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Ellakwa DES, Mushtaq N, Khan S, Jabbar A, Abdelmalek MA, Wadan AHS, Ellakwa TE, Raza A. Molecular functions of microRNAs in colorectal cancer: recent roles in proliferation, angiogenesis, apoptosis, and chemoresistance. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:5617-5630. [PMID: 38619588 DOI: 10.1007/s00210-024-03076-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 03/28/2024] [Indexed: 04/16/2024]
Abstract
MiRNAs (microRNAs) constitute a group of diminutive molecules of non-coding RNA intricately involved in regulating gene expression. This regulation is primarily accomplished through the binding of miRNAs to complementary sequences situated in the 3'-UTR of the messenger RNA (mRNA) target; as a result, they are degraded or repressed. The multifaceted biogenesis of miRNAs is characterized by a meticulously orchestrated sequence of events encompassing transcription, processing, transportation, and decay. Colorectal cancer stands as a pervasive and formidable ailment, afflicting millions across the globe. Colorectal cancer is not well diagnosed early, and metastasis rates are high, which results in low survival rates in advanced stages. The genesis and progression of colorectal cancer are subject to the influence of genetic and epigenetic factors, among which miRNAs play a pivotal role. When it comes to colorectal cancer, miRNAs have a dual character, depending on the genes they target, functioning as either tumor suppressors or oncogenes and the prevailing cellular milieu. Their impact extends to modulating critical facets of colorectal cancer pathogenesis, including proliferation, angiogenesis, apoptosis, chemoresistance, and radiotherapy response. The discernible potential of miRNAs which are used as biomarkers to diagnose colorectal cancer, prognosis, and treatment response has come to the forefront. Notably, miRNAs are easily found and detected readily in a variety of biological fluids, including saliva, blood, urine, and feces. This prominence is attributed to the inherent advantages of miRNAs over conventional biomarkers, including heightened stability, specificity, sensitivity, and accessibility. Various investigations have pinpointed miRNA signatures or panels capable of differentiating colorectal cancer patients from their healthy counterparts, predicting colorectal cancer stage and survival, and monitoring colorectal cancer recurrence and therapy response. Although there has been research on miRNAs in various diseases, there has been less research on miRNAs in cancer. Moreover, updated results of preclinical and clinical studies on miRNA biomarkers and drugs are required. Nevertheless, the integration of miRNAs as biomarkers for colorectal cancer is not devoid of challenges and limitations. These encompass the heterogeneity prevalent among colorectal cancer subtypes and stages, the variability in miRNA expression across different tissues and individuals, the absence of standardized methodologies for miRNA detection and quantification, and the imperative for validation through extensive clinical trials. Consequently, further research is imperative to conclusively establish the clinical utility and reliability of miRNAs as colorectal cancer biomarkers. MiR-21 demonstrates carcinogenic characteristics by targeting several tumor suppressor genes, which encourages cell division, invasion, and metastasis. On the other hand, by controlling the Wnt/β-catenin pathway, the tumor suppressor miRNA miR-34a prevents CRC cell proliferation, migration, and invasion. Furthermore, in colorectal cancer, the miR-200 family increases chemotherapy sensitivity while suppressing epithelial-mesenchymal transition (EMT). As an oncogene, the miR-17-92 cluster targets elements of the TGF-β signaling pathway to encourage the growth of CRC cells. Finally, miR-143/145, which is downregulated in CRC, influences apoptosis and the progression of the cell cycle. These miRNAs affect pathways like Wnt, TGF-β, PI3K-AKT, MAPK, and EMT, making them potential clinical biomarkers and therapeutic targets. This review summarizes recent research related to miRNAs, their role in tumor progression and metastasis, and their potential as biomarkers and therapeutic targets in colorectal cancer. In addition, we combined miRNAs' roles in tumorigenesis and development with the therapy of CRC patients, leading to novel perspectives on colorectal cancer diagnosis and treatment.
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Affiliation(s)
- Doha El-Sayed Ellakwa
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy for Girls, Al-Azhar University, Cairo, Egypt.
- Department of Biochemistry, Faculty of Pharmacy, Sinai University, Kantra Branch, Ismailia, Egypt.
| | - Nadia Mushtaq
- Department of Life Sciences, Lahore University of Management Sciences, Lahore, Pakistan
| | - Sahrish Khan
- Center for Applied Molecular Biology (CAMB), University of Punjab, Lahore, Pakistan
| | - Abdul Jabbar
- Department of Veterinary Medicine, University of Veterinary and Animal Sciences, Lahore, Pakistan
| | | | | | - Takwa E Ellakwa
- Physical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Ali Raza
- Department of Veterinary Microbiology, Faculty of Veterinary Medicine, Ataturk University, Erzurum, Turkey
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Wang Y, Liu J, Zheng S, Cao L, Li Y, Sheng R. The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/β-catenin signaling in cancer. FEBS Lett 2023; 597:3061-3071. [PMID: 37873736 DOI: 10.1002/1873-3468.14763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/25/2023] [Accepted: 09/29/2023] [Indexed: 10/25/2023]
Abstract
The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) axis pivotally controls cell metabolism and suppresses abnormal growth in various cancers. Wnt/β-catenin is a frequently dysregulated signaling pathway that drives oncogenesis. Here, we discovered a crosstalk mechanism between the LKB1/AMPK axis and Wnt/β-catenin signaling. Activated AMPK phosphorylates the deubiquitinase USP10 to potentiate the deubiquitination and stabilization of the key scaffold protein Axin1. This phosphorylation also strengthens the binding between USP10 and β-catenin and supports the phase transition of β-catenin. Both processes suppress Wnt/β-catenin amplitude in parallel and inhibit colorectal cancer growth in a clinically relevant manner. Collectively, we established a crosstalk route by which LKB1/AMPK regulates Wnt/β-catenin signaling in cancer. USP10 acts as the hub in this process, thus enabling LKB1/AMPK to suppress tumor growth via regulation of both metabolism and cell proliferation.
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Affiliation(s)
- Yinuo Wang
- College of Life and Health Science, Northeastern University, Shenyang, China
| | - Jingwei Liu
- College of Basic Medical Science, China Medical University, Shenyang, China
| | - Shaoqin Zheng
- College of Life and Health Science, Northeastern University, Shenyang, China
| | - Liu Cao
- College of Basic Medical Science, China Medical University, Shenyang, China
| | - Yiwei Li
- Key Laboratory for Biomedical Photonics of MOE at Wuhan National Laboratory for Optoelectronics - Hubei Bioinformatics and Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ren Sheng
- College of Life and Health Science, Northeastern University, Shenyang, China
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Zeng Z, Mao C, Vo A, Li X, Nugent JO, Khan SA, Clare SE, Luo Y. Deep learning for cancer type classification and driver gene identification. BMC Bioinformatics 2021; 22:491. [PMID: 34689757 PMCID: PMC8543824 DOI: 10.1186/s12859-021-04400-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 09/24/2021] [Indexed: 12/12/2022] Open
Abstract
Background Genetic information is becoming more readily available and is increasingly being used to predict patient cancer types as well as their subtypes. Most classification methods thus far utilize somatic mutations as independent features for classification and are limited by study power. We aim to develop a novel method to effectively explore the landscape of genetic variants, including germline variants, and small insertions and deletions for cancer type prediction.
Results We proposed DeepCues, a deep learning model that utilizes convolutional neural networks to unbiasedly derive features from raw cancer DNA sequencing data for disease classification and relevant gene discovery. Using raw whole-exome sequencing as features, germline variants and somatic mutations, including insertions and deletions, were interactively amalgamated for feature generation and cancer prediction. We applied DeepCues to a dataset from TCGA to classify seven different types of major cancers and obtained an overall accuracy of 77.6%. We compared DeepCues to conventional methods and demonstrated a significant overall improvement (p < 0.001). Strikingly, using DeepCues, the top 20 breast cancer relevant genes we have identified, had a 40% overlap with the top 20 known breast cancer driver genes. Conclusion Our results support DeepCues as a novel method to improve the representational resolution of DNA sequencings and its power in deriving features from raw sequences for cancer type prediction, as well as discovering new cancer relevant genes. Supplementary Information The online version contains supplementary material available at 10.1186/s12859-021-04400-4.
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Affiliation(s)
- Zexian Zeng
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 750 N Lake Shore Drive Room 11-189, Chicago, IL, 60611, USA.,Department of Data Sciences, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Chengsheng Mao
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 750 N Lake Shore Drive Room 11-189, Chicago, IL, 60611, USA
| | - Andy Vo
- Committee on Developmental Biology and Regenerative Medicine, The University of Chicago, Chicago, IL, USA
| | | | - Janna Ore Nugent
- Research Computing Services, Northwestern University, Chicago, IL, USA
| | - Seema A Khan
- Department of Surgery, Feinberg School of Medicine, Northwestern University, NMH/Prentice Women's Hospital Room 4-420 250 E Superior, Chicago, IL, 60611, USA.
| | - Susan E Clare
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Robert H Lurie Medical Research Center Room 4-113 250 E Superior, Chicago, IL, 60611, USA.
| | - Yuan Luo
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 750 N Lake Shore Drive Room 11-189, Chicago, IL, 60611, USA.
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Blumhagen RZ, Schwartz DA, Langefeld CD, Fingerlin TE. Identification of Influential Variants in Significant Aggregate Rare Variant Tests. Hum Hered 2021; 85:1-13. [PMID: 33567433 PMCID: PMC8353006 DOI: 10.1159/000513290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 11/19/2020] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Studies that examine the role of rare variants in both simple and complex disease are increasingly common. Though the usual approach of testing rare variants in aggregate sets is more powerful than testing individual variants, it is of interest to identify the variants that are plausible drivers of the association. We present a novel method for prioritization of rare variants after a significant aggregate test by quantifying the influence of the variant on the aggregate test of association. METHODS In addition to providing a measure used to rank variants, we use outlier detection methods to present the computationally efficient Rare Variant Influential Filtering Tool (RIFT) to identify a subset of variants that influence the disease association. We evaluated several outlier detection methods that vary based on the underlying variance measure: interquartile range (Tukey fences), median absolute deviation, and SD. We performed 1,000 simulations for 50 regions of size 3 kb and compared the true and false positive rates. We compared RIFT using the Inner Tukey to 2 existing methods: adaptive combination of p values (ADA) and a Bayesian hierarchical model (BeviMed). Finally, we applied this method to data from our targeted resequencing study in idiopathic pulmonary fibrosis (IPF). RESULTS All outlier detection methods observed higher sensitivity to detect uncommon variants (0.001 < minor allele frequency, MAF > 0.03) compared to very rare variants (MAF <0.001). For uncommon variants, RIFT had a lower median false positive rate compared to the ADA. ADA and RIFT had significantly higher true positive rates than that observed for BeviMed. When applied to 2 regions found previously associated with IPF including 100 rare variants, we identified 6 polymorphisms with the greatest evidence for influencing the association with IPF. DISCUSSION In summary, RIFT has a high true positive rate while maintaining a low false positive rate for identifying polymorphisms influencing rare variant association tests. This work provides an approach to obtain greater resolution of the rare variant signals within significant aggregate sets; this information can provide an objective measure to prioritize variants for follow-up experimental studies and insight into the biological pathways involved.
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Affiliation(s)
- Rachel Z Blumhagen
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA,
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA,
| | - David A Schwartz
- School of Medicine, University of Colorado, Aurora, Colorado, USA
| | - Carl D Langefeld
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
- Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA
- Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Tasha E Fingerlin
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, USA
- School of Medicine, University of Colorado, Aurora, Colorado, USA
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Rossetti LZ, Bekheirnia MR, Lewis AM, Mefford HC, Golden‐Grant K, Tarczy‐Hornoch K, Briere LC, Sweetser DA, Walker MA, Kravets E, Stevenson DA, Bruenner G, Sebastian J, Knapo J, Rosenfeld JA, Marcogliese PC, Wangler MF. Missense variants in CTNNB1 can be associated with vitreoretinopathy-Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype. Mol Genet Genomic Med 2021; 9:e1542. [PMID: 33350591 PMCID: PMC7963417 DOI: 10.1002/mgg3.1542] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/30/2020] [Accepted: 10/12/2020] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. METHODS We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. RESULTS Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. CONCLUSIONS Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.
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Affiliation(s)
- Linda Z. Rossetti
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Mir Reza Bekheirnia
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Andrea M. Lewis
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Heather C. Mefford
- Division of Genetic MedicineDepartment of PediatricsUniversity of WashingtonSeattleWAUSA
| | - Katie Golden‐Grant
- Division of Genetic MedicineDepartment of PediatricsUniversity of WashingtonSeattleWAUSA
| | | | - Lauren C. Briere
- Division of Medical Genetics and MetabolismDepartment of PediatricsMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - David A. Sweetser
- Division of Medical Genetics and MetabolismDepartment of PediatricsMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA
| | - Melissa A. Walker
- Department of NeurologyDivision of NeurogeneticsChild NeurologyMassachusetts General HospitalBostonMAUSA
| | - Elijah Kravets
- Division of Medical GeneticsDepartment of PediatricsStanford UniversityStanfordCAUSA
| | - David A. Stevenson
- Division of Medical GeneticsDepartment of PediatricsStanford UniversityStanfordCAUSA
| | - Georgette Bruenner
- Division of Medical GeneticsDepartment of PediatricsCohen Children’s Medical CenterQueensNYUSA
| | - Jessica Sebastian
- Division of Medical GeneticsDepartment of PediatricsUPMC Children’s Hospital of PittsburghPittsburghPAUSA
| | - Julia Knapo
- Division of Medical GeneticsDepartment of PediatricsUPMC Children’s Hospital of PittsburghPittsburghPAUSA
| | - Jill A. Rosenfeld
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
| | - Paul C. Marcogliese
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
- Jan and Dan Duncan Texas Children’s Neurological Research InstituteHoustonTXUSA
| | | | - Michael F. Wangler
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTXUSA
- Jan and Dan Duncan Texas Children’s Neurological Research InstituteHoustonTXUSA
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Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants. Proc Natl Acad Sci U S A 2020; 117:18924-18933. [PMID: 32753378 DOI: 10.1073/pnas.2005634117] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The reconciliation between Mendelian inheritance of discrete traits and the genetically based correlation between relatives for quantitative traits was Fisher's infinitesimal model of a large number of genetic variants, each with very small effects, whose causal effects could not be individually identified. The development of genome-wide genetic association studies (GWAS) raised the hope that it would be possible to identify single polymorphic variants with identifiable functional effects on complex traits. It soon became clear that, with larger and larger GWAS on more and more complex traits, most of the significant associations had such small effects, that identifying their individual functional effects was essentially hopeless. Polygenic risk scores that provide an overall estimate of the genetic propensity to a trait at the individual level have been developed using GWAS data. These provide useful identification of groups of individuals with substantially increased risks, which can lead to recommendations of medical treatments or behavioral modifications to reduce risks. However, each such claim will require extensive investigation to justify its practical application. The challenge now is to use limited genetic association studies to find individually identifiable variants of significant functional effect that can help to understand the molecular basis of complex diseases and traits, and so lead to improved disease prevention and treatment. This can best be achieved by 1) the study of rare variants, often chosen by careful candidate assessment, and 2) the careful choice of phenotypes, often extremes of a quantitative variable, or traits with relatively high heritability.
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Aghabozorgi AS, Ebrahimi R, Bahiraee A, Tehrani SS, Nabizadeh F, Setayesh L, Jafarzadeh-Esfehani R, Ferns GA, Avan A, Rashidi Z. The genetic factors associated with Wnt signaling pathway in colorectal cancer. Life Sci 2020; 256:118006. [PMID: 32593708 DOI: 10.1016/j.lfs.2020.118006] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/20/2020] [Accepted: 06/22/2020] [Indexed: 12/11/2022]
Abstract
Colorectal cancer (CRC) is a common cancer with poor prognosis and high mortality. There is growing information about the factors involved in the pathogenesis of CRC. However, the knowledge of the predisposing factors is limited. The development of CRC is strongly associated with the Wingless/Integrated (Wnt) signaling pathway. This pathway comprises several major target proteins, including LRP5/6, GSK3β, adenomatous polyposis coli (APC), axis inhibition protein (Axin), and β-catenin. Genetic variations in these components of the Wnt signaling pathway may lead to the activation of β-catenin, potentially increasing the proliferation of colorectal cells. Because of the potentially important role of the Wnt signaling pathway in CRC, we aimed to review the involvement of different mutations in the main downstream proteins of this pathway, including LRP5/6, APC, GSK3β, Axin, and β-catenin. Determination of the genetic risk factors involved in the progression of CRC may lead to novel approaches for the early diagnosis of CRC and the identification of potential therapeutic targets in the treatment of CRC.
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Affiliation(s)
- Amirsaeed Sabeti Aghabozorgi
- Medical Genetics Research Center, Basic Medical Sciences Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reyhane Ebrahimi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Bahiraee
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Sadra Samavarchi Tehrani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Nabizadeh
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Leila Setayesh
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran; Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Jafarzadeh-Esfehani
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK
| | - Amir Avan
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Zahra Rashidi
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of Anatomical Sciences, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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Prossomariti A, Piazzi G, Alquati C, Ricciardiello L. Are Wnt/β-Catenin and PI3K/AKT/mTORC1 Distinct Pathways in Colorectal Cancer? Cell Mol Gastroenterol Hepatol 2020; 10:491-506. [PMID: 32334125 PMCID: PMC7369353 DOI: 10.1016/j.jcmgh.2020.04.007] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 04/05/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023]
Abstract
Wnt/β-catenin and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathways both are critically involved in colorectal cancer (CRC) development, although they are implicated in the modulation of distinct oncogenic mechanisms. In homeostatic and pathologic conditions, these pathways show a fine regulation based mainly on feedback mechanisms, and are connected at multiple levels involving both upstream and downstream common effectors. The ability of the Wnt/β-catenin and PI3K/AKT/mTORC1 pathways to reciprocally control themselves represents one of the main resistance mechanisms to selective inhibitors in CRC, leading to the hypothesis that in specific settings, particularly in cancer driven by genetic alterations in Wnt/β-catenin signaling, the relationship between Wnt/β-catenin and PI3K/AKT/mTORC1 pathways could be so close that they should be considered as a unique therapeutic target. This review provides an update on the Wnt/β-catenin and PI3K/AKT/mTORC1 pathway interconnections in CRC, describing the main molecular players and the potential implications of combined inhibitors as an approach for CRC chemoprevention and treatment.
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Affiliation(s)
- Anna Prossomariti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Center for Applied Biomedical Research, S. Orsola Hospital, University of Bologna, Bologna, Italy,Anna Prossomariti, PhD, Center for Applied Biomedical Research, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy. fax: (39) 051-2143902.
| | - Giulia Piazzi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Center for Applied Biomedical Research, S. Orsola Hospital, University of Bologna, Bologna, Italy
| | - Chiara Alquati
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Center for Applied Biomedical Research, S. Orsola Hospital, University of Bologna, Bologna, Italy
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Center for Applied Biomedical Research, S. Orsola Hospital, University of Bologna, Bologna, Italy,Correspondence Address correspondence to: Luigi Ricciardiello, MD, Department of Medical and Surgical Sciences, Via Massarenti 9, 40138, Bologna, Italy. fax: (39) 051-2143381
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Collins TK, Houghten S. A centrality based multi-objective approach to disease gene association. Biosystems 2020; 193-194:104133. [PMID: 32243908 DOI: 10.1016/j.biosystems.2020.104133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 02/27/2020] [Accepted: 03/23/2020] [Indexed: 01/11/2023]
Abstract
Disease Gene Association finds genes that are involved in the presentation of a given genetic disease. We present a hybrid approach which implements a multi-objective genetic algorithm, where input consists of centrality measures based on various relational biological evidence types merged into a complex network. Multiple objective settings and parameters are studied including the development of a new exchange methodology, safe dealer-based crossover. Successful results with respect to breast cancer and Parkinson's disease compared to previous techniques and popular known databases are shown. In addition, the newly developed methodology is also successfully applied to Alzheimer's disease, further demonstrating its flexibility. Across all three case studies the strongest results were produced by the shortest path-based measures stress and betweenness, either in a single objective parameter setting or when used in conjunction in a multi-objective environment. The new crossover technique achieved the best results when applied to Alzheimer's disease.
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Affiliation(s)
- Tyler K Collins
- Computer Science Department, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada
| | - Sheridan Houghten
- Computer Science Department, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario L2S 3A1, Canada.
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10
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Houlleberghs H, Dekker M, Lusseveld J, Pieters W, van Ravesteyn T, Verhoef S, Hofstra RMW, Te Riele H. Three-step site-directed mutagenesis screen identifies pathogenic MLH1 variants associated with Lynch syndrome. J Med Genet 2019; 57:308-315. [PMID: 31784484 DOI: 10.1136/jmedgenet-2019-106520] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/12/2019] [Accepted: 10/16/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND Inactivating mutations in the MLH1 DNA mismatch repair (MMR) gene underlie 42% of Lynch syndrome (LS) cases. LS is a cancer predisposition causing early onset colorectal and endometrial cancer. Nonsense and frameshift alterations unambiguously cause LS. The phenotype of missense mutations that only alter a single amino acid is often unclear. These variants of uncertain significance (VUS) hinder LS diagnosis and family screening and therefore functional tests are urgently needed. We developed a functional test for MLH1 VUS termed 'oligonucleotide-directed mutation screening' (ODMS). METHODS The MLH1 variant was introduced by oligonucleotide-directed gene modification in mouse embryonic stem cells that were subsequently exposed to the guanine analogue 6-thioguanine to determine whether the variant abrogated MMR. RESUTS In a proof-of-principle analysis, we demonstrate that ODMS can distinguish pathogenic and non-pathogenic MLH1 variants with a sensitivity of >95% and a specificity of >91%. We subsequently applied the screen to 51 MLH1 VUS and identified 31 pathogenic variants. CONCLUSION ODMS is a reliable tool to identify pathogenic MLH1 variants. Implementation in clinical diagnostics will improve clinical care of patients with suspected LS and their relatives.
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Affiliation(s)
- Hellen Houlleberghs
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Marleen Dekker
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jarnick Lusseveld
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Wietske Pieters
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Thomas van Ravesteyn
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Senno Verhoef
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Robert M W Hofstra
- Department of Clinical Genetics, Erasmus MC, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Hein Te Riele
- Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Yadav S, Reeves A, Campian S, Paine A, Zakalik D. Outcomes of retesting BRCA negative patients using multigene panels. Fam Cancer 2018; 16:319-328. [PMID: 27878467 DOI: 10.1007/s10689-016-9956-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The utility of multigene panels in retesting patients who previously tested negative for a pathogenic mutation by BRCA1/2 testing is not well established. Patients who previously tested negative for a pathogenic BRCA1/2 mutation by standard sequencing, and who were seen in cancer genetics center between November 1, 2012 and June 30, 2015 for additional testing utilizing multigene panels, were identified using our genetic testing registry. Data on demographics, personal and family history of cancer, results of panel testing and the impact on patient management was collected retrospectively. A total of 122 patients underwent retesting during the study period. Thirteen (11%) pathogenic mutations were identified in the following genes: CHEK2(4), PALB2(3), ATM(2), CDH1, APC, BARD1 and MRE11A. Eleven out of these thirteen mutations were deemed actionable based on published guidelines. Of these eleven, seven patients had an actual change in clinical management as a result of retesting. Furthermore, retesting also led to a change in clinical management in the two patients with mutations in genes (BARD1 and MRE11A) which do not have clear guidelines for management. There were no significant differences in demographics and personal and family history of cancer between patients who tested positive and those who tested negative on retesting. This study demonstrates the clinical utility of multigene panels in a group of high risk individuals who previously tested negative for a BRCA1/2 mutation. This retesting approach revealed a pathogenic mutation in 11% of cases. Retesting led to significant change in clinical management in a majority of patients with actionable mutations (7 out of 11), as well as in those with mutations in genes which do not have specific management guidelines.
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Affiliation(s)
- Siddhartha Yadav
- Department of Internal Medicine, Beaumont Health, 3601 W 13 Mile Rd, Royal Oak, MI, 48073, USA. .,Nancy and James Grosfeld Cancer Genetics Center, Beaumont Health, 3577 W 13 Mile Rd, Suite 140, Royal Oak, MI, 48073, USA.
| | - Ashley Reeves
- Nancy and James Grosfeld Cancer Genetics Center, Beaumont Health, 3577 W 13 Mile Rd, Suite 140, Royal Oak, MI, 48073, USA
| | - Sarah Campian
- Nancy and James Grosfeld Cancer Genetics Center, Beaumont Health, 3577 W 13 Mile Rd, Suite 140, Royal Oak, MI, 48073, USA
| | - Amy Paine
- Nancy and James Grosfeld Cancer Genetics Center, Beaumont Health, 3577 W 13 Mile Rd, Suite 140, Royal Oak, MI, 48073, USA
| | - Dana Zakalik
- Nancy and James Grosfeld Cancer Genetics Center, Beaumont Health, 3577 W 13 Mile Rd, Suite 140, Royal Oak, MI, 48073, USA.,Oakland University William Beaumont School of Medicine, 2200 N Squirrel Rd, Rochester, MI, 48309, USA
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12
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Dishevelled1-3 contribute to multidrug resistance in colorectal cancer via activating Wnt/β-catenin signaling. Oncotarget 2017; 8:115803-115816. [PMID: 29383202 PMCID: PMC5777814 DOI: 10.18632/oncotarget.23253] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 11/13/2017] [Indexed: 12/31/2022] Open
Abstract
Multidrug resistance is a great obstacle in successful chemotherapy of colorectal cancer. However, the molecular mechanism underlying multidrug resistance is not fully understood. Dishevelled, a pivot in Wnt signaling, has been linked to cancer progression, while its role in chemoresistance remains unclear. Here, we found that Dishevelled1-3 was over-expressed in multidrug-resistant colorectal cancer cells (HCT-8/VCR) compared to their parental cells. Silencing Dishevelled1-3 resensitized HCT-8/VCR cells to multiple drugs including vincristine, 5-fluorouracil and oxaliplatin. Moreover, Dishevelled1-3 increased the protein levels of multidrug resistance protein 1 (P-gp/MDR1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP), Survivin and Bcl-2 which are correlated with multidrug resistance. shβ-catenin abolished Dishevelled-mediated these protein expressions. Unexpectedly, none of Dishevelled1-3 controlled β-catenin accumulation and nuclear translocation. Furthermore, the nuclear translocations of Dishevelled1-3 were promoted in HCT-8/VCR cells compared to HCT-8. Dishevelled1-3 bound to β-catenin in nucleus, and promoted nuclear complex formation and transcription activity of β-catenin/TCF. Taken together, Dishevelled1-3 contributed to multidrug resistance in colorectal cancer via activating Wnt/β-catenin signaling and inducing the expressions of P-gp, MRP2, BCRP, Survivin and Bcl-2, independently of β-catenin accumulation and nuclear translocation. Silencing Dishevelled1-3 resensitized multidrug-resistant colorectal cancer cells, providing a novel therapeutic target for successful chemotherapy of colorectal cancer.
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13
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Mik M, Dziki L, Malinowska K, Trzcinski R, Majsterek I, Dziki A. Polymorphism of MSH2 Gly322Asp and MLH1 -93G>A in non-familial colon cancer - a case-controlled study. Arch Med Sci 2017; 13:1295-1302. [PMID: 29181059 PMCID: PMC5701696 DOI: 10.5114/aoms.2017.67024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 03/13/2017] [Indexed: 12/30/2022] Open
Abstract
INTRODUCTION Our aim was to determine the effect of the single nucleotide polymorphisms (SNP) -93G>A of the MLH1 gene (rs1800734) and Gly322Asp of the MSH2 gene (rs4987188) on the risk of colon cancer (CC) and identify any relationship with clinical factors. MATERIAL AND METHODS The study included 144 unrelated patients with sporadic CC (71 males; mean age: 61.7 ±11 years) and 151 control patients (74 males; mean age: 63 ±11 years). DNA was extracted from peripheral blood lymphocytes, and genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. RESULTS In our population, the homozygous G/G genotype of the -93G>AMLH1 gene increased the risk of sporadic CC (OR = 2.07; 95% CI: 1.11-3.83; p < 0.02). For A/G and A/A genotypes, the MLH1-93G>A polymorphism was significantly more common in women (p = 0.034). The SNP demonstrated differences in allele distribution according to the location of the tumor, i.e. right vs. left side (p = 0.014), and disease recurrence (p = 0.022). Significant differences were found in the occurrence of Gly322Asp of MSH2 with regard to primary and recurrent disease (p = 0.001). CONCLUSIONS The -93G>AMLH1 polymorphism plays an important role in evaluating the risk of sporadic CC. It can also be used as an indicator in some patients with left-sided and recurrent tumors. MSH2 Gly322Asp is a potential marker in patients with risk of recurrence.
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Affiliation(s)
- Michal Mik
- Department of General and Colorectal Surgery, Medical University of Lodz, Lodz, Poland
| | - Lukasz Dziki
- Department of Nutrition, Department of General and Colorectal Surgery, Medical University of Lodz, Lodz, Poland
| | - Katarzyna Malinowska
- Department of Chemistry and Clinical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Radzislaw Trzcinski
- Department of General and Colorectal Surgery, Medical University of Lodz, Lodz, Poland
| | - Ireneusz Majsterek
- Department of Chemistry and Clinical Biochemistry, Medical University of Lodz, Lodz, Poland
| | - Adam Dziki
- Department of General and Colorectal Surgery, Medical University of Lodz, Lodz, Poland
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14
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Wong ML, Arcos-Burgos M, Liu S, Vélez JI, Yu C, Baune BT, Jawahar MC, Arolt V, Dannlowski U, Chuah A, Huttley GA, Fogarty R, Lewis MD, Bornstein SR, Licinio J. The PHF21B gene is associated with major depression and modulates the stress response. Mol Psychiatry 2017; 22:1015-1025. [PMID: 27777418 PMCID: PMC5461220 DOI: 10.1038/mp.2016.174] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/14/2016] [Accepted: 08/16/2016] [Indexed: 12/04/2022]
Abstract
Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.
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Affiliation(s)
- M-L Wong
- Mind & Brain Theme, South Australian
Health and Medical Research Institute (SAHMRI), Adelaide,
SA, Australia
- Department of Psychiatry, Flinders
University School of Medicine, Bedford Park, SA,
Australia
| | - M Arcos-Burgos
- Department of Genome Sciences, John
Curtin School of Medical Research, Australian National University,
Canberra, ACT, Australia
- University of Rosario International
Institute of Translational Medicine, Bogotá,
Colombia
| | - S Liu
- Mind & Brain Theme, South Australian
Health and Medical Research Institute (SAHMRI), Adelaide,
SA, Australia
- Department of Psychiatry, Flinders
University School of Medicine, Bedford Park, SA,
Australia
| | - J I Vélez
- Department of Genome Sciences, John
Curtin School of Medical Research, Australian National University,
Canberra, ACT, Australia
- Universidad del Norte,
Barranquilla, Colombia
| | - C Yu
- Mind & Brain Theme, South Australian
Health and Medical Research Institute (SAHMRI), Adelaide,
SA, Australia
- Department of Psychiatry, Flinders
University School of Medicine, Bedford Park, SA,
Australia
| | - B T Baune
- Discipline of Psychiatry, University of
Adelaide, Adelaide, SA, Australia
| | - M C Jawahar
- Discipline of Psychiatry, University of
Adelaide, Adelaide, SA, Australia
| | - V Arolt
- Department of Psychiatry and
Psychotherapy, University of Münster, Münster,
Germany
| | - U Dannlowski
- Department of Psychiatry and
Psychotherapy, University of Münster, Münster,
Germany
- Department of Psychiatry and
Psychotherapy, University of Marburg, Marburg,
Germany
| | - A Chuah
- Department of Genome Sciences, John
Curtin School of Medical Research, Australian National University,
Canberra, ACT, Australia
| | - G A Huttley
- Department of Genome Sciences, John
Curtin School of Medical Research, Australian National University,
Canberra, ACT, Australia
| | - R Fogarty
- Mind & Brain Theme, South Australian
Health and Medical Research Institute (SAHMRI), Adelaide,
SA, Australia
| | - M D Lewis
- Mind & Brain Theme, South Australian
Health and Medical Research Institute (SAHMRI), Adelaide,
SA, Australia
- Department of Psychiatry, Flinders
University School of Medicine, Bedford Park, SA,
Australia
| | - S R Bornstein
- Department of Psychiatry and
Psychotherapy, University of Münster, Münster,
Germany
- Medical Clinic III, Carl Gustav Carus
University Hospital, Dresden University of Technology, Dresden,
Germany
| | - J Licinio
- Mind & Brain Theme, South Australian
Health and Medical Research Institute (SAHMRI), Adelaide,
SA, Australia
- Department of Psychiatry, Flinders
University School of Medicine, Bedford Park, SA,
Australia
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15
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Abbasi S, Rasouli M. A rare FANCA gene variation as a breast cancer susceptibility allele in an Iranian population. Mol Med Rep 2017; 15:3983-3988. [PMID: 28440412 PMCID: PMC5436159 DOI: 10.3892/mmr.2017.6489] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 02/13/2017] [Indexed: 12/17/2022] Open
Abstract
Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure and Fanconi anemia complementation group A (FANCA) is also a potential breast and ovarian cancer susceptibility gene. A novel allele with tandem duplication of 13 base pair sequence in promoter region was identified. To investigate whether the 13 base pair sequence of tandem duplication in promoter region of the FANCA gene is of high penetrance in patients with breast cancer and to determine if the presence of the duplicated allele was associated with an altered risk of breast cancer, the present study screened DNA in blood samples from 304 breast cancer patients and 295 normal individuals as controls. The duplication allele had a frequency of 35.4 and 21.2% in patients with breast cancer and normal controls, respectively. There was a significant increase in the frequency of the duplication allele in patients with familial breast cancer compared with controls (45.1%, P=0.001). Furthermore, the estimated risk of breast cancer in individuals with a homozygote [odds ratio (OR), 4.093; 95% confidence intervals (CI), 1.957–8.561] or heterozygote duplicated genotype (OR, 3.315; 95% CI, 1.996–5.506) was higher compared with the corresponding normal homozygote genotype. In conclusion, the present study indicated that the higher the frequency of the duplicated allele, the higher the risk of breast cancer. To the best of our knowledge, the present study is the first to report FANCA gene duplication in patients with breast cancer.
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Affiliation(s)
- Sakineh Abbasi
- Department of Laboratory Medicine, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran 14177, Iran
| | - Mina Rasouli
- Laboratory of Vaccines and Immunotherapeutics, Institute of Bioscience, University Putra Malaysia, Serdang, Selangor 43400, Malaysia
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16
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Chen L, Mukerjee G, Dorfman R, Moghadas SM. Disease Risk Assessment Using a Voronoi-Based Network Analysis of Genes and Variants Scores. Front Genet 2017; 8:29. [PMID: 28326099 PMCID: PMC5339255 DOI: 10.3389/fgene.2017.00029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 02/22/2017] [Indexed: 11/18/2022] Open
Abstract
Much effort has been devoted to assess disease risk based on large-scale protein-protein network and genotype-phenotype associations. However, the challenge of risk prediction for complex diseases remains unaddressed. Here, we propose a framework to quantify the risk based on a Voronoi tessellation network analysis, taking into account the disease association scores of both genes and variants. By integrating ClinVar, SNPnexus, and DISEASES databases, we introduce a gene-variant map that is based on the pairwise disease-associated gene-variant scores. This map is clustered using Voronoi tessellation and network analysis with a threshold obtained from fitting the background Voronoi cell density distribution. We define the relative risk of disease that is inferred from the scores of the data points within the related clusters on the gene-variant map. We identify autoimmune-associated clusters that may interact at the system-level. The proposed framework can be used to determine the clusters that are specific to a subtype or contribute to multiple subtypes of complex diseases.
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Affiliation(s)
- Lin Chen
- Agent-Based Modelling Laboratory, York University Toronto, ON, Canada
| | | | | | - Seyed M Moghadas
- Agent-Based Modelling Laboratory, York University Toronto, ON, Canada
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17
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Venkitachalam S, Guda K. Altered glycosyltransferases in colorectal cancer. Expert Rev Gastroenterol Hepatol 2017; 11:5-7. [PMID: 27781489 PMCID: PMC5520968 DOI: 10.1080/17474124.2017.1253474] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 10/24/2016] [Indexed: 01/03/2023]
Affiliation(s)
- Srividya Venkitachalam
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH-44106 U.S.A
| | - Kishore Guda
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH-44106 U.S.A
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18
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Zhu Q, Shepherd L, Lunetta KL, Yao S, Liu Q, Hu Q, Haddad SA, Sucheston-Campbell L, Bensen JT, Bandera EV, Rosenberg L, Liu S, Haiman CA, Olshan AF, Palmer JR, Ambrosone CB. Trans-ethnic follow-up of breast cancer GWAS hits using the preferential linkage disequilibrium approach. Oncotarget 2016; 7:83160-83176. [PMID: 27825120 PMCID: PMC5341253 DOI: 10.18632/oncotarget.13075] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 10/12/2016] [Indexed: 12/22/2022] Open
Abstract
Leveraging population-distinct linkage equilibrium (LD) patterns, trans-ethnic follow-up of variants discovered from genome-wide association studies (GWAS) has proved to be useful in facilitating the identification of bona fide causal variants. We previously developed the preferential LD approach, a novel method that successfully identified causal variants driving the GWAS signals within European-descent populations even when the causal variants were only weakly linked with the GWAS-discovered variants. To evaluate the performance of our approach in a trans-ethnic setting, we applied it to follow up breast cancer GWAS hits identified mostly from populations of European ancestry in African Americans (AA). We evaluated 74 breast cancer GWAS variants in 8,315 AA women from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Only 27% of them were associated with breast cancer risk at significance level α=0.05, suggesting race-specificity of the identified breast cancer risk loci. We followed up on those replicated GWAS hits in the AMBER consortium utilizing the preferential LD approach, to search for causal variants or better breast cancer markers from the 1000 Genomes variant catalog. Our approach identified stronger breast cancer markers for 80% of the GWAS hits with at least nominal breast cancer association, and in 81% of these cases, the marker identified was among the top 10 of all 1000 Genomes variants in the corresponding locus. The results support trans-ethnic application of the preferential LD approach in search for candidate causal variants, and may have implications for future genetic research of breast cancer in AA women.
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Affiliation(s)
- Qianqian Zhu
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Lori Shepherd
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Kathryn L. Lunetta
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Song Yao
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Qian Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Qiang Hu
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | | | - Lara Sucheston-Campbell
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Jeannette T. Bensen
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Elisa V. Bandera
- Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Lynn Rosenberg
- Slone Epidemiology Center, Boston University, Boston, MA, USA
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Christopher A. Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Andrew F. Olshan
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Julie R. Palmer
- Slone Epidemiology Center, Boston University, Boston, MA, USA
| | - Christine B. Ambrosone
- Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
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19
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Vélez JI, Lopera F, Patel HR, Johar AS, Cai Y, Rivera D, Tobón C, Villegas A, Sepulveda-Falla D, Lehmann SG, Easteal S, Mastronardi CA, Arcos-Burgos M. Mutations modifying sporadic Alzheimer's disease age of onset. Am J Med Genet B Neuropsychiatr Genet 2016; 171:1116-1130. [PMID: 27573710 DOI: 10.1002/ajmg.b.32493] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 08/15/2016] [Indexed: 11/10/2022]
Abstract
The identification of mutations modifying the age of onset (AOO) in Alzheimer's disease (AD) is crucial for understanding the natural history of AD and, therefore, for early interventions. Patients with sporadic AD (sAD) from a genetic isolate in the extremes of the AOO distribution were whole-exome genotyped. Single- and multi-locus linear mixed-effects models were used to identify functional variants modifying AOO. A posteriori enrichment and bioinformatic analyses were applied to evaluate the non-random clustering of the associate variants to physiopathological pathways involved in AD. We identified more than 20 pathogenic, genome-wide statistically significant mutations of major modifier effect on the AOO. These variants are harbored in genes implicated in neuron apoptosis, neurogenesis, inflammatory processes linked to AD, oligodendrocyte differentiation, and memory processes. This set of new genes harboring these mutations could be of importance for prediction, follow-up and eventually as therapeutical targets of AD. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Jorge I Vélez
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.,Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - Francisco Lopera
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - Hardip R Patel
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Angad S Johar
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Yeping Cai
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Dora Rivera
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - Carlos Tobón
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - Andrés Villegas
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - Diego Sepulveda-Falla
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia.,Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Shaun G Lehmann
- Genome Diversity and Health Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Simon Easteal
- Genome Diversity and Health Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Claudio A Mastronardi
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Mauricio Arcos-Burgos
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.,Neuroscience Research Group, University of Antioquia, Medellín, Colombia
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20
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Association of APC I1307K and E1317Q polymorphisms with colorectal cancer among Egyptian subjects. Fam Cancer 2016; 15:49-56. [PMID: 26314409 DOI: 10.1007/s10689-015-9834-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Colorectal cancer is a multifactorial disease that involves both environmental and genetic factors. The gene encoding adenomatous polyposis coli (APC) has been reported to be associated with colorectal cancer (CRC) risk in several ethnic populations. The aim of this work is to assess the association of the APC I1307K and E1317Q polymorphisms with CRC risk among Egyptian subjects. This study included 120 unrelated CRC Egyptian patients who were compared to 100 healthy controls from the same locality. For all subjects, DNA was genotyped for APC I1307K and E1317Q polymorphisms using the PCR-ARMS technique. The frequency of APC I1307K carrier (TA+AA genotypes) was noted to be significantly higher among cases with CRC compared to controls (18.3 vs. 9.0 %, OR 2.58, 95 % CI 1.09-6.09, p = 0.03). Also the frequency of the APC I1307K A allele was significantly higher among cases compared to controls (10.4 vs. 4.5 %, OR 2.47; 95 % CI 1.12-5.42, p = 0.03). On the contrast, the frequencies of APC E1317Q GC genotype and C allele showed no significant difference among CRC patients compared to controls (3.3 vs. 2.0 %, OR 1.69; 95 % CI 0.30-9.42, p = 0.69 and 2.1 vs. 1.0 %, OR 2.11; 95 % CI 0.40-10.97, p = 0.46, respectively). Cases of the APC I1307K and E1317Q carriers (TA+AA and GC) showed no significant difference compared to those with I1307K and E1317Q non-carriers (TT and GG) regarding their clinical and laboratory markers. APC I1307K variant was associated with an increased risk of CRC among Egyptian subjects.
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21
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Zhang LL, Tang XJ, Wang XY, Zhu YW, Peng XB, Gong L. A promoter polymorphism in the hMLH1 gene (-93G/A) associated with sporadic colorectal cancer. Oncol Lett 2016; 12:4035-4040. [PMID: 27895767 DOI: 10.3892/ol.2016.5188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 08/19/2016] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is a worldwide problem for public health. mutL homolog 1 (MLH1) is a key component of the mismatch repair system, and the MLH1-93G/A polymorphism (rs1800734) is predicted to affect MLH1 protein expression, suggesting that the polymorphism may be associated with the cancer risk; however, the results concerning this have been inconsistent. In order to investigate the possible correlation between human (h)MLH1-93G/A polymorphism and the development and progression of sporadic CRC (SCRC) in China, the genotypes of hMLH1-93G/A were detected by the TaqMan MGB probe method in 312 SCRC patients and 300 healthy controls, and immunohistochemical staining was also performed to measure the expression of hMLH1 in cases with different alleles among the SCRC patients and normal controls. It was observed that the A/A genotype and A allele significantly increased the risk of developing Duke's stage C+D CRC and lymphatic metastasis. hMLH1 expression of the A allele was lower than that of the G allele in CRC. By contrast, there was no statistically significant difference in hMLH1 expression for the A allele and the G allele in the normal controls. These results suggested that hMLH1-93G/A polymorphism may not be associated with the overall risk of CRC, but that the hMLH1-93A/A genotype and A allele are associated with the progression of CRC.
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Affiliation(s)
- Li-Li Zhang
- Department of Gastroenterology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu 214000, P.R. China
| | - Xue-Jun Tang
- Department of Gastroenterology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu 214000, P.R. China
| | - Xiao-Yun Wang
- Department of Gastroenterology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu 214000, P.R. China
| | - Ying-Wei Zhu
- Department of Gastroenterology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu 214000, P.R. China
| | - Xiao-Bin Peng
- Department of Gastroenterology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu 214000, P.R. China
| | - Lei Gong
- Department of Gastroenterology, Wuxi No. 2 People's Hospital, Wuxi, Jiangsu 214000, P.R. China
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22
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Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, Kirfel J, Tafazzoli A, Horpaopan S, Uhlhaas S, Stienen D, Friedrichs N, Altmüller J, Laner A, Holzapfel S, Peters S, Kayser K, Thiele H, Holinski-Feder E, Marra G, Kristiansen G, Nöthen MM, Büttner R, Möslein G, Betz RC, Brieger A, Lifton RP, Aretz S. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am J Hum Genet 2016; 99:337-51. [PMID: 27476653 DOI: 10.1016/j.ajhg.2016.06.015] [Citation(s) in RCA: 172] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 06/14/2016] [Indexed: 12/20/2022] Open
Abstract
In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals' tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.
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Affiliation(s)
- Ronja Adam
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany
| | - Isabel Spier
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany
| | - Bixiao Zhao
- Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA
| | - Michael Kloth
- Institute of Pathology, University of Cologne, 50937 Cologne, Germany
| | - Jonathan Marquez
- Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA
| | - Inga Hinrichsen
- Medical Clinic 1, Biomedical Research Laboratory, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Jutta Kirfel
- Institute of Pathology, University of Bonn, 53127 Bonn, Germany
| | - Aylar Tafazzoli
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany
| | - Sukanya Horpaopan
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Chiang Mai 50200, Thailand
| | - Siegfried Uhlhaas
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
| | - Dietlinde Stienen
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
| | | | - Janine Altmüller
- Cologne Center for Genomics, University of Cologne, 50937 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50937 Cologne, Germany
| | - Andreas Laner
- Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, 80336 Munich, Germany; Medical Genetics Center, 80335 Munich, Germany
| | - Stefanie Holzapfel
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany
| | - Sophia Peters
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
| | - Katrin Kayser
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
| | - Holger Thiele
- Cologne Center for Genomics, University of Cologne, 50937 Cologne, Germany
| | - Elke Holinski-Feder
- Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, 80336 Munich, Germany; Medical Genetics Center, 80335 Munich, Germany
| | - Giancarlo Marra
- Institute of Molecular Cancer Research, University of Zurich, CH-8057 Zurich, Switzerland
| | | | - Markus M Nöthen
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany
| | - Reinhard Büttner
- Institute of Pathology, University of Cologne, 50937 Cologne, Germany
| | - Gabriela Möslein
- HELIOS Klinikum Wuppertal, University of Witten/Herdecke, 42283 Wuppertal, Germany
| | - Regina C Betz
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany
| | - Angela Brieger
- Medical Clinic 1, Biomedical Research Laboratory, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Richard P Lifton
- Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA
| | - Stefan Aretz
- Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany.
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23
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Vélez JI, Lopera F, Sepulveda-Falla D, Patel HR, Johar AS, Chuah A, Tobón C, Rivera D, Villegas A, Cai Y, Peng K, Arkell R, Castellanos FX, Andrews SJ, Silva Lara MF, Creagh PK, Easteal S, de Leon J, Wong ML, Licinio J, Mastronardi CA, Arcos-Burgos M. APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Mol Psychiatry 2016; 21:916-24. [PMID: 26619808 PMCID: PMC5414071 DOI: 10.1038/mp.2015.177] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 10/07/2015] [Accepted: 10/14/2015] [Indexed: 01/10/2023]
Abstract
Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (β=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 × 10(-8), PFDR=2.48 × 10(-3)). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (β=8.24, 95% CI: 4.45-12.01, P=3.84 × 10(-5)). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.
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Affiliation(s)
- J I Vélez
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - F Lopera
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - D Sepulveda-Falla
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia.,Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - H R Patel
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - A S Johar
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - A Chuah
- Genome Discovery Unit, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - C Tobón
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - D Rivera
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - A Villegas
- Neuroscience Research Group, University of Antioquia, Medellín, Colombia
| | - Y Cai
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - K Peng
- Biomolecular Resource Facility, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - R Arkell
- Early Mammalian Development Laboratory, Research School of Biology, The Australian National University, Canberra, ACT, Australia
| | - F X Castellanos
- NYU Child Study Center, NYU Langone Medical Center, New York, NY, USA.,Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA
| | - S J Andrews
- Genome Diversity and Health Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - M F Silva Lara
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - P K Creagh
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - S Easteal
- Genome Diversity and Health Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - J de Leon
- Mental Health Research Center at Eastern State Hospital, University of Kentucky, Lexington, KY, USA
| | - M L Wong
- South Australian Health and Medical Research Institute and Department of Psychiatry, School of Medicine, Flinders University, Adelaide, SA, Australia
| | - J Licinio
- South Australian Health and Medical Research Institute and Department of Psychiatry, School of Medicine, Flinders University, Adelaide, SA, Australia
| | - C A Mastronardi
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,South Australian Health and Medical Research Institute and Department of Psychiatry, School of Medicine, Flinders University, Adelaide, SA, Australia
| | - M Arcos-Burgos
- Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,Neuroscience Research Group, University of Antioquia, Medellín, Colombia
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24
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Li J, Wei Z, Hakonarson H. Application of computational methods in genetic study of inflammatory bowel disease. World J Gastroenterol 2016; 22:949-960. [PMID: 26811639 PMCID: PMC4716047 DOI: 10.3748/wjg.v22.i3.949] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 11/04/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
Genetic factors play an important role in the etiology of inflammatory bowel disease (IBD). The launch of genome-wide association study (GWAS) represents a landmark in the genetic study of human complex disease. Concurrently, computational methods have undergone rapid development during the past a few years, which led to the identification of numerous disease susceptibility loci. IBD is one of the successful examples of GWAS and related analyses. A total of 163 genetic loci and multiple signaling pathways have been identified to be associated with IBD. Pleiotropic effects were found for many of these loci; and risk prediction models were built based on a broad spectrum of genetic variants. Important gene-gene, gene-environment interactions and key contributions of gut microbiome are being discovered. Here we will review the different types of analyses that have been applied to IBD genetic study, discuss the computational methods for each type of analysis, and summarize the discoveries made in IBD research with the application of these methods.
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25
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Abstract
In this overview of my research, I have aimed to give the background as to how I came to be involved in my various areas of interest, with an emphasis on the early phases of my career, which largely determined my future directions. I had the enormous good fortune to have worked under two of the most outstanding scientists of the twentieth century, R.A. Fisher and Joshua Lederberg. From mathematics and statistics, I went to population genetics and the early use of computers for modeling and simulation. Molecular biology took me into the laboratory and eventually to somatic cell genetics and human gene mapping. One chance encounter led me into the HLA field and another led me into research on cancer, especially colorectal cancer. On the way, I became a champion of the Human Genome Project and of the need for scientists to help promote the public understanding of science.
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Affiliation(s)
- Walter Bodmer
- Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, Oxford OX3 9DS, United Kingdom
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26
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Mistry V, Bockett NA, Levine AP, Mirza MM, Hunt KA, Ciclitira PJ, Hummerich H, Neuhausen SL, Simpson MA, Plagnol V, van Heel DA. Exome sequencing of 75 individuals from multiply affected coeliac families and large scale resequencing follow up. PLoS One 2015; 10:e0116845. [PMID: 25635822 PMCID: PMC4312029 DOI: 10.1371/journal.pone.0116845] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 11/24/2014] [Indexed: 11/19/2022] Open
Abstract
Coeliac disease (CeD) is a highly heritable common autoimmune disease involving chronic small intestinal inflammation in response to dietary wheat. The human leukocyte antigen (HLA) region, and 40 newer regions identified by genome wide association studies (GWAS) and dense fine mapping, account for ∼40% of the disease heritability. We hypothesized that in pedigrees with multiple individuals with CeD rare [minor allele frequency (MAF) <0.5%] mutations of larger effect size (odds ratios of ∼2-5) might exist. We sequenced the exomes of 75 coeliac individuals of European ancestry from 55 multiply affected families. We selected interesting variants and genes for further follow up using a combination of: an assessment of shared variants between related subjects, a model-free linkage test, and gene burden tests for multiple, potentially causal, variants. We next performed highly multiplexed amplicon resequencing of all RefSeq exons from 24 candidate genes selected on the basis of the exome sequencing data in 2,248 unrelated coeliac cases and 2,230 controls. 1,335 variants with a 99.9% genotyping call rate were observed in 4,478 samples, of which 939 were present in coding regions of 24 genes (Ti/Tv 2.99). 91.7% of coding variants were rare (MAF <0.5%) and 60% were novel. Gene burden tests performed on rare functional variants identified no significant associations (p<1×10(-3)) in the resequenced candidate genes. Our strategy of sequencing multiply affected families with deep follow up of candidate genes has not identified any new CeD risk mutations.
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Affiliation(s)
- Vanisha Mistry
- Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, United Kingdom
- * E-mail:
| | - Nicholas A. Bockett
- Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, United Kingdom
| | - Adam P. Levine
- Division of Medicine, University College London, London, WC1E 6JF, United Kingdom
| | - Muddassar M. Mirza
- UCL Advanced Diagnostics, Molecular Profiling Laboratory, Sarah Cannon-UCL Laboratories, Ground Floor, Shropshire House, 1 Capper Street, London, WC1E 6JA, United Kingdom
| | - Karen A. Hunt
- Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, United Kingdom
| | - Paul J. Ciclitira
- King’s College London, Division of Diabetes and Nutritional Sciences, Gastroenterology, The Rayne Institute, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom
| | - Holger Hummerich
- Medical Research Council Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London WC1N 3BG, United Kingdom
| | - Susan L. Neuhausen
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California 91010, United States of America
| | - Michael A. Simpson
- Division of Genetics and Molecular Medicine, Kings College London School of Medicine, 8 Floor Tower Wing, Guy’s Hospital, London SE1 9RY, United Kingdom
| | - Vincent Plagnol
- University College London Genetics Institute, Gower Street, London WC1E 6BT, United Kingdom
| | - David A. van Heel
- Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, United Kingdom
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27
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Chen JJ, Zhong M, Dou TH, Wu ZY, Tang WJ. rs17501976 polymorphism of CLDN1 gene is associated with decreased risk of colorectal cancer in a Chinese population. Int J Clin Exp Med 2015; 8:1247-1252. [PMID: 25785120 PMCID: PMC4358575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Accepted: 01/07/2015] [Indexed: 06/04/2023]
Abstract
The purpose of this study was to determine the relationship between polymorphisms in Claudin-1 (CLDN1) and the risk of colorectal cancer in a Chinese population. In this study, a case-control study was conducted in which polymorphisms in CLDN1 were analyzed in 50 patients with colorectal cancer (CRC) and 50 healthy individuals as controls. No rs16865344 and rs17429833 polymorphism were found among all analyzed samples. For the rs17501976 polymorphism, the TC genotype (OR = 0. 41, 95% CI = 0.18-0.91, and P = 0.045) was closely associated with the risk of colorectal cancer compared with the more common TT genotype. And the TC + CC genotypes (OR = 0.41, 95% CI = 0.18-0.91, and P = 0.045) were also significantly associated with the risk of CRC compared with the TT genotype. However, a C > T change of the rs17501976 polymorphism did not show a difference in transcription factor binding to the promoter region of CLDN1. For rs12696600 polymorphism, no significant difference was found in colorectal cancer risk between cases and controls in corresponding genotypes. Collectively, our data suggest that rs17501976 polymorphism significantly associated with a decreased susceptibility to CRC in a Chinese population.
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Affiliation(s)
- Jian-Jun Chen
- Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, P.R. China
| | - Ming Zhong
- Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, P.R. China
| | - Tong-Hai Dou
- Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, P.R. China
| | - Zhi-Yong Wu
- Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, P.R. China
| | - Wei-Jun Tang
- Department of General Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, P.R. China
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28
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Spataro N, Calafell F, Cervera-Carles L, Casals F, Pagonabarraga J, Pascual-Sedano B, Campolongo A, Kulisevsky J, Lleó A, Navarro A, Clarimón J, Bosch E. Mendelian genes for Parkinson's disease contribute to the sporadic forms of the disease†. Hum Mol Genet 2014; 24:2023-34. [PMID: 25504046 DOI: 10.1093/hmg/ddu616] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Affiliation(s)
- Nino Spataro
- Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
| | - Francesc Calafell
- Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
| | - Laura Cervera-Carles
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Ferran Casals
- Genomics Core Facility, Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), 08003 Barcelona, Spain
| | - Javier Pagonabarraga
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Berta Pascual-Sedano
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Antònia Campolongo
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Jaime Kulisevsky
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain, Health Sciences Department, Universitat Oberta de Catalunya, Catalonia, Spain
| | - Alberto Lleó
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Arcadi Navarro
- Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain, National Institute for Bioinformatics (INB), Barcelona Biomedical Research Park (PRBB), 08003 Barcelona, Spain, Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona Biomedical Research Park (PRBB), 08003 Barcelona, Spain and Center for Genomic Regulation (CRG), Barcelona Biomedical Research Park (PRBB), 08003 Barcelona, Spain
| | - Jordi Clarimón
- Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Elena Bosch
- Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain,
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29
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Horpaopan S, Spier I, Zink AM, Altmüller J, Holzapfel S, Laner A, Vogt S, Uhlhaas S, Heilmann S, Stienen D, Pasternack SM, Keppler K, Adam R, Kayser K, Moebus S, Draaken M, Degenhardt F, Engels H, Hofmann A, Nöthen MM, Steinke V, Perez-Bouza A, Herms S, Holinski-Feder E, Fröhlich H, Thiele H, Hoffmann P, Aretz S. Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis. Int J Cancer 2014; 136:E578-89. [PMID: 25219767 DOI: 10.1002/ijc.29215] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 08/04/2014] [Accepted: 09/03/2014] [Indexed: 12/27/2022]
Abstract
To uncover novel causative genes in patients with unexplained adenomatous polyposis, a model disease for colorectal cancer, we performed a genome-wide analysis of germline copy number variants (CNV) in a large, well characterized APC and MUTYH mutation negative patient cohort followed by a targeted next generation sequencing (NGS) approach. Genomic DNA from 221 unrelated German patients was genotyped on high-resolution SNP arrays. Putative CNVs were filtered according to stringent criteria, compared with those of 531 population-based German controls, and validated by qPCR. Candidate genes were prioritized using in silico, expression, and segregation analyses, data mining and enrichment analyses of genes and pathways. In 27% of the 221 unrelated patients, a total of 77 protein coding genes displayed rare, nonrecurrent, germline CNVs. The set included 26 candidates with molecular and cellular functions related to tumorigenesis. Targeted high-throughput sequencing found truncating point mutations in 12% (10/77) of the prioritized genes. No clear evidence was found for autosomal recessive subtypes. Six patients had potentially causative mutations in more than one of the 26 genes. Combined with data from recent studies of early-onset colorectal and breast cancer, recurrent potential loss-of-function alterations were detected in CNTN6, FOCAD (KIAA1797), HSPH1, KIF26B, MCM3AP, YBEY and in three genes from the ARHGAP family. In the canonical Wnt pathway oncogene CTNNB1 (β-catenin), two potential gain-of-function mutations were found. In conclusion, the present study identified a group of rarely affected genes which are likely to predispose to colorectal adenoma formation and confirmed previously published candidates for tumor predisposition as etiologically relevant.
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Abstract
A major impetus to initiating the Human Genome Project was the belief that information encoded in the human genome would "accelerate progress in understanding disease pathogenesis and in developing new approaches to diagnosis, treatment, and prevention in many areas of medicine". Alopecia areata (AA) is a notable example of how understanding the genetic basis of a disease can have an impact on the care of patients in a relatively short time. Our first genome-wide association study in AA identified an initial set of common variants that increase risk of AA, some of which are shared with other autoimmune diseases. Thus, there has already been rapid progress in the translation of this information into new therapeutic strategies for patients, as drugs are already on the market for some of these disorders that can now be tested in AA. Informed by the progress achieved with genetic studies for mechanistically aligned autoimmune diseases, we are poised to carry this work forward and interrogate the underlying disease mechanisms in AA. Importantly, future genetic studies aimed at identifying additional susceptibility genes will further establish the foundation for the application of precision medicine in the care of AA patients.
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Mazzoni SM, Fearon ER. AXIN1 and AXIN2 variants in gastrointestinal cancers. Cancer Lett 2014; 355:1-8. [PMID: 25236910 DOI: 10.1016/j.canlet.2014.09.018] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 09/08/2014] [Accepted: 09/10/2014] [Indexed: 01/12/2023]
Abstract
Mutations in the APC (adenomatous polyposis coli) gene, which encodes a multi-functional protein with a well-defined role in the canonical Wnt pathway, underlie familial adenomatous polypsosis, a rare, inherited form of colorectal cancer (CRC) and contribute to the majority of sporadic CRCs. However, not all sporadic and familial CRCs can be explained by mutations in APC or other genes with well-established roles in CRC. The AXIN1 and AXIN2 proteins function in the canonical Wnt pathway, and AXIN1/2 alterations have been proposed as key defects in some cancers. Here, we review AXIN1 and AXIN2 sequence alterations reported in gastrointestinal cancers, with the goal of vetting the evidence that some of the variants may have key functional roles in cancer development.
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Affiliation(s)
- Serina M Mazzoni
- Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
| | - Eric R Fearon
- Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA; Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA; Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
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MLH1 and MSH2 mutation screening in HNPCC families of Hungary - Two new MMR gene mutations. Eur J Surg Oncol 2014; 40:1445-52. [PMID: 25107687 DOI: 10.1016/j.ejso.2014.07.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 06/03/2014] [Accepted: 07/11/2014] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION Hereditary Non-Polyposis Colorectal Cancer is an inherited disease with deleterious germline mutations in the DNA mismatch repair genes causing the development of colon cancer and other malignancies. This is the first study in Hungary screening the population of our colorectal cancer patients in order to identify the prevalence of the disease. METHODS In families who met the Modified Amsterdam and Bethesda Criteria the removed tumor tissue was first examined by immunohistochemistry and microsatellite instability analysis. Those cases which showed high microsatellite instability underwent DNA sequencing and multiple ligation dependent probe amplification. RESULTS Of the 1576 patients with colorectal cancer underwent screening for the modified Amsterdam and Bethesda criteria, 69 (4.4%) and 166 (10.5%) fulfilled the criteria respectively. 15 patients (31%) of the Amsterdam positive group and 19 patients from the Bethesda positive (18.1%) were MSI-H. There were 8 pathogenic mutations identified in 9 families (60%) in the Amsterdam positive group. 5 mutations were found in 5 families (26%) in the Bethesda positive group. 12 pathogenic mutations were identified, two of these are newly identified, and being published first in this work. These two new mutations were located on MLH1 (g.31276_35231del) and MSH2 (c.969_970delTC) genes. CONCLUSION The prevalence of the mutations in the MLH1 and MSH2 genes was almost equal in our Hungarian colorectal cancer patients. One mutation in the MLH1 gene (c.143A > C; p.Q48P) was identified in three different families. Whether this mutation is the most frequent in the Hungarian population is still unidentified and warrant further investigation.
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Allen EK, Manichaikul A, Sale MM. Genetic contributors to otitis media: agnostic discovery approaches. Curr Allergy Asthma Rep 2014; 14:411. [PMID: 24415464 DOI: 10.1007/s11882-013-0411-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Otitis media (OM) is the most common disease in children in the United States, with about $5 billion spent each year in direct and indirect costs. OM is the number one reason for pediatric antibiotic usage and surgery, although treatment options are limited. Numerous studies have established the high heritability of OM and a genetic contribution to OM pathogenesis. Candidate gene studies have highlighted the roles of inflammation, mucin secretion, and pathogen recognition, but this approach is unable to identify novel pathways to target for treatment or screening purposes. Here, we review the current literature on agnostic approaches to discover novel genes and pathways involved in OM pathogenesis.
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Affiliation(s)
- E Kaitlynn Allen
- Center for Public Health Genomics, University of Virginia, PO Box 800717, Charlottesville, VA, 22908, USA
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Yan S, Li Y. BETASEQ: a powerful novel method to control type-I error inflation in partially sequenced data for rare variant association testing. ACTA ACUST UNITED AC 2014; 30:480-7. [PMID: 24336643 DOI: 10.1093/bioinformatics/btt719] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
SUMMARY Despite its great capability to detect rare variant associations, next-generation sequencing is still prohibitively expensive when applied to large samples. In case-control studies, it is thus appealing to sequence only a subset of cases to discover variants and genotype the identified variants in controls and the remaining cases under the reasonable assumption that causal variants are usually enriched among cases. However, this approach leads to inflated type-I error if analyzed naively for rare variant association. Several methods have been proposed in recent literature to control type-I error at the cost of either excluding some sequenced cases or correcting the genotypes of discovered rare variants. All of these approaches thus suffer from certain extent of information loss and thus are underpowered. We propose a novel method (BETASEQ), which corrects inflation of type-I error by supplementing pseudo-variants while keeps the original sequence and genotype data intact. Extensive simulations and real data analysis demonstrate that, in most practical situations, BETASEQ leads to higher testing powers than existing approaches with guaranteed (controlled or conservative) type-I error. AVAILABILITY AND IMPLEMENTATION BETASEQ and associated R files, including documentation, examples, are available at http://www.unc.edu/~yunmli/betaseq
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Affiliation(s)
- Song Yan
- Department of Biostatistics, University of North Carolina, 3101 McGavran-Greenberg Hall, Chapel Hill, NC 27599, USA, Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA and Department of Computer Science, University of North Carolina, Chapel Hill, NC 27599, USA
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Qiao D, Cho MH, Fier H, Bakke PS, Gulsvik A, Silverman EK, Lange C. On the simultaneous association analysis of large genomic regions: a massive multi-locus association test. ACTA ACUST UNITED AC 2013; 30:157-64. [PMID: 24262215 DOI: 10.1093/bioinformatics/btt654] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
MOTIVATION For samples of unrelated individuals, we propose a general analysis framework in which hundred thousands of genetic loci can be tested simultaneously for association with complex phenotypes. The approach is built on spatial-clustering methodology, assuming that genetic loci that are associated with the target phenotype cluster in certain genomic regions. In contrast to standard methodology for multilocus analysis, which has focused on the dimension reduction of the data, our multilocus association-clustering test profits from the availability of large numbers of genetic loci by detecting clusters of loci that are associated with the phenotype. RESULTS The approach is computationally fast and powerful, enabling the simultaneous association testing of large genomic regions. Even the entire genome or certain chromosomes can be tested simultaneously. Using simulation studies, the properties of the approach are evaluated. In an application to a genome-wide association study for chronic obstructive pulmonary disease, we illustrate the practical relevance of the proposed method by simultaneously testing all genotyped loci of the genome-wide association study and by testing each chromosome individually. Our findings suggest that statistical methodology that incorporates spatial-clustering information will be especially useful in whole-genome sequencing studies in which millions or billions of base pairs are recorded and grouped by genomic regions or genes, and are tested jointly for association. AVAILABILITY AND IMPLEMENTATION Implementation of the approach is available upon request.
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Affiliation(s)
- Dandi Qiao
- Department of Biostatistics, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 20115, USA, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA, Department of Genomic Mathematics, University of Bonn, 53113 Bonn, Germany and Department of Thoracic Medicine, Haukeland University Hospital and Section for Respiratory Medicine Institute of Medicine, University of Bergen, 5006 Bergen, Norway
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Evaluating empirical bounds on complex disease genetic architecture. Nat Genet 2013; 45:1418-27. [PMID: 24141362 DOI: 10.1038/ng.2804] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 09/30/2013] [Indexed: 12/13/2022]
Abstract
The genetic architecture of human diseases governs the success of genetic mapping and the future of personalized medicine. Although numerous studies have queried the genetic basis of common disease, contradictory hypotheses have been advocated about features of genetic architecture (for example, the contribution of rare versus common variants). We developed an integrated simulation framework, calibrated to empirical data, to enable the systematic evaluation of such hypotheses. For type 2 diabetes (T2D), two simple parameters--(i) the target size for causal mutation and (ii) the coupling between selection and phenotypic effect--define a broad space of architectures. Whereas extreme models are excluded by the combination of epidemiology, linkage and genome-wide association studies, many models remain consistent, including those where rare variants explain either little (<25%) or most (>80%) of T2D heritability. Ongoing sequencing and genotyping studies will further constrain the space of possible architectures, but very large samples (for example, >250,000 unselected individuals) will be required to localize most of the heritability underlying T2D and other traits characterized by these models.
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Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet 2013; 132:1077-130. [PMID: 23820649 PMCID: PMC3778950 DOI: 10.1007/s00439-013-1331-2] [Citation(s) in RCA: 435] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 06/15/2013] [Indexed: 02/06/2023]
Abstract
Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as 'reduced (or incomplete) penetrance'. Reduced penetrance is not uncommon; indeed, there are many known examples of 'disease-causing mutations' that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.
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Affiliation(s)
- David N. Cooper
- Institute of Medical Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN UK
| | - Michael Krawczak
- Institute of Medical Informatics and Statistics, Christian-Albrechts University, 24105 Kiel, Germany
| | | | - Chris Tyler-Smith
- The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA UK
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Wang S, Yang Z, Ma JZ, Payne TJ, Li MD. Introduction to deep sequencing and its application to drug addiction research with a focus on rare variants. Mol Neurobiol 2013; 49:601-14. [PMID: 23990377 DOI: 10.1007/s12035-013-8541-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 08/16/2013] [Indexed: 11/30/2022]
Abstract
Through linkage analysis, candidate gene approach, and genome-wide association studies (GWAS), many genetic susceptibility factors for substance dependence have been discovered such as the alcohol dehydrogenase gene (ALDH2) for alcohol dependence (AD) and nicotinic acetylcholine receptor (nAChR) subunit variants on chromosomes 8 and 15 for nicotine dependence (ND). However, these confirmed genetic factors contribute only a small portion of the heritability responsible for each addiction. Among many potential factors, rare variants in those identified and unidentified susceptibility genes are supposed to contribute greatly to the missing heritability. Several studies focusing on rare variants have been conducted by taking advantage of next-generation sequencing technologies, which revealed that some rare variants of nAChR subunits are associated with ND in both genetic and functional studies. However, these studies investigated variants for only a small number of genes and need to be expanded to broad regions/genes in a larger population. This review presents an update on recently developed methods for rare-variant identification and association analysis and on studies focused on rare-variant discovery and function related to addictions.
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Affiliation(s)
- Shaolin Wang
- Department of Psychiatry & Neurobiology Science, University of Virginia, 1670 Discovery Drive, Suite 110, Charlottesville, VA, 22911, USA
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Long N, Dickson SP, Maia JM, Kim HS, Zhu Q, Allen AS. Leveraging prior information to detect causal variants via multi-variant regression. PLoS Comput Biol 2013; 9:e1003093. [PMID: 23762022 PMCID: PMC3675126 DOI: 10.1371/journal.pcbi.1003093] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Accepted: 04/29/2013] [Indexed: 01/03/2023] Open
Abstract
Although many methods are available to test sequence variants for association with complex diseases and traits, methods that specifically seek to identify causal variants are less developed. Here we develop and evaluate a Bayesian hierarchical regression method that incorporates prior information on the likelihood of variant causality through weighting of variant effects. By simulation studies using both simulated and real sequence variants, we compared a standard single variant test for analyzing variant-disease association with the proposed method using different weighting schemes. We found that by leveraging linkage disequilibrium of variants with known GWAS signals and sequence conservation (phastCons), the proposed method provides a powerful approach for detecting causal variants while controlling false positives. The decline in DNA sequencing cost permits the interrogation of potentially all variants across the entire allele frequency spectrum for their associations with complex human diseases and traits. However, the identification of causal variants remains challenging. Existing single variant tests do not distinguish between causal association and association induced by linkage disequilibrium and tend to be underpowered for rare or low-frequency variants, whereas variant grouping methods do not identify individual causal variants. We propose a novel Bayesian hierarchical regression approach that estimates effects of multiple variants on a disease trait simultaneously and incorporates prior information on the likelihood of causality. By simulation, we show that by combining linkage disequilibrium with known genome wide association signals and functional conservation, the proposed method, the first of its kind, is powerful to correctly detect causal variants.
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Affiliation(s)
- Nanye Long
- Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, United States of America.
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Liang J, Lin C, Hu F, Wang F, Zhu L, Yao X, Wang Y, Zhao Y. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am J Epidemiol 2013; 177:1169-79. [PMID: 23576677 DOI: 10.1093/aje/kws382] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Adenomatous polyposis coli gene (APC) polymorphisms may influence the risk for colorectal neoplasia. However, results thus far have been inconclusive. We performed a systematic literature search of the Medline, Embase, Cochrane Collaboration, and HuGE databases and reviewed the references of pertinent articles through May 2012. Odds ratios with 95% confidence intervals were used to estimate the association between 3 APC polymorphisms (D1822V, E1317Q, and I1307K) and colorectal neoplasia. In total, 40 studies from 1997 to 2010 were included in this meta-analysis, and individuals with the D1822V variant homozygote VV genotype had a slight decrease in the risk for colorectal neoplasia compared with the wild-type homozygote DD genotype (pooled odds ratio = 0.87, 95% confidence interval: 0.77, 0.99). There was a small association between the APC E1317Q polymorphism and a risk for colorectal neoplasia (variant vs. wild-type: pooled odds ratio = 1.41, 95% confidence interval: 1.14, 1.76), particularly for colorectal adenomas (variant vs. wild-type: odds ratio = 2.89, 95% confidence interval: 1.83, 4.56). Compared with those who carried the wild-type I1307K, Ashkenazi Jews who carried the I1307K variant were at a significantly increased risk for colorectal neoplasia, with a pooled odds ratio of 2.17 (95% confidence interval: 1.64, 2.86). Our study suggests that APC is a candidate gene for colorectal neoplasia susceptibility.
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Affiliation(s)
- Jing Liang
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, China
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Haiman CA, Han Y, Feng Y, Xia L, Hsu C, Sheng X, Pooler LC, Patel Y, Kolonel LN, Carter E, Park K, Le Marchand L, Van Den Berg D, Henderson BE, Stram DO. Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. PLoS Genet 2013; 9:e1003419. [PMID: 23555315 PMCID: PMC3610631 DOI: 10.1371/journal.pgen.1003419] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Accepted: 02/12/2013] [Indexed: 12/19/2022] Open
Abstract
Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes LDLRAD1, SLC19A1, FGFBP3, CASP5, MMAB, SLC16A6, and INS-IGF2. In prostate cancer, one of the most associated SNPs was in the gene GPRC6A (rs2274911, Pro91Ser, OR = 0.88, P = 1.3 × 10(-5)) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as F13A1, ANXA4, MANSC1, and GP6. For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in LDLRAD1, p = 2.5 × 10(-7) only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.
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Affiliation(s)
- Christopher A. Haiman
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Ying Han
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Ye Feng
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Lucy Xia
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Chris Hsu
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Xin Sheng
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Loreall C. Pooler
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Yesha Patel
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Laurence N. Kolonel
- Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii, United States of America
| | - Erin Carter
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Karen Park
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Loic Le Marchand
- Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, Hawaii, United States of America
| | - David Van Den Berg
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Brian E. Henderson
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Daniel O. Stram
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
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Abstract
Keratoconus (KC) is one of the leading causes for keratoplasty. While the genetic aetiology of more and more corneal dystrophies is revealed, KC falls behind. And it is not because of lack of effort. The diversity in the many published results from over two decades is discussed in relation to the present knowledge in molecular biology. Results that at first appear to be in conflict with each other make sense when placed in the right context. Ophthalmologists often refer to KC as a heterogeneous disease. This review demonstrates that it truly is a multifactorial disease. Despite the many attempts to reveal the aetiology of KC, the pathological mechanism(s) still remain to be solved.
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Affiliation(s)
- Kim Nielsen
- Department of Ophthalmology, Aarhus University Hospital, Aarhus C, Denmark.
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Wagner MJ. Rare-variant genome-wide association studies: a new frontier in genetic analysis of complex traits. Pharmacogenomics 2013; 14:413-24. [DOI: 10.2217/pgs.13.36] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Genome-wide association studies have, in the last few years, identified thousands of common genetic variants associated with common complex traits and diseases, implicating many genes not previously known to be involved in the biology of those traits. However, these variants have so far explained little of the population variance in trait values or disease susceptibility. As large-scale genome sequencing efforts have revealed the extent of genetic variation at the low end of the frequency range in human populations, the effects of rare variants have been proposed as an explanation of the ‘missing genetic variance.’ Improved technologies for genotyping rare variants, including inexpensive whole-genome and whole-exome sequencing and rare-variant genotyping chips, coupled with novel analytical methods, are making genome-wide scans for the effects of rare variants possible, and seem likely to usher in a new era in the genetic analysis of complex traits.
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Affiliation(s)
- Michael J Wagner
- Institute for Pharmacogenomics & Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7361, USA
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Thornton KR, Foran AJ, Long AD. Properties and modeling of GWAS when complex disease risk is due to non-complementing, deleterious mutations in genes of large effect. PLoS Genet 2013; 9:e1003258. [PMID: 23437004 PMCID: PMC3578756 DOI: 10.1371/journal.pgen.1003258] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 12/02/2012] [Indexed: 01/08/2023] Open
Abstract
Current genome-wide association studies (GWAS) have high power to detect intermediate frequency SNPs making modest contributions to complex disease, but they are underpowered to detect rare alleles of large effect (RALE). This has led to speculation that the bulk of variation for most complex diseases is due to RALE. One concern with existing models of RALE is that they do not make explicit assumptions about the evolution of a phenotype and its molecular basis. Rather, much of the existing literature relies on arbitrary mapping of phenotypes onto genotypes obtained either from standard population-genetic simulation tools or from non-genetic models. We introduce a novel simulation of a 100-kilobase gene region, based on the standard definition of a gene, in which mutations are unconditionally deleterious, are continuously arising, have partially recessive and non-complementing effects on phenotype (analogous to what is widely observed for most Mendelian disorders), and are interspersed with neutral markers that can be genotyped. Genes evolving according to this model exhibit a characteristic GWAS signature consisting of an excess of marginally significant markers. Existing tests for an excess burden of rare alleles in cases have low power while a simple new statistic has high power to identify disease genes evolving under our model. The structure of linkage disequilibrium between causative mutations and significantly associated markers under our model differs fundamentally from that seen when rare causative markers are assumed to be neutral. Rather than tagging single haplotypes bearing a large number of rare causative alleles, we find that significant SNPs in a GWAS tend to tag single causative mutations of small effect relative to other mutations in the same gene. Our results emphasize the importance of evaluating the power to detect associations under models that are genetically and evolutionarily motivated. Current GWA studies typically only explain a small fraction of heritable variation in complex traits, resulting in speculation that a large fraction of variation in such traits may be due to rare alleles of large effect (RALE). The most parsimonious evolutionary mechanism that results in an inverse relationship between the frequency and effect size of causative alleles is an equilibrium between newly arising deleterious mutations and selection eliminating those mutations, resulting in an inverse relation between effect size and average frequency. This assumption is not built into many current models of RALE and, as a result, power calculations may be misleading. We use forward population genetic simulations to explore the ability of GWAS to detect genes in which unconditionally deleterious, partially recessive mutations arise each generation. Our model is based on the standard definition of a gene as a region within which loss-of-function mutations fail to complement, consistent with the multi-allelic basis for Mendelian disorders. Our model predicts that it may not be uncommon for single genes evolving under our model to contribute upwards of 5% to variation in a complex trait, and that such genes could be routinely detected via modified GWAS approaches.
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Affiliation(s)
- Kevin R. Thornton
- Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, California, United States of America
- * E-mail: (KRT); (ADL)
| | - Andrew J. Foran
- Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, California, United States of America
| | - Anthony D. Long
- Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, California, United States of America
- * E-mail: (KRT); (ADL)
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APC Germline Mutations in Individuals Being Evaluated for Familial Adenomatous Polyposis. J Mol Diagn 2013; 15:31-43. [DOI: 10.1016/j.jmoldx.2012.07.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Revised: 06/04/2012] [Accepted: 07/13/2012] [Indexed: 02/07/2023] Open
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Affiliation(s)
- Karen Nuytemans
- Department of Human Genetics, University of Miami, Miami, FL 33136, USA
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Role of rare variants in undetermined multiple adenomatous polyposis and early-onset colorectal cancer. J Hum Genet 2012; 57:709-716. [PMID: 22875147 DOI: 10.1038/jhg.2012.99] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Some 15-20% of multiple adenomatous polyposis have no genetic explanation and 20-30% of colorectal cancer (CRC) cases are thought to be due to inherited multifactorial causes. Accumulation of deleterious effects of low-frequency dominant and independently acting variants may be a partial explanation for such patients. The aim of this study was to type a selection of rare and low-frequency variants (<5%) to elucidate their role in CRC susceptibility. A total of 1181 subjects were included (866 controls; 315 cases). Cases comprised UK (n=184) and French (n=131) patients with MAP (n=187) or early-onset CRC (n=128). Seventy variants in 17 genes were examined in cases and controls. The effect of the variant effect on protein function was investigated in silico. Out of the 70 variants typed, 36 (51%) were tested for association. Twenty-one variants were rare (minor allele frequency (MAF) <1%). Four rare variants were found to have a significantly higher MAF in cases (EXO1-12, MLH1-1, CTNNB1-1 and BRCA2-37, P<0.05) than in controls. Pooling all rare variants with a MAF <0.5% showed an excess risk in cases (odds ratio=3.2; 95% confidence interval=1.1-9.5; P=0.04). Rare variants are important risk factors in CRC and, as such, should be systematically assayed alongside common variation in the search for the genetic basis of complex diseases.
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A functional germline variant in the P53 polyadenylation signal and risk of esophageal squamous cell carcinoma. Gene 2012; 506:295-7. [PMID: 22800615 DOI: 10.1016/j.gene.2012.07.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 07/03/2012] [Accepted: 07/05/2012] [Indexed: 11/22/2022]
Abstract
AIM P53 plays a critical role in the maintenance of genomic stability as well as the control of cell growth and apoptosis. Recently, an uncommon P53 genetic variant (rs78378222) was reported to be significantly associated with multiple cancers in Caucasians in a genome-wide association study. rs78378222 locates in the 3'-untranslated region of the P53 gene, and this A-to-C polymorphism results in changes of the AATAAA polyadenylation signal to AATACA, which leads to impaired 3'-end processing of P53 mRNA and decreased P53 expression. METHODS We evaluated the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk in a case-control cohort consisting of 405 ESCC patients and 810 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. RESULTS We did observe this polymorphism with low minor allele frequency in Chinese Han population. Additionally, significantly increased ESCC risk was associated with P53 rs78378222 A>C polymorphism. Compared with rs78378222AA carriers, the OR of developing ESCC for AC carriers was 3.22 (95% CI=1.71-6.33, P=1.34×10(-4)). CONCLUSION These results suggest that this functional uncommon P53 rs78378222 variant is associated with ESCC risk in the current Han Chinese population.
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A noncomplementation screen for quantitative trait alleles in saccharomyces cerevisiae. G3-GENES GENOMES GENETICS 2012; 2:753-60. [PMID: 22870398 PMCID: PMC3385981 DOI: 10.1534/g3.112.002550] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 04/30/2012] [Indexed: 11/18/2022]
Abstract
Both linkage and linkage disequilibrium mapping provide well-defined approaches to mapping quantitative trait alleles. However, alleles of small effect are particularly difficult to refine to individual genes and causative mutations. Quantitative noncomplementation provides a means of directly testing individual genes for quantitative trait alleles in a fixed genetic background. Here, we implement a genome-wide noncomplementation screen for quantitative trait alleles that affect colony color or size by using the yeast deletion collection. As proof of principle, we find a previously known allele of CYS4 that affects colony color and a novel allele of CTT1 that affects resistance to hydrogen peroxide. To screen nearly 4700 genes in nine diverse yeast strains, we developed a high-throughput robotic plating assay to quantify colony color and size. Although we found hundreds of candidate alleles, reciprocal hemizygosity analysis of a select subset revealed that many of the candidates were false positives, in part the result of background-dependent haploinsufficiency or second-site mutations within the yeast deletion collection. Our results highlight the difficulty of identifying small-effect alleles but support the use of noncomplementation as a rapid means of identifying quantitative trait alleles of large effect.
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Sanghera DK, Blackett PR. Type 2 Diabetes Genetics: Beyond GWAS. JOURNAL OF DIABETES & METABOLISM 2012; 3:6948. [PMID: 23243555 PMCID: PMC3521576 DOI: 10.4172/2155-6156.1000198] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The global epidemic of type 2 diabetes mellitus (T2D) is one of the most challenging problems of the 21(st) century leading cause of and the fifth death worldwide. Substantial evidence suggests that T2D is a multifactorial disease with a strong genetic component. Recent genome-wide association studies (GWAS) have successfully identified and replicated nearly 75 susceptibility loci associated with T2D and related metabolic traits, mostly in Europeans, and some in African, and South Asian populations. The GWAS serve as a starting point for future genetic and functional studies since the mechanisms of action by which these associated loci influence disease is still unclear and it is difficult to predict potential implication of these findings in clinical settings. Despite extensive replication, no study has unequivocally demonstrated their clinical role in the disease management beyond progression to T2D from impaired glucose tolerance. However, these studies are revealing new molecular pathways underlying diabetes etiology, gene-environment interactions, epigenetic modifications, and gene function. This review highlights evolving progress made in the rapidly moving field of T2D genetics that is starting to unravel the pathophysiology of a complex phenotype and has potential to show clinical relevance in the near future.
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