS in the top 1% would have an estimated 7.7-fold increased risk. Personalised screening would then result in 26% fewer men and women being eligible for screening with 7% and 5% fewer screen-detected cases. CONCLUSION Personalised screening using PRS has the potential to optimise population screening for CRC and to define those likely to maximally benefit from chemoprevention. There are however significant technical and operational details to be addressed before any such programme is introduced.
Collapse
Affiliation(s)
- M J E Frampton
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London
| | - P Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London
| | - K Litchfield
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London
| | - E J Morris
- Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds
| | - D Kerr
- Oxford Cancer Centre, Department of Oncology, University of Oxford, Churchill Hospital, Oxford
| | - C Turnbull
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London William Harvey Research Institute, Queen Mary University London, London
| | - I P Tomlinson
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - R S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London
| |
Collapse
|
|
36
|
Walcott FL, Patel J, Lubet R, Rodriguez L, Calzone KA. Hereditary cancer syndromes as model systems for chemopreventive agent development. Semin Oncol 2016; 43:134-145. [PMID: 26970132 PMCID: PMC10433689 DOI: 10.1053/j.seminoncol.2015.09.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Research in chemoprevention has undergone a shift in emphasis for pragmatic reasons from large, phase III randomized studies to earlier phase studies focused on safety, mechanisms, and utilization of surrogate endpoints such as biomarkers instead of cancer incidence. This transition permits trials to be conducted in smaller populations and at substantially reduced costs while still yielding valuable information. This article will summarize some of the current chemoprevention challenges and the justification for the use of animal models to facilitate identification and testing of chemopreventive agents as illustrated though four inherited cancer syndromes. Preclinical models of inherited cancer syndromes serve as prototypical systems in which chemopreventive agents can be developed for ultimate application to both the sporadic and inherited cancer settings.
Collapse
Affiliation(s)
- Farzana L Walcott
- National Institutes of Health, National Cancer Institute, Division of Cancer Prevention, Bethesda, MD, USA.
| | - Jigar Patel
- National Institutes of Health, National Cancer Institute, Division of Cancer Prevention, Bethesda, MD, USA
| | - Ronald Lubet
- Consultant to National Institutes of Health, National Cancer Institute, Division of Cancer Prevention, Chemopreventive Agent Development Research Group, Bethesda, MD, USA
| | - Luz Rodriguez
- National Institutes of Health, National Cancer Institute, Division of Cancer Prevention, Gastrointestinal & Other Cancers Research, Bethesda, MD, USA
| | - Kathleen A Calzone
- National Institutes of Health, National Cancer Institute, Center for Cancer Research, Genetics Branch, Bethesda, MD, USA.
| |
Collapse
|
|
37
|
Pajares JA, Perea J. Multiple primary colorectal cancer: Individual or familial predisposition? World J Gastrointest Oncol 2015; 7:434-444. [PMID: 26688706 PMCID: PMC4678390 DOI: 10.4251/wjgo.v7.i12.434] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 09/28/2015] [Accepted: 10/20/2015] [Indexed: 02/05/2023] Open
Abstract
Colorectal carcinoma (CRC) is one of the most frequent cancers. Along the surface of the large bowel, several foci of CRC may appear simultaneously or over the time. The development of at least two different tumours has been defined as multiple primary CRC (MPCRC): When more than one tumour is diagnosed at the same time, it is known as synchronous CRC (SCRC), while when a second neoplasm is diagnosed some time after the resection and/or diagnosis of the first lesion, it is called metachronous CRC (MCRC). Multiple issues can promote the development of MPCRC, ranging from different personal factors, such as environmental exposure, to familial predisposition due to hereditary factors. However, most studies do not distinguish this dichotomy. High- and low-pentrance genetic variants are involved in MPCRC. An increased risk for MPCRC has been described in Lynch syndrome, familial adenomatous polyposis, and serrated polyposis. Non-syndromic familial CRCs should also be considered as risk factors for MPCRC. Environmental factors can promote damage to colon mucosae that enable the concurrence of MPCRC. Epigenetics are thought to play a major role in the carcinogenesis of sporadic MPCRC. The methylation state of the DNA depends on multiple environmental factors (e.g., smoking and eating foods cooked at high temperatures), and this can contribute to increasing the MPCRC rate. Certain clinical features may also suggest individual predisposition for MPCRC. Different etiopathogenic factors are suspected to be involved in SCRC and MCRC, and different familial vs individual factors may be implicated. MCRC seems to follow a familial pattern, whereas individual factors are more important in SCRC. Further studies must be carried out to know the molecular basis of risks for MPCRC in order to modify, if necessary, its clinical management, especially from a preventive point of view.
Collapse
|
|
38
|
Ahmed NS, Shafik NM, Elraheem OA, Abou-Elnoeman SEA. Association of paraoxonase-1(Q192R and L55M) gene polymorphisms and activity with colorectal cancer and effect of surgical intervention. Asian Pac J Cancer Prev 2015; 16:803-9. [PMID: 25684529 DOI: 10.7314/apjcp.2015.16.2.803] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a leading cause of cancer-related death. Oxidative DNA damage may contribute to cancer risk and the antioxidant paraoxonase is one endogenous free radical scavenger in the human body which could therefore exert an influeence. PURPOSE Aim of this study was to determine the role of serum arylesterase (ARE) and paraoxonase 1(PON1) activities in CRC patients and to find any association between (PON1) Q192R and L55M gene polymorphisms in CRC patients. Also the serum ARE and PON1 activities in CRC patients will be investigated before and after surgery Materials and Methods: This study involved a total of 50 patients with newly diagnosed CRC and 80 healthy controls. PON1 and ARE activities were determined using an enzymatic spectrophotometric method. PON1 Q192R and L55M gene polymorphisms were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) based restriction fragment analysis. The restriction enzyme AlwI was used to examine the Q192R polymorphism and Hsp92II for the L55M polymorphism. RESULTS Significant differences in the PON1 Q192R polymorphism were found between patients and controls. The Q allele was more frequent in the patient group than in controls, while the R allele was more frequent in the controls. Significant differences were found in the L55M polymorphism. Additionally, there were significant differences in L and M allele frequencies (p=0.001). The serum activities of PON1 and ARE were low in QQ and MM genotype. CONCLUSIONS serum PON1 and ARE activities were significantly lower in CRC patients compared to healthy subjects. The R allele may protect against colorectal cancer.
Collapse
Affiliation(s)
- Nagwa S Ahmed
- Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt E-mail :
| | | | | | | |
Collapse
|
|
39
|
Yao K, Hua L, Wei L, Meng J, Hu J. Correlation Between CASC8, SMAD7 Polymorphisms and the Susceptibility to Colorectal Cancer: An Updated Meta-Analysis Based on GWAS Results. Medicine (Baltimore) 2015; 94:e1884. [PMID: 26579801 PMCID: PMC4652810 DOI: 10.1097/md.0000000000001884] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Genome-wide association studies (GWASs) and a number of case-control studies have suggested that several single nucleotide polymorphisms (SNPs), rs7837328, rs7014346, rs6983267, rs10505477 on CASC8 gene and rs4939827, rs4464148, rs12953717 on SMAD7 gene are significantly correlated with the susceptibility to colorectal cancer (CRC). For the sake of clarifying the association, a meta-analysis was conducted and population heterogeneity was considered in the study.A total of 34 articles including 90 studies (168,471 cases and 163,223 controls) that evaluated the relationship between the CASC8, SMAD7 genes and the risk of CRC under the allelic model were reviewed. Also subgroup analysis was performed by ethnicity (Caucasian, Asian, and African) and all of the analyses were implemented in R 3.2.1 software.Pooled data from the meta-analysis revealed that the A allele of rs7837328, the A allele of rs7014346, the G allele of rs6983267, the A allele of rs10505477, the T allele of rs4939827, the T of rs4464148, and the T of rs12953717 were significantly associated with an increased risk of CRC under the allelic model. Additionally, subgroup analyses of 6 SNPs by ethnicity (rs4464148 excepted) witnessed that the A allele of rs7837328, the G allele of rs6983267, and the T of rs12953717 were notably associated with an increased risk of CRC among Caucasian and Asian. Furthermore, the A allele of rs7014346, the A allele of rs10505477, and the T allele of rs4939827 were significantly related with an elevated risk of CRC only among Caucasian.Our study suggested that for CASC8 gene, SNP of rs7837328 and rs6983267 are risk factors for CRC among both Caucasian and Asian whereas rs7014346 and rs10505477 are risky gene polymorphisms only among Caucasian. For SMAD7 gene, rs4939827 and rs4464148 are risk factors for CRC among Caucasian whereas rs12953717 could elevate the susceptibility to CRC in both Caucasian and Asian.
Collapse
Affiliation(s)
- Kunhou Yao
- From the Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan Province, China (KY, LH, JM, JH); and Department of Digestive Medicine, Huaihe Hospital of Henan University, Kaifeng, Henan Province, China (LW)
| | | | | | | | | |
Collapse
|
|
40
|
Rohlin A, Eiengård F, Lundstam U, Zagoras T, Nilsson S, Edsjö A, Pedersen J, Svensson J, Skullman S, Karlsson BG, Björk J, Nordling M. GREM1 and POLE variants in hereditary colorectal cancer syndromes. Genes Chromosomes Cancer 2015; 55:95-106. [PMID: 26493165 PMCID: PMC5057327 DOI: 10.1002/gcc.22314] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 09/06/2015] [Accepted: 09/10/2015] [Indexed: 02/03/2023] Open
Abstract
Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high-penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy-number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease-causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease-causing mutations in hereditary CRC syndromes.
Collapse
Affiliation(s)
- Anna Rohlin
- Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Frida Eiengård
- Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Ulf Lundstam
- Department of Surgery, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Theofanis Zagoras
- Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Staffan Nilsson
- Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
| | - Anders Edsjö
- Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden.,Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Jan Pedersen
- Department of Medical Genetics, Rikshospitalet, University Hospital, Oslo, Norway
| | | | | | - B Göran Karlsson
- The Swedish NMR-Centre at University of Gothenburg, Gothenburg, Sweden
| | - Jan Björk
- Department of Medicine, The Swedish Polyposis Registry, Karolinska Institute, Stockholm, Sweden
| | - Margareta Nordling
- Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, Gothenburg, Sweden
| |
Collapse
|
|
41
|
Walker JG, Licqurish S, Chiang PPC, Pirotta M, Emery JD. Cancer risk assessment tools in primary care: a systematic review of randomized controlled trials. Ann Fam Med 2015; 13:480-9. [PMID: 26371271 PMCID: PMC4569458 DOI: 10.1370/afm.1837] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 05/14/2015] [Accepted: 06/09/2015] [Indexed: 12/21/2022] Open
Abstract
PURPOSE We conducted this review to identify published randomized controlled trials (RCTs) of cancer risk assessment tools used in primary care and to determine their impact on clinical utility (clinicians), screening uptake (patients), and psychosocial outcomes (patients). METHODS We searched EMBASE, PubMed and the Cochrane databases for RCTs of cancer risk assessment tools in primary care up to May 2014. Only studies set in primary care, with patients eligible for screening, and English-language articles were included. RESULTS The review included 11 trials of 7 risk tools. The trials were heterogeneous with respect to type of tool that was used, type(s) of cancer assessed, and outcomes measured. Evidence suggested risk tools improved patient risk perception, knowledge, and screening intentions, but not necessarily screening behavior. Overall, uptake of a tool was greater if initiated by patients, if used by a dedicated clinician, and when combined with decision support. There was no increase in cancer worry. Health promotion messages within the tool had positive effects on behavior change. Trials were limited by low-recruitment uptake, and the heterogeneity of the findings necessitated a narrative review rather than a meta-analysis. CONCLUSIONS Risk tools may increase intentions to have cancer screening, but additional interventions at the clinician or health system levels may be needed to increase risk-appropriate cancer screening behavior.
Collapse
Affiliation(s)
- J G Walker
- Department of General Practice, Melbourne Medical School, University of Melbourne, Carlton, Australia
| | - S Licqurish
- Department of General Practice, Melbourne Medical School, University of Melbourne, Carlton, Australia
| | - P P C Chiang
- Department of General Practice, Melbourne Medical School, University of Melbourne, Carlton, Australia
| | - M Pirotta
- Department of General Practice, Melbourne Medical School, University of Melbourne, Carlton, Australia
| | - J D Emery
- Department of General Practice, Melbourne Medical School, University of Melbourne, Carlton, Australia General Practice, School of Primary Aboriginal and Rural Health Care, University of Western Australia, Crawley, Australia The Primary Care Unit, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| |
Collapse
|
|
42
|
Bai J, Gao J, Mao Z, Wang J, Li J, Li W, Lei Y, Li S, Wu Z, Tang C, Jones L, Ye H, Lou F, Liu Z, Dong Z, Guo B, Huang XF, Chen SY, Zhang E. Genetic mutations in human rectal cancers detected by targeted sequencing. J Hum Genet 2015; 60:589-96. [PMID: 26134512 DOI: 10.1038/jhg.2015.71] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 05/08/2015] [Accepted: 05/19/2015] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is widespread with significant mortality. Both inherited and sporadic mutations in various signaling pathways influence the development and progression of the cancer. Identifying genetic mutations in CRC is important for optimal patient treatment and many approaches currently exist to uncover these mutations, including next-generation sequencing (NGS) and commercially available kits. In the present study, we used a semiconductor-based targeted DNA-sequencing approach to sequence and identify genetic mutations in 91 human rectal cancer samples. Analysis revealed frequent mutations in KRAS (58.2%), TP53 (28.6%), APC (16.5%), FBXW7 (9.9%) and PIK3CA (9.9%), and additional mutations in BRAF, CTNNB1, ERBB2 and SMAD4 were also detected at lesser frequencies. Thirty-eight samples (41.8%) also contained two or more mutations, with common combination mutations occurring between KRAS and TP53 (42.1%), and KRAS and APC (31.6%). DNA sequencing for individual cancers is of clinical importance for targeted drug therapy and the advantages of such targeted gene sequencing over other NGS platforms or commercially available kits in sensitivity, cost and time effectiveness may aid clinicians in treating CRC patients in the near future.
Collapse
Affiliation(s)
- Jun Bai
- Department of Oncology, People's Hospital of Shaan Xi Province, Xi'an, China
| | - Jinglong Gao
- Central Laboratory, People's Hospital of Shaan Xi Province, Xi'an, China
| | - Zhijun Mao
- Department of General Surgery, People's Hospital of Shaan Xi Province, Xi'an, China
| | - Jianhua Wang
- Department of General Surgery, People's Hospital of Shaan Xi Province, Xi'an, China
| | - Jianhui Li
- Department of Oncology, People's Hospital of Shaan Xi Province, Xi'an, China
| | - Wensheng Li
- Department of Pathology, People's Hospital of Shaan Xi Province, Xi'an, China
| | - Yu Lei
- Department of Oncology, People's Hospital of Shaan Xi Province, Xi'an, China
| | - Shuaishuai Li
- Central Laboratory, People's Hospital of Shaan Xi Province, Xi'an, China
| | - Zhuo Wu
- Central Laboratory, People's Hospital of Shaan Xi Province, Xi'an, China
| | | | - Lindsey Jones
- Norris Comprehensive Cancer Center, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Hua Ye
- San Valley Biotechnology Incorporated, Beijing, China
| | - Feng Lou
- San Valley Biotechnology Incorporated, Beijing, China
| | - Zhiyuan Liu
- San Valley Biotechnology Incorporated, Beijing, China
| | - Zhishou Dong
- San Valley Biotechnology Incorporated, Beijing, China
| | - Baishuai Guo
- San Valley Biotechnology Incorporated, Beijing, China
| | - Xue F Huang
- Norris Comprehensive Cancer Center, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Si-Yi Chen
- Norris Comprehensive Cancer Center, Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Enke Zhang
- Central Laboratory, People's Hospital of Shaan Xi Province, Xi'an, China
| |
Collapse
|
|
43
|
Abstract
Women who report a history of endometrial cancer in a first-degree relative are at increased risk of endometrial cancer, with a hazard ratio of 1.5 to 2.0. Only a minority of patients with familial endometrial cancer have a recognized cancer syndrome. Lynch syndrome is the most common genetic syndrome associated with endometrial cancer and a marked increased risk of colon cancer. Cowden syndrome is a rare condition resulting from a mutation in the tumor suppressor gene phosphatase and tensin homolog. The risk for endometrial cancer is about five times higher in women with Cowden syndrome than in the general population. Recently, a novel germline mutation in the POLD1 gene that encodes the catalytic subunit of DNA polymerase δ was described in several families with multiple cases of endometrial cancer. This mutation is also associated with colorectal cancer. The association between BRCA1 mutations and endometrial cancer has been investigated in several studies; it appears that the risk of endometrial cancer is restricted to women with a history of tamoxifen exposure. In recent years, research has focused on genetic polymorphisms that are associated with endometrial cancer risk. Although many polymorphisms have been identified, their clinical significance is unclear and they have not been adapted for clinical practice.
Collapse
|
|
44
|
Al-Tassan NA, Whiffin N, Hosking FJ, Palles C, Farrington SM, Dobbins SE, Harris R, Gorman M, Tenesa A, Meyer BF, Wakil SM, Kinnersley B, Campbell H, Martin L, Smith CG, Idziaszczyk S, Barclay E, Maughan TS, Kaplan R, Kerr R, Kerr D, Buchannan DD, Ko Win A, Hopper J, Jenkins M, Lindor NM, Newcomb PA, Gallinger S, Conti D, Schumacher F, Casey G, Dunlop MG, Tomlinson IP, Cheadle JP, Houlston RS. A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer. Sci Rep 2015; 5:10442. [PMID: 25990418 PMCID: PMC4438486 DOI: 10.1038/srep10442] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 04/13/2015] [Indexed: 12/17/2022] Open
Abstract
Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.
Collapse
Affiliation(s)
- Nada A. Al-Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O.Box 3354, Riyadh 11211, Saudi Arabia
| | - Nicola Whiffin
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Fay J. Hosking
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Claire Palles
- Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK
| | - Susan M. Farrington
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK
| | - Sara E. Dobbins
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Rebecca Harris
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Maggie Gorman
- Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK
| | - Albert Tenesa
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK
- The Roslin Institute, University of Edinburgh, Easter Bush, Roslin, EH25 9RG, UK
| | - Brian F. Meyer
- Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O.Box 3354, Riyadh 11211, Saudi Arabia
| | - Salma M. Wakil
- Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O.Box 3354, Riyadh 11211, Saudi Arabia
| | - Ben Kinnersley
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Harry Campbell
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, EH8 9AG, UK
| | - Lynn Martin
- Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK
| | - Christopher G. Smith
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Shelley Idziaszczyk
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Ella Barclay
- Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK
| | - Timothy S. Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - Richard Kaplan
- MRC Clinical Trials Unit, Aviation House, 125 Kingsway, London, WC2B 6NH, UK
| | - Rachel Kerr
- Oxford Cancer Centre, Department of Oncology, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, UK
| | - David Kerr
- Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK
| | - Daniel D. Buchannan
- Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The Univers‡ity of Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
| | - John Hopper
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
| | - Mark Jenkins
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
| | - Noralane M. Lindor
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA
| | - Polly A. Newcomb
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Steve Gallinger
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - David Conti
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Fred Schumacher
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Graham Casey
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Malcolm G. Dunlop
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK
| | - Ian P. Tomlinson
- Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK
| | - Jeremy P. Cheadle
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Richard S. Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| |
Collapse
|
|
45
|
Zhou L, Xie J, Gu EL, Huang Y, Qu Y, Xu AP, Zhu Y, Wang H. Common genetic variant on BMP4 contributes to colorectal adenoma and cancer: A meta-analysis based on 15 studies. Cytokine 2015; 72:154-9. [PMID: 25647270 DOI: 10.1016/j.cyto.2014.12.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 12/05/2014] [Accepted: 12/25/2014] [Indexed: 12/21/2022]
Abstract
Epidemiological studies indicate a genetic contribution to colorectal cancer (CRC), but specific genetic variants remain unknown. Genome-wide association studies have identified rs4444235 at BMP4 as a new colorectal cancer (CRC) and colorectal adenoma (CRA) susceptibility locus in populations of European descent. After that, several validation studies have been conducted among various ethnic populations to investigate if the SNP was associated with CRC/CRA, but the results have been inconsistent. To investigate this inconsistency and derive a more precise estimation of the relationship, a meta-analysis involving 54,631 CRC cases, 3995 CRA cases and 88,098 controls from 15 studies was performed. Potential sources of heterogeneity including ethnicity, sample size, study design and endpoint were also assessed. Overall, the summary OR of CRC was 1.06 (95% CI: 1.04-1.08, P<10(-5)). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians (OR=1.07, 95% CI: 1.01-1.12, P=0.01) and Caucasians (OR=1.07, 95% CI: 1.05-1.10, P<10(-5)); while no significant associations were found among African Americans and other ethnic populations in all genetic models. In addition, significant associations were also detected for CRA with per-allele OR of 1.09 (95% CI: 1.03-1.14, P=0.001). Our findings demonstrated that BMP4-rs4444235 is a risk factor associated with increased CRC and CRA susceptibility, but these associations vary in different ethnic populations.
Collapse
Affiliation(s)
- Lei Zhou
- Department of Gastroenterology, Jing'an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing'an Branch), 200040, PR China
| | - Jun Xie
- Department of Gastroenterology, Jing'an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing'an Branch), 200040, PR China
| | - Er-li Gu
- Department of Gastroenterology, Jing'an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing'an Branch), 200040, PR China
| | - Yao Huang
- Department of Gastroenterology, Jing'an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing'an Branch), 200040, PR China
| | - Yan Qu
- Department of Gastroenterology, Jing'an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing'an Branch), 200040, PR China
| | - Ai-Ping Xu
- Department of Gastroenterology, Jing'an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing'an Branch), 200040, PR China
| | - Yin Zhu
- Department of Gastroenterology, Jing'an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing'an Branch), 200040, PR China
| | - Hong Wang
- Department of Gastroenterology, Jing'an District Centre Hospital of Shanghai (Huashan Hospital Fudan University Jing'an Branch), 200040, PR China.
| |
Collapse
|
|
46
|
Dębniak T, Gromowski T, Scott RJ, Gronwald J, Huzarski T, Byrski T, Kurzawski G, Dymerska D, Górski B, Paszkowska-Szczur K, Cybulski C, Serrano-Fernandez P, Lubiński J. Management of ovarian and endometrial cancers in women belonging to HNPCC carrier families: review of the literature and results of cancer risk assessment in Polish HNPCC families. Hered Cancer Clin Pract 2015; 13:3. [PMID: 25606063 PMCID: PMC4300044 DOI: 10.1186/s13053-015-0025-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 01/05/2015] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Over half the cancer deaths in HNPCC families are due to extra-colonic malignancies that include endometrial and ovarian cancers. The benefits of surveillance for gynecological cancers are not yet proven and there is no consensus on the optimal surveillance recommendations for women with MMR mutations. METHODS We performed a systematic review of the literature and evaluated gynecological cancer risk in a series of 631 Polish HNPCC families classified into either Lynch Syndrome (LS, MMR mutations detected) or HNPCC (fulfillment of the Amsterdam or modified Amsterdam criteria). RESULTS Published data clearly indicates no benefit for ovarian cancer screening in contrast to risk reducing surgery. We confirmed a significantly increased risk of OC in Polish LS families (OR = 4,6, p < 0.001) and an especially high risk of OC was found for women under 50 years of age: OR = 32,6, p < 0.0001 (95% CI 12,96-81,87). The cumulative OC risk to 50 year of life was calculated to be 10%. Six out of 19 (32%) early-onset patients from LS families died from OC within 2 years of diagnosis. We confirmed a significantly increased risk of EC (OR = 26, 95% CI 11,36-58,8; p < 0,001). The cumulative risk for EC in Polish LS families was calculated to be 67%. CONCLUSIONS Due to the increased risk of OC and absence of any benefit from gynecological screening reported in the literature it is recommended that prophylactic oophorectomy for female carriers of MMR mutations after 35 year of age should be considered as a risk reducing option. Annual transvaginal ultrasound supported by CA125 or HE4 marker testing should be performed after prophylactic surgery in these women. Due to the high risk of EC it is reasonable to offer, after the age of 35 years, annual clinical gynecologic examinations with transvaginal ultrasound supported by routine aspiration sampling of the endometrium for women from either LS or HNPCC families. An alternative option, which could be taken into consideration for women preferring surgical prevention, is risk reducing total hysterectomy (with bilateral salpingo-oophorectomy) for carriers after childbearing is complete.
Collapse
Affiliation(s)
- Tadeusz Dębniak
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Tomasz Gromowski
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Rodney J Scott
- Discipline of Medical Genetics, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW Australia
| | - Jacek Gronwald
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Tomasz Huzarski
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Tomasz Byrski
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Grzegorz Kurzawski
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Dagmara Dymerska
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Bohdan Górski
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Katarzyna Paszkowska-Szczur
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Cezary Cybulski
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Pablo Serrano-Fernandez
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| | - Jan Lubiński
- Department o f Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland
| |
Collapse
|
|
47
|
Yurgelun MB. Next-generation strategies for hereditary colorectal cancer risk assessment. J Clin Oncol 2015; 33:388-93. [PMID: 25559814 DOI: 10.1200/jco.2014.58.9895] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
|
|
48
|
Quantitative assessment of the influence of common variation rs16892766 at 8q23.3 with colorectal adenoma and cancer susceptibility. Mol Genet Genomics 2014; 290:461-9. [DOI: 10.1007/s00438-014-0928-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2014] [Accepted: 09/19/2014] [Indexed: 01/04/2023]
|
|
49
|
Whiffin N, Hosking FJ, Farrington SM, Palles C, Dobbins SE, Zgaga L, Lloyd A, Kinnersley B, Gorman M, Tenesa A, Broderick P, Wang Y, Barclay E, Hayward C, Martin L, Buchanan DD, Win AK, Hopper J, Jenkins M, Lindor NM, Newcomb PA, Gallinger S, Conti D, Schumacher F, Casey G, Liu T, Campbell H, Lindblom A, Houlston RS, Tomlinson IP, Dunlop MG. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum Mol Genet 2014; 23:4729-37. [PMID: 24737748 PMCID: PMC4133584 DOI: 10.1093/hmg/ddu177] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 04/03/2014] [Accepted: 04/10/2014] [Indexed: 02/06/2023] Open
Abstract
To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC.
Collapse
Affiliation(s)
- Nicola Whiffin
- Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Fay J Hosking
- Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Susan M Farrington
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
| | - Claire Palles
- Wellcome Trust Centre for Human Genetics, Oxford, UK
| | - Sara E Dobbins
- Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Lina Zgaga
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
| | - Amy Lloyd
- Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Ben Kinnersley
- Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Maggie Gorman
- Wellcome Trust Centre for Human Genetics, Oxford, UK
| | - Albert Tenesa
- The Roslin Institute, University of Edinburgh, Easter Bush, Roslin EH25 9RG, UK
| | - Peter Broderick
- Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Yufei Wang
- Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Ella Barclay
- Wellcome Trust Centre for Human Genetics, Oxford, UK
| | - Caroline Hayward
- Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK
| | - Lynn Martin
- Wellcome Trust Centre for Human Genetics, Oxford, UK
| | - Daniel D Buchanan
- Cancer and Population Studies Group, Queensland Institute of Medical Research, Queensland, Australia
| | - Aung Ko Win
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Victoria, Australia
| | - John Hopper
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Victoria, Australia
| | - Mark Jenkins
- Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Victoria, Australia
| | - Noralane M Lindor
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA
| | - Polly A Newcomb
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Steve Gallinger
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - David Conti
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Fred Schumacher
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Graham Casey
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Tao Liu
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Harry Campbell
- Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Richard S Houlston
- Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Ian P Tomlinson
- The Roslin Institute, University of Edinburgh, Easter Bush, Roslin EH25 9RG, UK
| | - Malcolm G Dunlop
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
| |
Collapse
|
|
50
|
Valle L. Genetic predisposition to colorectal cancer: Where we stand and future perspectives. World J Gastroenterol 2014; 20:9828-9849. [PMID: 25110415 PMCID: PMC4123366 DOI: 10.3748/wjg.v20.i29.9828] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 02/10/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
The development of colorectal cancer (CRC) can be influenced by genetic factors in both familial cases and sporadic cases. Familial CRC has been associated with genetic changes in high-, moderate- and low-penetrance susceptibility genes. However, despite the availability of current gene-identification techniques, the genetic causes of a considerable proportion of hereditary cases remain unknown. Genome-wide association studies of CRC have identified a number of common low-penetrance alleles associated with a slightly increased or decreased risk of CRC. The accumulation of low-risk variants may partly explain the familial risk of CRC, and some of these variants may modify the risk of cancer in patients with mutations in high-penetrance genes. Understanding the predisposition to develop CRC will require investigators to address the following challenges: the identification of genes that cause uncharacterized hereditary cases of CRC such as familial CRC type X and serrated polyposis; the classification of variants of unknown significance in known CRC-predisposing genes; and the identification of additional cancer risk modifiers that can be used to perform risk assessments for individual mutation carriers. We performed a comprehensive review of the genetically characterized and uncharacterized hereditary CRC syndromes and of low- and moderate-penetrance loci and variants identified through genome-wide association studies and candidate-gene approaches. Current challenges and future perspectives in the field of CRC predisposition are also discussed.
Collapse
|