#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#
preLekára.sk / Odborné časopisy / PLOS Genetics / 2013 - 10

Eleven Candidate Susceptibility Genes for Common Familial Colorectal Cancer

English version České info

Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.

Vyšlo v časopise: Eleven Candidate Susceptibility Genes for Common Familial Colorectal Cancer. PLoS Genet 9(10): e32767. doi:10.1371/journal.pgen.1003876
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003876

Souhrn

Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.

Zdroje

1. ParkinDM, BrayF, FerlayJ, PisaniP (2005) Global cancer statistics, 2002. CA Cancer J Clin 55 : 74–108.

2. American Cancer Society (2013) Cancer Facts & Figures 2013. Available: http://www.cancer.org/acs/groups/content/epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed 26 July 2013.

3. LichtensteinP, HolmNV, VerkasaloPK, IliadouA, KaprioJ, et al. (2000) Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from sweden, denmark, and finland. N Engl J Med 343 : 78–85.

4. AaltonenLA, SalovaaraR, KristoP, CanzianF, HemminkiA, et al. (1998) Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 338 : 1481–1487.

5. PallesC, CazierJB, HowarthKM, DomingoE, JonesAM, et al. (2012) Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 45 : 136–144.

6. PearsonP, FrancomanoC, FosterP, BocchiniC, LiP, et al. (1994) The status of online mendelian inheritance in man (OMIM) medio 1994. Nucleic Acids Res 22 : 3470–3473.

7. LakenSJ, PetersenGM, GruberSB, OddouxC, OstrerH, et al. (1997) Familial colorectal cancer in ashkenazim due to a hypermutable tract in APC. Nat Genet 17 : 79–83.

8. ClearySP, ZhangW, Di NicolaN, AronsonM, AubeJ, et al. (2003) Heterozygosity for the BLM(ash) mutation and cancer risk. Cancer Res 63 : 1769–1771.

9. GudaK, MoinovaH, HeJ, JamisonO, RaviL, et al. (2009) Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers. Proc Natl Acad Sci U S A 106 : 12921–12925.

10. LubbeSJ, Di BernardoMC, BroderickP, ChandlerI, HoulstonRS (2012) Comprehensive evaluation of the impact of 14 genetic variants on colorectal cancer phenotype and risk. Am J Epidemiol 175 : 1–10.

11. DunlopMG, DobbinsSE, FarringtonSM, JonesAM, PallesC, et al. (2012) Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat Genet 44 : 770–776.

12. DunlopMG, TenesaA, FarringtonSM, BallereauS, BrewsterDH, et al. (2013) Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. Gut 62 : 871–881.

13. NiittymakiI, KaasinenE, TuupanenS, KarhuA, JarvinenH, et al. (2010) Low-penetrance susceptibility variants in familial colorectal cancer. Cancer Epidemiol Biomarkers Prev 19 : 1478–1483.

14. PeltonenL, PalotieA, LangeK (2000) Use of population isolates for mapping complex traits. Nat Rev Genet 1 : 182–190.

15. JakkulaE, RehnstromK, VariloT, PietilainenOP, PaunioT, et al. (2008) The genome-wide patterns of variation expose significant substructure in a founder population. Am J Hum Genet 83 : 787–794.

16. Genomes Project Consortium (2012) AbecasisGR, AutonA, BrooksLD, DePristoMA, et al. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491 : 56–65.

17. KuCS, NaidooN, PawitanY (2011) Revisiting mendelian disorders through exome sequencing. Hum Genet 129 : 351–370.

18. SalovaaraR, LoukolaA, KristoP, KaariainenH, AhtolaH, et al. (2000) Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 18 : 2193–2200.

19. FletcherO, HoulstonRS (2010) Architecture of inherited susceptibility to common cancer. Nat Rev Cancer 10 : 353–361.

20. BodmerW, BonillaC (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40 : 695–701.

21. GibsonG (2012) Rare and common variants: twenty arguments. Nat Rev Genet 13 : 135–145.

22. LiuL, SakaiT, SanoN, FukuiK (2004) Nucling mediates apoptosis by inhibiting expression of galectin-3 through interference with nuclear factor kappaB signalling. Biochem J 380 : 31–41.

23. MoravcikovaE, KrepelaE, ProchazkaJ, RousalovaI, CermakJ, et al. (2012) Down-regulated expression of apoptosis-associated genes APIP and UACA in non-small cell lung carcinoma. Int J Oncol 40 : 2111–2121.

24. ChangC, HoltzmanDA, ChauS, ChickeringT, WoolfEA, et al. (2001) Twisted gastrulation can function as a BMP antagonist. Nature 410 : 483–487.

25. TzachanisD, LiL, LafuenteEM, BerezovskayaA, FreemanGJ, et al. (2007) Twisted gastrulation (tsg) is regulated by tob and enhances TGF-beta signaling in activated T lymphocytes. Blood 109 : 2944–2952.

26. MeachamF, BoffelliD, DhahbiJ, MartinDI, SingerM, et al. (2011) Identification and correction of systematic error in high-throughput sequence data. BMC Bioinformatics 12 : 451-2105-12-451.

27. TuupanenS, NiittymakiI, NousiainenK, VanharantaS, MecklinJP, et al. (2008) Allelic imbalance at rs6983267 suggests selection of the risk allele in somatic colorectal tumor evolution. Cancer Res 68 : 14–17.

Štítky
Genetika Reprodukčná medicína
Článek Defending Sperm Function
Článek How to Choose the Right Mate
Článek A Mutation in the Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation
Článek Conserved Translatome Remodeling in Nematode Species Executing a Shared Developmental Transition
Článek A Novel Actin mRNA Splice Variant Regulates ACTG1 Expression
Článek Tracking Proliferative History in Lymphocyte Development with Cre-Mediated Sister Chromatid Recombination
Článek Correlated Occurrence and Bypass of Frame-Shifting Insertion-Deletions (InDels) to Give Functional Proteins
Článek Chimeric Protein Complexes in Hybrid Species Generate Novel Phenotypes
Článek Loss of miR-10a Activates and Collaborates with Activated Wnt Signaling in Inducing Intestinal Neoplasia in Female Mice
Článek Both Rare and Copy Number Variants Are Prevalent in Agenesis of the Corpus Callosum but Not in Cerebellar Hypoplasia or Polymicrogyria
Článek Reverse PCA, a Systematic Approach for Identifying Genes Important for the Physical Interaction between Protein Pairs
Článek Partial Deletion of Chromosome 8 β-defensin Cluster Confers Sperm Dysfunction and Infertility in Male Mice
Článek Genome-Wide and Cell-Specific Epigenetic Analysis Challenges the Role of Polycomb in Spermatogenesis
Článek Coordinate Regulation of Mature Dopaminergic Axon Morphology by Macroautophagy and the PTEN Signaling Pathway
Článek Cooperation between RUNX1-ETO9a and Novel Transcriptional Partner KLF6 in Upregulation of in Acute Myeloid Leukemia
Článek Mobility of the Native Conjugative Plasmid pLS20 Is Regulated by Intercellular Signaling
Článek FliZ Is a Global Regulatory Protein Affecting the Expression of Flagellar and Virulence Genes in Individual Bacterial Cells
Článek Specific Tandem Repeats Are Sufficient for Paramutation-Induced Trans-Generational Silencing
Článek Condensin II Subunit dCAP-D3 Restricts Retrotransposon Mobilization in Somatic Cells
Článek Dominant Mutations in Identify the Mlh1-Pms1 Endonuclease Active Site and an Exonuclease 1-Independent Mismatch Repair Pathway
Článek The Insulator Homie Promotes Expression and Protects the Adjacent Gene from Repression by Polycomb Spreading
Článek Human Intellectual Disability Genes Form Conserved Functional Modules in
Článek Coordination of Cell Proliferation and Cell Fate Determination by CES-1 Snail
Článek ORFs in Drosophila Are Important to Organismal Fitness and Evolved Rapidly from Previously Non-coding Sequences
Článek Different Roles of Eukaryotic MutS and MutL Complexes in Repair of Small Insertion and Deletion Loops in Yeast
Článek The Spore Differentiation Pathway in the Enteric Pathogen
Článek Acceleration of the Glycolytic Flux by Steroid Receptor Coactivator-2 Is Essential for Endometrial Decidualization
Článek The Human Nuclear Poly(A)-Binding Protein Promotes RNA Hyperadenylation and Decay
Článek Genome Wide Analysis Reveals Zic3 Interaction with Distal Regulatory Elements of Stage Specific Developmental Genes in Zebrafish
Článek Xbp1 Directs Global Repression of Budding Yeast Transcription during the Transition to Quiescence and Is Important for the Longevity and Reversibility of the Quiescent State
Článek The Integrator Complex Subunit 6 (Ints6) Confines the Dorsal Organizer in Vertebrate Embryogenesis
Článek Incorporating Motif Analysis into Gene Co-expression Networks Reveals Novel Modular Expression Pattern and New Signaling Pathways
Článek The Bacterial Response Regulator ArcA Uses a Diverse Binding Site Architecture to Regulate Carbon Oxidation Globally
Článek Direct Monitoring of the Strand Passage Reaction of DNA Topoisomerase II Triggers Checkpoint Activation
Článek Multiple bHLH Proteins form Heterodimers to Mediate CRY2-Dependent Regulation of Flowering-Time in
Článek A Reversible Histone H3 Acetylation Cooperates with Mismatch Repair and Replicative Polymerases in Maintaining Genome Stability
Článek ALS-Associated Mutations Result in Compromised Alternative Splicing and Autoregulation
Článek Robust Demographic Inference from Genomic and SNP Data
Článek Preferential Binding to Elk-1 by SLE-Associated Risk Allele Upregulates Expression
Článek Rad52 Sumoylation Prevents the Toxicity of Unproductive Rad51 Filaments Independently of the Anti-Recombinase Srs2
Článek The Serum Resistome of a Globally Disseminated Multidrug Resistant Uropathogenic Clone
Článek Identification of 526 Conserved Metazoan Genetic Innovations Exposes a New Role for Cofactor E-like in Neuronal Microtubule Homeostasis
Článek SUMO Localizes to the Central Element of Synaptonemal Complex and Is Required for the Full Synapsis of Meiotic Chromosomes in Budding Yeast
Článek Integrated Enrichment Analysis of Variants and Pathways in Genome-Wide Association Studies Indicates Central Role for IL-2 Signaling Genes in Type 1 Diabetes, and Cytokine Signaling Genes in Crohn's Disease
Článek Genome-Wide High-Resolution Mapping of UV-Induced Mitotic Recombination Events in
Článek Genome-Wide Analysis of Cell Type-Specific Gene Transcription during Spore Formation in
Článek Playing the Field: Sox10 Recruits Different Partners to Drive Central and Peripheral Myelination
Článek Two Portable Recombination Enhancers Direct Donor Choice in Fission Yeast Heterochromatin
Článek Mining the Human Phenome Using Allelic Scores That Index Biological Intermediates
Článek Yeast Tdh3 (Glyceraldehyde 3-Phosphate Dehydrogenase) Is a Sir2-Interacting Factor That Regulates Transcriptional Silencing and rDNA Recombination
Článek A Minimal Nitrogen Fixation Gene Cluster from sp. WLY78 Enables Expression of Active Nitrogenase in
Článek A Review of Bacteria-Animal Lateral Gene Transfer May Inform Our Understanding of Diseases like Cancer
Článek High Throughput Sequencing Reveals Alterations in the Recombination Signatures with Diminishing Spo11 Activity
Článek Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture
Článek A GDF5 Point Mutation Strikes Twice - Causing BDA1 and SYNS2
Článek Systematic Unraveling of the Unsolved Pathway of Nicotine Degradation in
Článek Natural Genetic Variation of Integrin Alpha L () Modulates Ischemic Brain Injury in Stroke
Článek Evolutionary Tuning of Protein Expression Levels of a Positively Autoregulated Two-Component System
Článek Evolutionary Change within a Bipotential Switch Shaped the Sperm/Oocyte Decision in Hermaphroditic Nematodes
Článek Limiting of the Innate Immune Response by SF3A-Dependent Control of MyD88 Alternative mRNA Splicing
Článek Multiple Signaling Pathways Coordinate to Induce a Threshold Response in a Chordate Embryo
Článek Distinct Regulatory Mechanisms Act to Establish and Maintain Pax3 Expression in the Developing Neural Tube
Článek Genome Wide Analysis of Narcolepsy in China Implicates Novel Immune Loci and Reveals Changes in Association Prior to Versus After the 2009 H1N1 Influenza Pandemic
Článek Mismatch Repair Genes and Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches
Článek The Histone H3 K27 Methyltransferase KMT6 Regulates Development and Expression of Secondary Metabolite Gene Clusters
Článek Hsp70-Hsp40 Chaperone Complex Functions in Controlling Polarized Growth by Repressing Hsf1-Driven Heat Stress-Associated Transcription
Článek Function and Evolution of DNA Methylation in
Článek Stimulation of mTORC1 with L-leucine Rescues Defects Associated with Roberts Syndrome
Článek Transcription Termination and Chimeric RNA Formation Controlled by FPA
Článok vyšiel v časopise

PLOS Genetics

2013 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

nový kurz
Autori: doc. MUDr. David Zemánek, Ph.D., MUDr. Anna Chaloupka, Ph.D.
Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#