Abnormal DNA methylation as a cell-free circulating DNA biomarker for colorectal cancer detection:A review of literature
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摘要
Colorectal cancer(CRC) is one of the most prevalent malignancies in the world. CRC-associated morbidity and mortality is continuously increasing, in part due to a lack of early detection. The existing screening tools such as colonoscopy, are invasive and yet high cost, affecting the willingness of patients to participate in screening programs. In recent years, evidence is accumulating that the interaction of aberrant genetic and epigenetic modifications is the cornerstone for the CRC development and progression by alternating the function of tumor suppressor genes, DNA repair genes and oncogenes of colonic cells. Apart from the understanding of the underlying mechanism(s) of carcinogenesis, the aforementioned interaction has also allowed identification of clinical biomarkers, especially epigenetic, for the early detection and prognosis of cancer patients. One of the ways to detect these epigenetic biomarkers is the cell-free circulating DNA(circ DNA), a blood-based cancer diagnostic test, mainly focusing in the molecular alterations found in tumor cells, such as DNA mutations and DNA methylation.In this brief review, we epitomize the current knowledge on the research in circ DNA biomarkers-mainly focusing on DNA methylation-as potential blood-based tests for early detection of colorectal cancer and the challenges for validation and globally implementation of this emergent technology.
Colorectal cancer(CRC) is one of the most prevalent malignancies in the world. CRC-associated morbidity and mortality is continuously increasing, in part due to a lack of early detection. The existing screening tools such as colonoscopy, are invasive and yet high cost, affecting the willingness of patients to participate in screening programs. In recent years, evidence is accumulating that the interaction of aberrant genetic and epigenetic modifications is the cornerstone for the CRC development and progression by alternating the function of tumor suppressor genes, DNA repair genes and oncogenes of colonic cells. Apart from the understanding of the underlying mechanism(s) of carcinogenesis, the aforementioned interaction has also allowed identification of clinical biomarkers, especially epigenetic, for the early detection and prognosis of cancer patients. One of the ways to detect these epigenetic biomarkers is the cell-free circulating DNA(circ DNA), a blood-based cancer diagnostic test, mainly focusing in the molecular alterations found in tumor cells, such as DNA mutations and DNA methylation.In this brief review, we epitomize the current knowledge on the research in circ DNA biomarkers-mainly focusing on DNA methylation-as potential blood-based tests for early detection of colorectal cancer and the challenges for validation and globally implementation of this emergent technology.
Colorectal cancer(CRC) is one of the most prevalent malignancies in the world. CRC-associated morbidity and mortality is continuously increasing, in part due to a lack of early detection. The existing screening tools such as colonoscopy, are invasive and yet high cost, affecting the willingness of patients to participate in screening programs. In recent years, evidence is accumulating that the interaction of aberrant genetic and epigenetic modifications is the cornerstone for the CRC development and progression by alternating the function of tumor suppressor genes, DNA repair genes and oncogenes of colonic cells. Apart from the understanding of the underlying mechanism(s) of carcinogenesis, the aforementioned interaction has also allowed identification of clinical biomarkers, especially epigenetic, for the early detection and prognosis of cancer patients. One of the ways to detect these epigenetic biomarkers is the cell-free circulating DNA(circ DNA), a blood-based cancer diagnostic test, mainly focusing in the molecular alterations found in tumor cells, such as DNA mutations and DNA methylation.In this brief review, we epitomize the current knowledge on the research in circ DNA biomarkers-mainly focusing on DNA methylation-as potential blood-based tests for early detection of colorectal cancer and the challenges for validation and globally implementation of this emergent technology.
引文
1 Siegel R,Desantis C,Jemal A.Colorectal cancer statistics,2014.CACancer J Clin 2014;64:104-117[PMID:24639052 DOI:10.3322/caac.21208]
2 Ferlay J,Shin HR,Bray F,Forman D,Mathers C and Parkin DM.GLOBOCAN 2008 v2.0,Cancer Incidence and Mortality Worldwide:IARC Cancer Base No.10[Internet].Lyon,France:International Agency for Research on Cancer,2010 Available from:URL:http://globocan.iarc.fr/
3 World Cancer Report.Cancer syte by syte-colorectal cancer.In:Boyle P,Levin B,editors.World cancer report 2008.Lyon:International Agency for Research on Cancer,2008:374-379
4 T?nzer M,Liebl M,Quante M.Molecular biomarkers in esophageal,gastric,and colorectal adenocarcinoma.Pharmacol Ther 2013;140:133-147[PMID:23791941 DOI:10.1016/j.pharmthera.2013.06.005]
5 Migliore L,Migheli F,Spisni R,CoppedèF.Genetics,cytogenetics,and epigenetics of colorectal cancer.J Biomed Biotechnol 2011;2011:792362[PMID:21490705]
6 Rodenhiser D,Mann M.Epigenetics and human disease:translating basic biology into clinical applications.CMAJ 2006;174:341-348[PMID:16446478 DOI:10.1503/cmaj.050774]
7 Segnan N,Patnick J,von Karsa L,editors.European guidelines for quality assurance in colorectal cancer screening and diagnosis.European guidelines for quality assurance in colorectal cancer screening and diagnosis-First edition.Luxembourg:European Commission,Publications Office of the European Union,2010
8 Brenner H,Chang-Claude J,Jansen L,Knebel P,Stock C,Hoffmeister M.Reduced risk of colorectal cancer up to 10 years after screening,surveillance,or diagnostic colonoscopy.Gastroenterology2014;146:709-717[PMID:24012982]
9 Corley DA,Jensen CD,Marks AR.Can we improve adenoma detection rates?A systematic review of intervention studies.Gastrointest Endosc 2011;74:656-665[PMID:21741643 DOI:10.1016/j.gie.2011.04.017]
10 Schoen RE,Pinsky PF,Weissfeld JL,Yokochi LA,Church T,Laiyemo AO,Bresalier R,Andriole GL,Buys SS,Crawford ED,Fouad MN,Isaacs C,Johnson CC,Reding DJ,O’Brien B,Carrick DM,Wright P,Riley TL,Purdue MP,Izmirlian G,Kramer BS,Miller AB,Gohagan JK,Prorok PC,Berg CD.Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy.NEngl J Med 2012;366:2345-2357[PMID:22612596 DOI:10.1056/NEJMoa1114635]
11 Shaukat A,Mongin SJ,Geisser MS,Lederle FA,Bond JH,Mandel JS,Church TR.Long-term mortality after screening for colorectal cancer.N Engl J Med 2013;369:1106-1114[PMID:24047060 DOI:10.1056/NEJMoa1300720]
12 Kaminski MF,Regula J,Kraszewska E,Polkowski M,Wojciechowska U,Didkowska J,Zwierko M,Rupinski M,Nowacki MP,Butruk E.Quality indicators for colonoscopy and the risk of interval cancer.N Engl J Med 2010;362:1795-1803[PMID:20463339 DOI:10.1056/NEJMoa0907667]
13 Binefa G,Rodríguez-Moranta F,Teule A,Medina-Hayas M.Colorectal cancer:from prevention to personalized medicine.World JGastroenterol 2014;20:6786-6808[PMID:24944469 DOI:10.3748/wjg.v20.i22.6786]
14 Fearon ER,Vogelstein B.A genetic model for colorectal tumorigenesis.Cell 1990;61:759-767[PMID:2188735]
15 Pino MS,Chung DC.The chromosomal instability pathway in colon cancer.Gastroenterology 2010;138:2059-2072[PMID:20420946DOI:10.1053/j.gastro.2009.12.065]
16 Boland CR,Sinicrope FA,Brenner DE,Carethers JM.Colorectal cancer prevention and treatment.Gastroenterology 2000;118:S115-S128[PMID:10868902]
17 Boland CR,Goel A.Microsatellite instability in colorectal cancer.Gastroenterology 2010;138:2073-2087.e3[PMID:20420947 DOI:10.1053/j.gastro.2009.12.064]
18 Wong JJ,Hawkins NJ,Ward RL.Colorectal cancer:a model for epigenetic tumorigenesis.Gut 2007;56:140-148[PMID:16840508DOI:10.1136/gut.2005.088799]
19 Jass JR.Classification of colorectal cancer based on correlation of clinical,morphological and molecular features.Histopathology2007;50:113-130[PMID:17204026 DOI:10.1111/j.1365-2559.2006.02549.x]
20 Feinberg AP,Vogelstein B.Hypomethylation distinguishes genes of some human cancers from their normal counterparts.Nature 1983;301:89-92[PMID:6185846 DOI:10.1038/301089a0]
21 Feinberg AP,Vogelstein B.Hypomethylation of ras oncogenes in primary human cancers.Biochem Biophys Res Commun 1983;111:47-54[PMID:6187346 DOI:10.1016/s0006-291x(83)80115-6]
22 Yamashita K,Dai T,Dai Y,Yamamoto F,Perucho M.Genetics supersedes epigenetics in colon cancer phenotype.Cancer Cell 2003;4:121-131[PMID:12957287 DOI:10.1016/s1535-6108(03)00190-9]
23 Goel A,Boland CR.Epigenetics of colorectal cancer.Gastroenterology2012;143:1442-1460.e1[PMID:23000599]
24 Luo L,Chen WD,Pretlow TP.Cp G island methylation in aberrant crypt foci and cancers from the same patients.Int J Cancer 2005;115:747-751[PMID:15704093 DOI:10.1002/ijc.20936]
25 Subramaniam MM,Chan JY,Soong R,Ito K,Yeoh KG,Wong R,Guenther T,Will O,Chen CL,Kumarasinghe MP,Ito Y,Salto-Tellez M.RUNX3 inactivation in colorectal polyps arising through different pathways of colonic carcinogenesis.Am J Gastroenterol 2009;104:426-436[PMID:19174785 DOI:10.1038/ajg.2008.141]
26 Wendt MK,Johanesen PA,Kang-Decker N,Binion DG,Shah V,Dwinell MB.Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis.Oncogene 2006;25:4986-4997[PMID:16568088 DOI:10.1038/sj.onc.1209505]
27 Umetani N,Takeuchi H,Fujimoto A,Shinozaki M,Bilchik AJ,Hoon DS.Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis.Clin Cancer Res2004;10:7475-7483[PMID:15569977 DOI:10.1158/1078-0432.CCR-04-0689]
28 Goel A,Nagasaka T,Arnold CN,Inoue T,Hamilton C,Niedzwiecki D,Compton C,Mayer RJ,Goldberg R,Bertagnolli MM,Boland CR.The Cp G island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer.Gastroenterology 2007;132:127-138[PMID:17087942 DOI:10.1053/j.gastro.2006.09.018]
29 Notterman DA,Alon U,Sierk AJ,Levine AJ.Transcriptional gene expression profiles of colorectal adenoma,adenocarcinoma,and normal tissue examined by oligonucleotide arrays.Cancer Res 2001;61:3124-3130[PMID:11306497]
30 Mandel P,Metais P.Les acides nucléiques du plasma sanguine chezl’homme.C R Seances Soc Biol Fil 1948;142:241-243[PMID:18875018]
31 Asworth TR.A case of cancer in which cells similar to those in tumors were seen in the blood after death.Aust Med J 1869;14:146-149
32 Imperiale TF,Ransohoff DF,Itzkowitz SH,Turnbull BA,Ross ME.Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population.N Engl J Med 2004;351:2704-2714[PMID:15616205 DOI:10.1056/NEJMoa033403]
33 Müller HM,Oberwalder M,Fiegl H,Morandell M,Goebel G,Zitt M,Mühlthaler M,Ofner D,Margreiter R,Widschwendter M.Methylation changes in faecal DNA:a marker for colorectal cancer screening?Lancet 2004;363:1283-1285[PMID:15094274 DOI:10.1016/S0140-6736(04)16002-9]
34 Sidransky D,Tokino T,Hamilton SR,Kinzler KW,Levin B,Frost P,Vogelstein B.Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors.Science 1992;256:102-105[PMID:1566048 DOI:10.1126/science.1566048]
35 Leon SA,Shapiro B,Sklaroff DM,Yaros MJ.Free DNA in the serum of cancer patients and the effect of therapy.Cancer Res 1977;37:646-650[PMID:837366]
36 Chen K,Zhang H,Zhang LN,Ju SQ,Qi J,Huang DF,Li F,Wei Q,Zhang J.Value of circulating cell-free DNA in diagnosis of hepatocelluar carcinoma.World J Gastroenterol 2013;19:3143-3149[PMID:23716996 DOI:10.3748/wjg.v19.i20.3143]
37 Qi J,Qian C,Shi W,Wu X,Jing R,Zhang L,Wang Z,Ju S.Alu-based cell-free DNA:a potential complementary biomarker for diagnosis of colorectal cancer.Clin Biochem 2013;46:64-69[PMID:22975639DOI:10.1016/j.clinbiochem.2012.08.026]
38 Kaiser J.Medicine.Keeping tabs on tumor DNA.Science 2010;327:1074[PMID:20185705 DOI:10.1126/science.327.5969.1074]
39 Herman JG,Graff JR,My?h?nen S,Nelkin BD,Baylin SB.Methylation-specific PCR:a novel PCR assay for methylation status of Cp G islands.Proc Natl Acad Sci USA 1996;93:9821-9826[PMID:8790415 DOI:10.1073/pnas.93.18.9821]
40 Kristensen LS,Mikeska T,Krypuy M,Dobrovic A.Sensitive Melting Analysis after Real Time-Methylation Specific PCR(SMART-MSP):high-throughput and probe-free quantitative DNA methylation detection.Nucleic Acids Res 2008;36:e42[PMID:18344521 DOI:10.1093/nar/gkn113]
41 Li M,Chen WD,Papadopoulos N,Goodman SN,Bjerregaard NC,Laurberg S,Levin B,Juhl H,Arber N,Moinova H,Durkee K,Schmidt K,He Y,Diehl F,Velculescu VE,Zhou S,Diaz LA,Kinzler KW,Markowitz SD,Vogelstein B.Sensitive digital quantification of DNA methylation in clinical samples.Nat Biotechnol 2009;27:858-863[PMID:19684580 DOI:10.1038/nbt.1559]
42 Leary RJ,Sausen M,Kinde I,Papadopoulos N,Carpten JD,Craig D,O’Shaughnessy J,Kinzler KW,Parmigiani G,Vogelstein B,Diaz LA,Velculescu VE.Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing.Sci Transl Med 2012;4:162ra154[PMID:23197571 DOI:10.1126/scitranslmed.3004742]
43 Schwarzenbach H,Stoehlmacher J,Pantel K,Goekkurt E.Detection and monitoring of cell-free DNA in blood of patients with colorectal cancer.Ann N Y Acad Sci 2008;1137:190-196[PMID:18837946DOI:10.1196/annals.1448.025]
44 Rykova EY,Morozkin ES,Ponomaryova AA,Loseva EM,Zaporozhchenko IA,Cherdyntseva NV,Vlassov VV,Laktionov PP.Cell-free and cell-bound circulating nucleic acid complexes:mechanisms of generation,concentration and content.Expert Opin Biol Ther 2012;12 Suppl 1:S141-S153[PMID:22500614 DOI:10.1517/14712598.2012.673577]
45 Umetani N,Kim J,Hiramatsu S,Reber HA,Hines OJ,Bilchik AJ,Hoon DS.Increased integrity of free circulating DNA in sera of patients with colorectal or periampullary cancer:direct quantitative PCR for ALU repeats.Clin Chem 2006;52:1062-1069[PMID:16723681 DOI:10.1373/clinchem.2006.068577]
46 da Silva Filho BF,Gurgel AP,Neto Má,de Azevedo DA,de Freitas AC,Silva Neto Jda C,Silva LA.Circulating cell-free DNA in serum as a biomarker of colorectal cancer.J Clin Pathol 2013;66:775-778[PMID:23833048 DOI:10.1136/jclinpath-2013-201521]
47 Leszinski G,Lehner J,Gezer U,Holdenrieder S.Increased DNAintegrity in colorectal cancer.In Vivo 2014;28:299-303[PMID:24815830]
48 Mouliere F,Robert B,Arnau Peyrotte E,Del Rio M,Ychou M,Molina F,Gongora C,Thierry AR.High fragmentation characterizes tumour-derived circulating DNA.PLo S One 2011;6:e23418[PMID:21909401 DOI:10.1371/journal.pone.0023418]
49 Mead R,Duku M,Bhandari P,Cree IA.Circulating tumour markers can define patients with normal colons,benign polyps,and cancers.Br J Cancer 2011;105:239-245[PMID:21712823 DOI:10.1038/bjc.2011.230]
50 Mouliere F,El Messaoudi S,Pang D,Dritschilo A,Thierry AR.Multimarker analysis of circulating cell-free DNA toward personalized medicine for colorectal cancer.Mol Oncol 2014;8:927-941[PMID:24698732 DOI:10.1016/j.molonc.2014.02.005]
51 Y?rüker EE,?zgür E,Keskin M,Dalay N,Holdenrieder S,Gezer U.Assessment of circulating serum DNA integrity in colorectal cancer patients.Anticancer Res 2015;35:2435-2440[PMID:25862911]
52 Hao TB,Shi W,Shen XJ,Qi J,Wu XH,Wu Y,Tang YY,Ju SQ.Circulating cell-free DNA in serum as a biomarker for diagnosis and prognostic prediction of colorectal cancer.Br J Cancer 2014;111:1482-1489[PMID:25157833 DOI:10.1038/bjc.2014.470]
53 Lazarev I,Leibovitch L,Czeiger D,Sion-Vardi N,Geffen DB,Douvdevani A,Ariad S.Cell-free DNA blood levels in colorectal cancer patients do not correlate with mismatch repair-proficiency.In Vivo 2014;28:349-354[PMID:24815837]
54 Cavalli LR,Liang BC.Mutagenesis,tumorigenicity,and apoptosis:are the mitochondria involved?Mutat Res 1998;398:19-26[PMID:9626961]
55 Zhu W,Qin W,Bradley P,Wessel A,Puckett CL,Sauter ER.Mitochondrial DNA mutations in breast cancer tissue and in matched nipple aspirate fluid.Carcinogenesis 2005;26:145-152[PMID:15375011 DOI:10.1093/carcin/bgh282]
56 Hibi K,Nakayama H,Yamazaki T,Takase T,Taguchi M,Kasai Y,Ito K,Akiyama S,Nakao A.Detection of mitochondrial DNA alterations in primary tumors and corresponding serum of colorectal cancer patients.Int J Cancer 2001;94:429-431[PMID:11745425 DOI:10.1002/ijc.1480]
57 Lecomte T,Berger A,ZinzindohouéF,Micard S,Landi B,Blons H,Beaune P,Cugnenc PH,Laurent-Puig P.Detection of free-circulating tumor-associated DNA in plasma of colorectal cancer patients and its association with prognosis.Int J Cancer 2002;100:542-548[PMID:12124803 DOI:10.1002/ijc.10526]
58 Diehl F,Li M,Dressman D,He Y,Shen D,Szabo S,Diaz LA,Goodman SN,David KA,Juhl H,Kinzler KW,Vogelstein B.Detection and quantification of mutations in the plasma of patients with colorectal tumors.Proc Natl Acad Sci USA 2005;102:16368-16373[PMID:16258065 DOI:10.1073/pnas.0507904102]
59 Yin H,Liang Y,Yan Z,Liu B,Su Q.Mutation spectrum in human colorectal cancers and potential functional relevance.BMC Med Genet2013;14:32[PMID:23497483 DOI:10.1186/1471-2350-14-32]
60 Jia D,Jurkowska RZ,Zhang X,Jeltsch A,Cheng X.Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNAmethylation.Nature 2007;449:248-251[PMID:17713477 DOI:10.1038/nature06146]
61 Esteller M.Epigenetics in cancer.N Engl J Med 2008;358:1148-1159[PMID:18337604 DOI:10.1056/NEJMra072067]
62 Hellman A,Chess A.Gene body-specific methylation on the active Xchromosome.Science 2007;315:1141-1143[PMID:17322062 DOI:10.1126/science.1136352]
63 Peeters M,Douillard JY,Van Cutsem E,Siena S,Zhang K,Williams R,Wiezorek J.Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer:assessment as prognostic and predictive biomarkers of response to panitumumab.J Clin Oncol 2013;31:759-765[PMID:23182985 DOI:10.1200/JCO.2012.45.1492]
64 Grützmann R,Molnar B,Pilarsky C,Habermann JK,Schlag PM,Saeger HD,Miehlke S,Stolz T,Model F,Roblick UJ,Bruch HP,Koch R,Liebenberg V,Devos T,Song X,Day RH,Sledziewski AZ,LoftonDay C.Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay.PLo S One 2008;3:e3759[PMID:19018278 DOI:10.1371/journal.pone.0003759]
65 Warren JD,Xiong W,Bunker AM,Vaughn CP,Furtado LV,Roberts WL,Fang JC,Samowitz WS,Heichman KA.Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer.BMCMed 2011;9:133[PMID:22168215 DOI:10.1186/1741-7015-9-133]
66 Church TR,Wandell M,Lofton-Day C,Mongin SJ,Burger M,Payne SR,Casta?os-Vélez E,Blumenstein BA,R?sch T,Osborn N,Snover D,Day RW,Ransohoff DF.Prospective evaluation of methylated SEPT9in plasma for detection of asymptomatic colorectal cancer.Gut 2014;63:317-325[PMID:23408352 DOI:10.1136/gutjnl-2012-304149]
67 T?nzer M,Balluff B,Distler J,Hale K,Leodolter A,R?cken C,Molnar B,Schmid R,Lofton-Day C,Schuster T,Ebert MP.Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions.PLo S One 2010;5:e9061[PMID:20140221 DOI:10.1371/journal.pone.0009061]
68 Kostin PA,Zakharzhevskaia NB,Generozov EV,Govorun VM,Chernyshov SV,Shchelygin Iu A.[Hypermethylation of the CDH1,SEPT9,HLTF and ALX4 genes and their diagnostic significance in colorectal cancer].Vopr Onkol 2010;56:162-168[PMID:20552891]
69 He Q,Chen HY,Bai EQ,Luo YX,Fu RJ,He YS,Jiang J,Wang HQ.Development of a multiplex Methy Light assay for the detection of multigene methylation in human colorectal cancer.Cancer Genet Cytogenet 2010;202:1-10[PMID:20804913 DOI:10.1016/j.cancerg encyto.2010.05.018]
70 Ahlquist DA,Taylor WR,Mahoney DW,Zou H,Domanico M,Thibodeau SN,Boardman LA,Berger BM,Lidgard GP.The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia.Clin Gastroenterol Hepatol 2012;10:272-277.e1[PMID:22019796 DOI:10.1016/j.cgh.2011.10.008]
71 Carmona FJ,Azuara D,Berenguer-Llergo A,Fernández AF,Biondo S,de Oca J,Rodriguez-Moranta F,Salazar R,Villanueva A,Fraga MF,Guardiola J,CapelláG,Esteller M,Moreno V.DNAmethylation biomarkers for noninvasive diagnosis of colorectal cancer.Cancer Prev Res(Phila)2013;6:656-665[PMID:23694962 DOI:10.1158/1940-6207.CAPR-12-0501]
72 Cassinotti E,Melson J,Liggett T,Melnikov A,Yi Q,Replogle C,Mobarhan S,Boni L,Segato S,Levenson V.DNA methylation patterns in blood of patients with colorectal cancer and adenomatous colorectal polyps.Int J Cancer 2012;131:1153-1157[PMID:22020530 DOI:10.1002/ijc.26484]
73 Lind GE,Danielsen SA,Ahlquist T,Merok MA,Andresen K,Skotheim RI,Hektoen M,Rognum TO,Meling GI,Hoff G,Bretthauer M,Thiis-Evensen E,Nesbakken A,Lothe RA.Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas.Mol Cancer 2011;10:85[PMID:21777459 DOI:10.1186/1476-4598-10-85]
74 Lee BB,Lee EJ,Jung EH,Chun HK,Chang DK,Song SY,Park J,Kim DH.Aberrant methylation of APC,MGMT,RASSF2A,and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer.Clin Cancer Res 2009;15:6185-6191[PMID:19773381 DOI:10.1158/1078-0432.CCR-09-0111]
75 Lange CP,Campan M,Hinoue T,Schmitz RF,van der Meulen-de Jong AE,Slingerland H,Kok PJ,van Dijk CM,Weisenberger DJ,Shen H,Tollenaar RA,Laird PW.Genome-scale discovery of DNA-methylation biomarkers for blood-based detection of colorectal cancer.PLo S One 2012;7:e50266[PMID:23209692 DOI:10.1371/journal.pone.0050266]
76 Ebert MP,Model F,Mooney S,Hale K,Lograsso J,Tonnes-Priddy L,Hoffmann J,Csepregi A,R?cken C,Molnar B,Schulz HU,Malfertheiner P,Lofton-Day C.Aristaless-like homeobox-4 gene methylation is a potential marker for colorectal adenocarcinomas.Gastroenterology 2006;131:1418-1430[PMID:17101318 DOI:10.1053/j.gastro.2006.08.034]
77 Gl?ckner SC,Dhir M,Yi JM,Mc Garvey KE,Van Neste L,Louwagie J,Chan TA,Kleeberger W,de Bru?ne AP,Smits KM,Khalidde Bakker CA,Jonkers DM,Stockbrügger RW,Meijer GA,Oort FA,Iacobuzio-Donahue C,Bierau K,Herman JG,Baylin SB,Van Engeland M,Schuebel KE,Ahuja N.Methylation of TFPI2 in stool DNA:a potential novel biomarker for the detection of colorectal cancer.Cancer Res 2009;69:4691-4699[PMID:19435926 DOI:10.1158/0008-5472.CAN-08-0142]
78 Hibi K,Goto T,Kitamura YH,Yokomizo K,Sakuraba K,Shirahata A,Mizukami H,Saito M,Ishibashi K,Kigawa G,Nemoto H,Sanada Y.Methylation of TFPI2 gene is frequently detected in advanced welldifferentiated colorectal cancer.Anticancer Res 2010;30:1205-1207[PMID:20530429]
79 Hibi K,Goto T,Shirahata A,Saito M,Kigawa G,Nemoto H,Sanada Y.Detection of TFPI2 methylation in the serum of colorectal cancer patients.Cancer Lett 2011;311:96-100[PMID:21820798 DOI:10.1016/j.canlet.2011.07.006]
80 Takada H,Wakabayashi N,Dohi O,Yasui K,Sakakura C,Mitsufuji S,Taniwaki M,Yoshikawa T.Tissue factor pathway inhibitor 2(TFPI2)is frequently silenced by aberrant promoter hypermethylation in gastric cancer.Cancer Genet Cytogenet 2010;197:16-24[PMID:20113832DOI:10.1016/j.cancergencyto.2009.11.004]
81 Oh T,Kim N,Moon Y,Kim MS,Hoehn BD,Park CH,Kim TS,Kim NK,Chung HC,An S.Genome-wide identification and validation of a novel methylation biomarker,SDC2,for blood-based detection of colorectal cancer.J Mol Diagn 2013;15:498-507[PMID:23747112DOI:10.1016/j.jmoldx.2013.03.004]
82 Nishio M,Sakakura C,Nagata T,Komiyama S,Miyashita A,Hamada T,Kuryu Y,Ikoma H,Kubota T,Kimura A,Nakanishi M,Ichikawa D,Fujiwara H,Okamoto K,Ochiai T,Kokuba Y,Sonoyama T,Ida H,Ito K,Chiba T,Ito Y,Otsuji E.RUNX3 promoter methylation in colorectal cancer:its relationship with microsatellite instability and its suitability as a novel serum tumor marker.Anticancer Res 2010;30:2673-2682[PMID:20682997]
83 Tan SH,Ida H,Lau QC,Goh BC,Chieng WS,Loh M,Ito Y.Detection of promoter hypermethylation in serum samples of cancer patients by methylation-specific polymerase chain reaction for tumour suppressor genes including RUNX3.Oncol Rep 2007;18:1225-1230[PMID:17914577]
84 Herbst A,Rahmig K,Stieber P,Philipp A,Jung A,Ofner A,Crispin A,Neumann J,Lamerz R,Kolligs FT.Methylation of NEUROG1 in serum is a sensitive marker for the detection of early colorectal cancer.Am J Gastroenterol 2011;106:1110-1118[PMID:21326223 DOI:10.1038/ajg.2011.6]
85 Lofton-Day C,Model F,Devos T,Tetzner R,Distler J,Schuster M,Song X,Lesche R,Liebenberg V,Ebert M,Molnar B,Grützmann R,Pilarsky C,Sledziewski A.DNA methylation biomarkers for bloodbased colorectal cancer screening.Clin Chem 2008;54:414-423[PMID:18089654 DOI:10.1373/clinchem.2007.095992]
86 de Vos T,Tetzner R,Model F,Weiss G,Schuster M,Distler J,Steiger KV,Grützmann R,Pilarsky C,Habermann JK,Fleshner PR,Oubre BM,Day R,Sledziewski AZ,Lofton-Day C.Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer.Clin Chem 2009;55:1337-1346[PMID:19406918 DOI:10.1373/clinchem.2008.115808]
87 Leung WK,To KF,Man EP,Chan MW,Bai AH,Hui AJ,Chan FK,Sung JJ.Quantitative detection of promoter hypermethylation in multiple genes in the serum of patients with colorectal cancer.Am JGastroenterol 2005;100:2274-2279[PMID:16181380]
88 Wallner M,Herbst A,Behrens A,Crispin A,Stieber P,G?ke B,Lamerz R,Kolligs FT.Methylation of serum DNA is an independent prognostic marker in colorectal cancer.Clin Cancer Res 2006;12:7347-7352[PMID:17189406]
89 Tang D,Liu J,Wang DR,Yu HF,Li YK,Zhang JQ.Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer.Clin Invest Med 2011;34:E88-E95[PMID:21463549]
90 Pack SC,Kim HR,Lim SW,Kim HY,Ko JY,Lee KS,Hwang D,Park SI,Kang H,Park SW,Hong GY,Hwang SM,Shin MG,Lee S.Usefulness of plasma epigenetic changes of five major genes involved in the pathogenesis of colorectal cancer.Int J Colorectal Dis 2013;28:139-147[PMID:22990173 DOI:10.1007/s00384-012-1566-8]
91 Pedersen SK,Mitchell SM,Graham LD,Mc Evoy A,Thomas ML,Baker RT,Ross JP,Xu ZZ,Ho T,La Pointe LC,Young GP,Molloy PL.CAHM,a long non-coding RNA gene hypermethylated in colorectal neoplasia.Epigenetics 2014;9:1071-1082[PMID:24799664 DOI:10.4161/epi.29046]
92 Suzuki H,Yamamoto E,Maruyama R,Niinuma T,Kai M.Biological significance of the Cp G island methylator phenotype.Biochem Biophys Res Commun 2014;455:35-42[PMID:25016183 DOI:10.1016/j.bbrc.2014.07.007]
93 Potter NT,Hurban P,White MN,Whitlock KD,Lofton-Day CE,Tetzner R,Koenig T,Quigley NB,Weiss G.Validation of a realtime PCR-based qualitative assay for the detection of methylated SEPT9 DNA in human plasma.Clin Chem 2014;60:1183-1191[PMID:24938752 DOI:10.1373/clinchem.2013.221044]
94 Lo YM,Tein MS,Lau TK,Haines CJ,Leung TN,Poon PM,Wainscoat JS,Johnson PJ,Chang AM,Hjelm NM.Quantitative analysis of fetal DNA in maternal plasma and serum:implications for noninvasive prenatal diagnosis.Am J Hum Genet 1998;62:768-775[PMID:9529358 DOI:10.1086/301800]
95 Warton K,Lin V,Navin T,Armstrong NJ,Kaplan W,Ying K,Gloss B,Mangs H,Nair SS,Hacker NF,Sutherland RL,Clark SJ,Samimi G.Methylation-capture and Next-Generation Sequencing of free circulating DNA from human plasma.BMC Genomics2014;15:476[PMID:24929644 DOI:10.1186/1471-2164-15-476]
96 Jung M,Klotzek S,Lewandowski M,Fleischhacker M,Jung K.Changes in concentration of DNA in serum and plasma during storage of blood samples.Clin Chem 2003;49:1028-1029[PMID:12766024 DOI:10.1373/49.6.1028]
2 Ferlay J,Shin HR,Bray F,Forman D,Mathers C and Parkin DM.GLOBOCAN 2008 v2.0,Cancer Incidence and Mortality Worldwide:IARC Cancer Base No.10[Internet].Lyon,France:International Agency for Research on Cancer,2010 Available from:URL:http://globocan.iarc.fr/
3 World Cancer Report.Cancer syte by syte-colorectal cancer.In:Boyle P,Levin B,editors.World cancer report 2008.Lyon:International Agency for Research on Cancer,2008:374-379
4 T?nzer M,Liebl M,Quante M.Molecular biomarkers in esophageal,gastric,and colorectal adenocarcinoma.Pharmacol Ther 2013;140:133-147[PMID:23791941 DOI:10.1016/j.pharmthera.2013.06.005]
5 Migliore L,Migheli F,Spisni R,CoppedèF.Genetics,cytogenetics,and epigenetics of colorectal cancer.J Biomed Biotechnol 2011;2011:792362[PMID:21490705]
6 Rodenhiser D,Mann M.Epigenetics and human disease:translating basic biology into clinical applications.CMAJ 2006;174:341-348[PMID:16446478 DOI:10.1503/cmaj.050774]
7 Segnan N,Patnick J,von Karsa L,editors.European guidelines for quality assurance in colorectal cancer screening and diagnosis.European guidelines for quality assurance in colorectal cancer screening and diagnosis-First edition.Luxembourg:European Commission,Publications Office of the European Union,2010
8 Brenner H,Chang-Claude J,Jansen L,Knebel P,Stock C,Hoffmeister M.Reduced risk of colorectal cancer up to 10 years after screening,surveillance,or diagnostic colonoscopy.Gastroenterology2014;146:709-717[PMID:24012982]
9 Corley DA,Jensen CD,Marks AR.Can we improve adenoma detection rates?A systematic review of intervention studies.Gastrointest Endosc 2011;74:656-665[PMID:21741643 DOI:10.1016/j.gie.2011.04.017]
10 Schoen RE,Pinsky PF,Weissfeld JL,Yokochi LA,Church T,Laiyemo AO,Bresalier R,Andriole GL,Buys SS,Crawford ED,Fouad MN,Isaacs C,Johnson CC,Reding DJ,O’Brien B,Carrick DM,Wright P,Riley TL,Purdue MP,Izmirlian G,Kramer BS,Miller AB,Gohagan JK,Prorok PC,Berg CD.Colorectal-cancer incidence and mortality with screening flexible sigmoidoscopy.NEngl J Med 2012;366:2345-2357[PMID:22612596 DOI:10.1056/NEJMoa1114635]
11 Shaukat A,Mongin SJ,Geisser MS,Lederle FA,Bond JH,Mandel JS,Church TR.Long-term mortality after screening for colorectal cancer.N Engl J Med 2013;369:1106-1114[PMID:24047060 DOI:10.1056/NEJMoa1300720]
12 Kaminski MF,Regula J,Kraszewska E,Polkowski M,Wojciechowska U,Didkowska J,Zwierko M,Rupinski M,Nowacki MP,Butruk E.Quality indicators for colonoscopy and the risk of interval cancer.N Engl J Med 2010;362:1795-1803[PMID:20463339 DOI:10.1056/NEJMoa0907667]
13 Binefa G,Rodríguez-Moranta F,Teule A,Medina-Hayas M.Colorectal cancer:from prevention to personalized medicine.World JGastroenterol 2014;20:6786-6808[PMID:24944469 DOI:10.3748/wjg.v20.i22.6786]
14 Fearon ER,Vogelstein B.A genetic model for colorectal tumorigenesis.Cell 1990;61:759-767[PMID:2188735]
15 Pino MS,Chung DC.The chromosomal instability pathway in colon cancer.Gastroenterology 2010;138:2059-2072[PMID:20420946DOI:10.1053/j.gastro.2009.12.065]
16 Boland CR,Sinicrope FA,Brenner DE,Carethers JM.Colorectal cancer prevention and treatment.Gastroenterology 2000;118:S115-S128[PMID:10868902]
17 Boland CR,Goel A.Microsatellite instability in colorectal cancer.Gastroenterology 2010;138:2073-2087.e3[PMID:20420947 DOI:10.1053/j.gastro.2009.12.064]
18 Wong JJ,Hawkins NJ,Ward RL.Colorectal cancer:a model for epigenetic tumorigenesis.Gut 2007;56:140-148[PMID:16840508DOI:10.1136/gut.2005.088799]
19 Jass JR.Classification of colorectal cancer based on correlation of clinical,morphological and molecular features.Histopathology2007;50:113-130[PMID:17204026 DOI:10.1111/j.1365-2559.2006.02549.x]
20 Feinberg AP,Vogelstein B.Hypomethylation distinguishes genes of some human cancers from their normal counterparts.Nature 1983;301:89-92[PMID:6185846 DOI:10.1038/301089a0]
21 Feinberg AP,Vogelstein B.Hypomethylation of ras oncogenes in primary human cancers.Biochem Biophys Res Commun 1983;111:47-54[PMID:6187346 DOI:10.1016/s0006-291x(83)80115-6]
22 Yamashita K,Dai T,Dai Y,Yamamoto F,Perucho M.Genetics supersedes epigenetics in colon cancer phenotype.Cancer Cell 2003;4:121-131[PMID:12957287 DOI:10.1016/s1535-6108(03)00190-9]
23 Goel A,Boland CR.Epigenetics of colorectal cancer.Gastroenterology2012;143:1442-1460.e1[PMID:23000599]
24 Luo L,Chen WD,Pretlow TP.Cp G island methylation in aberrant crypt foci and cancers from the same patients.Int J Cancer 2005;115:747-751[PMID:15704093 DOI:10.1002/ijc.20936]
25 Subramaniam MM,Chan JY,Soong R,Ito K,Yeoh KG,Wong R,Guenther T,Will O,Chen CL,Kumarasinghe MP,Ito Y,Salto-Tellez M.RUNX3 inactivation in colorectal polyps arising through different pathways of colonic carcinogenesis.Am J Gastroenterol 2009;104:426-436[PMID:19174785 DOI:10.1038/ajg.2008.141]
26 Wendt MK,Johanesen PA,Kang-Decker N,Binion DG,Shah V,Dwinell MB.Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis.Oncogene 2006;25:4986-4997[PMID:16568088 DOI:10.1038/sj.onc.1209505]
27 Umetani N,Takeuchi H,Fujimoto A,Shinozaki M,Bilchik AJ,Hoon DS.Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis.Clin Cancer Res2004;10:7475-7483[PMID:15569977 DOI:10.1158/1078-0432.CCR-04-0689]
28 Goel A,Nagasaka T,Arnold CN,Inoue T,Hamilton C,Niedzwiecki D,Compton C,Mayer RJ,Goldberg R,Bertagnolli MM,Boland CR.The Cp G island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer.Gastroenterology 2007;132:127-138[PMID:17087942 DOI:10.1053/j.gastro.2006.09.018]
29 Notterman DA,Alon U,Sierk AJ,Levine AJ.Transcriptional gene expression profiles of colorectal adenoma,adenocarcinoma,and normal tissue examined by oligonucleotide arrays.Cancer Res 2001;61:3124-3130[PMID:11306497]
30 Mandel P,Metais P.Les acides nucléiques du plasma sanguine chezl’homme.C R Seances Soc Biol Fil 1948;142:241-243[PMID:18875018]
31 Asworth TR.A case of cancer in which cells similar to those in tumors were seen in the blood after death.Aust Med J 1869;14:146-149
32 Imperiale TF,Ransohoff DF,Itzkowitz SH,Turnbull BA,Ross ME.Fecal DNA versus fecal occult blood for colorectal-cancer screening in an average-risk population.N Engl J Med 2004;351:2704-2714[PMID:15616205 DOI:10.1056/NEJMoa033403]
33 Müller HM,Oberwalder M,Fiegl H,Morandell M,Goebel G,Zitt M,Mühlthaler M,Ofner D,Margreiter R,Widschwendter M.Methylation changes in faecal DNA:a marker for colorectal cancer screening?Lancet 2004;363:1283-1285[PMID:15094274 DOI:10.1016/S0140-6736(04)16002-9]
34 Sidransky D,Tokino T,Hamilton SR,Kinzler KW,Levin B,Frost P,Vogelstein B.Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors.Science 1992;256:102-105[PMID:1566048 DOI:10.1126/science.1566048]
35 Leon SA,Shapiro B,Sklaroff DM,Yaros MJ.Free DNA in the serum of cancer patients and the effect of therapy.Cancer Res 1977;37:646-650[PMID:837366]
36 Chen K,Zhang H,Zhang LN,Ju SQ,Qi J,Huang DF,Li F,Wei Q,Zhang J.Value of circulating cell-free DNA in diagnosis of hepatocelluar carcinoma.World J Gastroenterol 2013;19:3143-3149[PMID:23716996 DOI:10.3748/wjg.v19.i20.3143]
37 Qi J,Qian C,Shi W,Wu X,Jing R,Zhang L,Wang Z,Ju S.Alu-based cell-free DNA:a potential complementary biomarker for diagnosis of colorectal cancer.Clin Biochem 2013;46:64-69[PMID:22975639DOI:10.1016/j.clinbiochem.2012.08.026]
38 Kaiser J.Medicine.Keeping tabs on tumor DNA.Science 2010;327:1074[PMID:20185705 DOI:10.1126/science.327.5969.1074]
39 Herman JG,Graff JR,My?h?nen S,Nelkin BD,Baylin SB.Methylation-specific PCR:a novel PCR assay for methylation status of Cp G islands.Proc Natl Acad Sci USA 1996;93:9821-9826[PMID:8790415 DOI:10.1073/pnas.93.18.9821]
40 Kristensen LS,Mikeska T,Krypuy M,Dobrovic A.Sensitive Melting Analysis after Real Time-Methylation Specific PCR(SMART-MSP):high-throughput and probe-free quantitative DNA methylation detection.Nucleic Acids Res 2008;36:e42[PMID:18344521 DOI:10.1093/nar/gkn113]
41 Li M,Chen WD,Papadopoulos N,Goodman SN,Bjerregaard NC,Laurberg S,Levin B,Juhl H,Arber N,Moinova H,Durkee K,Schmidt K,He Y,Diehl F,Velculescu VE,Zhou S,Diaz LA,Kinzler KW,Markowitz SD,Vogelstein B.Sensitive digital quantification of DNA methylation in clinical samples.Nat Biotechnol 2009;27:858-863[PMID:19684580 DOI:10.1038/nbt.1559]
42 Leary RJ,Sausen M,Kinde I,Papadopoulos N,Carpten JD,Craig D,O’Shaughnessy J,Kinzler KW,Parmigiani G,Vogelstein B,Diaz LA,Velculescu VE.Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing.Sci Transl Med 2012;4:162ra154[PMID:23197571 DOI:10.1126/scitranslmed.3004742]
43 Schwarzenbach H,Stoehlmacher J,Pantel K,Goekkurt E.Detection and monitoring of cell-free DNA in blood of patients with colorectal cancer.Ann N Y Acad Sci 2008;1137:190-196[PMID:18837946DOI:10.1196/annals.1448.025]
44 Rykova EY,Morozkin ES,Ponomaryova AA,Loseva EM,Zaporozhchenko IA,Cherdyntseva NV,Vlassov VV,Laktionov PP.Cell-free and cell-bound circulating nucleic acid complexes:mechanisms of generation,concentration and content.Expert Opin Biol Ther 2012;12 Suppl 1:S141-S153[PMID:22500614 DOI:10.1517/14712598.2012.673577]
45 Umetani N,Kim J,Hiramatsu S,Reber HA,Hines OJ,Bilchik AJ,Hoon DS.Increased integrity of free circulating DNA in sera of patients with colorectal or periampullary cancer:direct quantitative PCR for ALU repeats.Clin Chem 2006;52:1062-1069[PMID:16723681 DOI:10.1373/clinchem.2006.068577]
46 da Silva Filho BF,Gurgel AP,Neto Má,de Azevedo DA,de Freitas AC,Silva Neto Jda C,Silva LA.Circulating cell-free DNA in serum as a biomarker of colorectal cancer.J Clin Pathol 2013;66:775-778[PMID:23833048 DOI:10.1136/jclinpath-2013-201521]
47 Leszinski G,Lehner J,Gezer U,Holdenrieder S.Increased DNAintegrity in colorectal cancer.In Vivo 2014;28:299-303[PMID:24815830]
48 Mouliere F,Robert B,Arnau Peyrotte E,Del Rio M,Ychou M,Molina F,Gongora C,Thierry AR.High fragmentation characterizes tumour-derived circulating DNA.PLo S One 2011;6:e23418[PMID:21909401 DOI:10.1371/journal.pone.0023418]
49 Mead R,Duku M,Bhandari P,Cree IA.Circulating tumour markers can define patients with normal colons,benign polyps,and cancers.Br J Cancer 2011;105:239-245[PMID:21712823 DOI:10.1038/bjc.2011.230]
50 Mouliere F,El Messaoudi S,Pang D,Dritschilo A,Thierry AR.Multimarker analysis of circulating cell-free DNA toward personalized medicine for colorectal cancer.Mol Oncol 2014;8:927-941[PMID:24698732 DOI:10.1016/j.molonc.2014.02.005]
51 Y?rüker EE,?zgür E,Keskin M,Dalay N,Holdenrieder S,Gezer U.Assessment of circulating serum DNA integrity in colorectal cancer patients.Anticancer Res 2015;35:2435-2440[PMID:25862911]
52 Hao TB,Shi W,Shen XJ,Qi J,Wu XH,Wu Y,Tang YY,Ju SQ.Circulating cell-free DNA in serum as a biomarker for diagnosis and prognostic prediction of colorectal cancer.Br J Cancer 2014;111:1482-1489[PMID:25157833 DOI:10.1038/bjc.2014.470]
53 Lazarev I,Leibovitch L,Czeiger D,Sion-Vardi N,Geffen DB,Douvdevani A,Ariad S.Cell-free DNA blood levels in colorectal cancer patients do not correlate with mismatch repair-proficiency.In Vivo 2014;28:349-354[PMID:24815837]
54 Cavalli LR,Liang BC.Mutagenesis,tumorigenicity,and apoptosis:are the mitochondria involved?Mutat Res 1998;398:19-26[PMID:9626961]
55 Zhu W,Qin W,Bradley P,Wessel A,Puckett CL,Sauter ER.Mitochondrial DNA mutations in breast cancer tissue and in matched nipple aspirate fluid.Carcinogenesis 2005;26:145-152[PMID:15375011 DOI:10.1093/carcin/bgh282]
56 Hibi K,Nakayama H,Yamazaki T,Takase T,Taguchi M,Kasai Y,Ito K,Akiyama S,Nakao A.Detection of mitochondrial DNA alterations in primary tumors and corresponding serum of colorectal cancer patients.Int J Cancer 2001;94:429-431[PMID:11745425 DOI:10.1002/ijc.1480]
57 Lecomte T,Berger A,ZinzindohouéF,Micard S,Landi B,Blons H,Beaune P,Cugnenc PH,Laurent-Puig P.Detection of free-circulating tumor-associated DNA in plasma of colorectal cancer patients and its association with prognosis.Int J Cancer 2002;100:542-548[PMID:12124803 DOI:10.1002/ijc.10526]
58 Diehl F,Li M,Dressman D,He Y,Shen D,Szabo S,Diaz LA,Goodman SN,David KA,Juhl H,Kinzler KW,Vogelstein B.Detection and quantification of mutations in the plasma of patients with colorectal tumors.Proc Natl Acad Sci USA 2005;102:16368-16373[PMID:16258065 DOI:10.1073/pnas.0507904102]
59 Yin H,Liang Y,Yan Z,Liu B,Su Q.Mutation spectrum in human colorectal cancers and potential functional relevance.BMC Med Genet2013;14:32[PMID:23497483 DOI:10.1186/1471-2350-14-32]
60 Jia D,Jurkowska RZ,Zhang X,Jeltsch A,Cheng X.Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNAmethylation.Nature 2007;449:248-251[PMID:17713477 DOI:10.1038/nature06146]
61 Esteller M.Epigenetics in cancer.N Engl J Med 2008;358:1148-1159[PMID:18337604 DOI:10.1056/NEJMra072067]
62 Hellman A,Chess A.Gene body-specific methylation on the active Xchromosome.Science 2007;315:1141-1143[PMID:17322062 DOI:10.1126/science.1136352]
63 Peeters M,Douillard JY,Van Cutsem E,Siena S,Zhang K,Williams R,Wiezorek J.Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer:assessment as prognostic and predictive biomarkers of response to panitumumab.J Clin Oncol 2013;31:759-765[PMID:23182985 DOI:10.1200/JCO.2012.45.1492]
64 Grützmann R,Molnar B,Pilarsky C,Habermann JK,Schlag PM,Saeger HD,Miehlke S,Stolz T,Model F,Roblick UJ,Bruch HP,Koch R,Liebenberg V,Devos T,Song X,Day RH,Sledziewski AZ,LoftonDay C.Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay.PLo S One 2008;3:e3759[PMID:19018278 DOI:10.1371/journal.pone.0003759]
65 Warren JD,Xiong W,Bunker AM,Vaughn CP,Furtado LV,Roberts WL,Fang JC,Samowitz WS,Heichman KA.Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer.BMCMed 2011;9:133[PMID:22168215 DOI:10.1186/1741-7015-9-133]
66 Church TR,Wandell M,Lofton-Day C,Mongin SJ,Burger M,Payne SR,Casta?os-Vélez E,Blumenstein BA,R?sch T,Osborn N,Snover D,Day RW,Ransohoff DF.Prospective evaluation of methylated SEPT9in plasma for detection of asymptomatic colorectal cancer.Gut 2014;63:317-325[PMID:23408352 DOI:10.1136/gutjnl-2012-304149]
67 T?nzer M,Balluff B,Distler J,Hale K,Leodolter A,R?cken C,Molnar B,Schmid R,Lofton-Day C,Schuster T,Ebert MP.Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions.PLo S One 2010;5:e9061[PMID:20140221 DOI:10.1371/journal.pone.0009061]
68 Kostin PA,Zakharzhevskaia NB,Generozov EV,Govorun VM,Chernyshov SV,Shchelygin Iu A.[Hypermethylation of the CDH1,SEPT9,HLTF and ALX4 genes and their diagnostic significance in colorectal cancer].Vopr Onkol 2010;56:162-168[PMID:20552891]
69 He Q,Chen HY,Bai EQ,Luo YX,Fu RJ,He YS,Jiang J,Wang HQ.Development of a multiplex Methy Light assay for the detection of multigene methylation in human colorectal cancer.Cancer Genet Cytogenet 2010;202:1-10[PMID:20804913 DOI:10.1016/j.cancerg encyto.2010.05.018]
70 Ahlquist DA,Taylor WR,Mahoney DW,Zou H,Domanico M,Thibodeau SN,Boardman LA,Berger BM,Lidgard GP.The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia.Clin Gastroenterol Hepatol 2012;10:272-277.e1[PMID:22019796 DOI:10.1016/j.cgh.2011.10.008]
71 Carmona FJ,Azuara D,Berenguer-Llergo A,Fernández AF,Biondo S,de Oca J,Rodriguez-Moranta F,Salazar R,Villanueva A,Fraga MF,Guardiola J,CapelláG,Esteller M,Moreno V.DNAmethylation biomarkers for noninvasive diagnosis of colorectal cancer.Cancer Prev Res(Phila)2013;6:656-665[PMID:23694962 DOI:10.1158/1940-6207.CAPR-12-0501]
72 Cassinotti E,Melson J,Liggett T,Melnikov A,Yi Q,Replogle C,Mobarhan S,Boni L,Segato S,Levenson V.DNA methylation patterns in blood of patients with colorectal cancer and adenomatous colorectal polyps.Int J Cancer 2012;131:1153-1157[PMID:22020530 DOI:10.1002/ijc.26484]
73 Lind GE,Danielsen SA,Ahlquist T,Merok MA,Andresen K,Skotheim RI,Hektoen M,Rognum TO,Meling GI,Hoff G,Bretthauer M,Thiis-Evensen E,Nesbakken A,Lothe RA.Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas.Mol Cancer 2011;10:85[PMID:21777459 DOI:10.1186/1476-4598-10-85]
74 Lee BB,Lee EJ,Jung EH,Chun HK,Chang DK,Song SY,Park J,Kim DH.Aberrant methylation of APC,MGMT,RASSF2A,and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer.Clin Cancer Res 2009;15:6185-6191[PMID:19773381 DOI:10.1158/1078-0432.CCR-09-0111]
75 Lange CP,Campan M,Hinoue T,Schmitz RF,van der Meulen-de Jong AE,Slingerland H,Kok PJ,van Dijk CM,Weisenberger DJ,Shen H,Tollenaar RA,Laird PW.Genome-scale discovery of DNA-methylation biomarkers for blood-based detection of colorectal cancer.PLo S One 2012;7:e50266[PMID:23209692 DOI:10.1371/journal.pone.0050266]
76 Ebert MP,Model F,Mooney S,Hale K,Lograsso J,Tonnes-Priddy L,Hoffmann J,Csepregi A,R?cken C,Molnar B,Schulz HU,Malfertheiner P,Lofton-Day C.Aristaless-like homeobox-4 gene methylation is a potential marker for colorectal adenocarcinomas.Gastroenterology 2006;131:1418-1430[PMID:17101318 DOI:10.1053/j.gastro.2006.08.034]
77 Gl?ckner SC,Dhir M,Yi JM,Mc Garvey KE,Van Neste L,Louwagie J,Chan TA,Kleeberger W,de Bru?ne AP,Smits KM,Khalidde Bakker CA,Jonkers DM,Stockbrügger RW,Meijer GA,Oort FA,Iacobuzio-Donahue C,Bierau K,Herman JG,Baylin SB,Van Engeland M,Schuebel KE,Ahuja N.Methylation of TFPI2 in stool DNA:a potential novel biomarker for the detection of colorectal cancer.Cancer Res 2009;69:4691-4699[PMID:19435926 DOI:10.1158/0008-5472.CAN-08-0142]
78 Hibi K,Goto T,Kitamura YH,Yokomizo K,Sakuraba K,Shirahata A,Mizukami H,Saito M,Ishibashi K,Kigawa G,Nemoto H,Sanada Y.Methylation of TFPI2 gene is frequently detected in advanced welldifferentiated colorectal cancer.Anticancer Res 2010;30:1205-1207[PMID:20530429]
79 Hibi K,Goto T,Shirahata A,Saito M,Kigawa G,Nemoto H,Sanada Y.Detection of TFPI2 methylation in the serum of colorectal cancer patients.Cancer Lett 2011;311:96-100[PMID:21820798 DOI:10.1016/j.canlet.2011.07.006]
80 Takada H,Wakabayashi N,Dohi O,Yasui K,Sakakura C,Mitsufuji S,Taniwaki M,Yoshikawa T.Tissue factor pathway inhibitor 2(TFPI2)is frequently silenced by aberrant promoter hypermethylation in gastric cancer.Cancer Genet Cytogenet 2010;197:16-24[PMID:20113832DOI:10.1016/j.cancergencyto.2009.11.004]
81 Oh T,Kim N,Moon Y,Kim MS,Hoehn BD,Park CH,Kim TS,Kim NK,Chung HC,An S.Genome-wide identification and validation of a novel methylation biomarker,SDC2,for blood-based detection of colorectal cancer.J Mol Diagn 2013;15:498-507[PMID:23747112DOI:10.1016/j.jmoldx.2013.03.004]
82 Nishio M,Sakakura C,Nagata T,Komiyama S,Miyashita A,Hamada T,Kuryu Y,Ikoma H,Kubota T,Kimura A,Nakanishi M,Ichikawa D,Fujiwara H,Okamoto K,Ochiai T,Kokuba Y,Sonoyama T,Ida H,Ito K,Chiba T,Ito Y,Otsuji E.RUNX3 promoter methylation in colorectal cancer:its relationship with microsatellite instability and its suitability as a novel serum tumor marker.Anticancer Res 2010;30:2673-2682[PMID:20682997]
83 Tan SH,Ida H,Lau QC,Goh BC,Chieng WS,Loh M,Ito Y.Detection of promoter hypermethylation in serum samples of cancer patients by methylation-specific polymerase chain reaction for tumour suppressor genes including RUNX3.Oncol Rep 2007;18:1225-1230[PMID:17914577]
84 Herbst A,Rahmig K,Stieber P,Philipp A,Jung A,Ofner A,Crispin A,Neumann J,Lamerz R,Kolligs FT.Methylation of NEUROG1 in serum is a sensitive marker for the detection of early colorectal cancer.Am J Gastroenterol 2011;106:1110-1118[PMID:21326223 DOI:10.1038/ajg.2011.6]
85 Lofton-Day C,Model F,Devos T,Tetzner R,Distler J,Schuster M,Song X,Lesche R,Liebenberg V,Ebert M,Molnar B,Grützmann R,Pilarsky C,Sledziewski A.DNA methylation biomarkers for bloodbased colorectal cancer screening.Clin Chem 2008;54:414-423[PMID:18089654 DOI:10.1373/clinchem.2007.095992]
86 de Vos T,Tetzner R,Model F,Weiss G,Schuster M,Distler J,Steiger KV,Grützmann R,Pilarsky C,Habermann JK,Fleshner PR,Oubre BM,Day R,Sledziewski AZ,Lofton-Day C.Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer.Clin Chem 2009;55:1337-1346[PMID:19406918 DOI:10.1373/clinchem.2008.115808]
87 Leung WK,To KF,Man EP,Chan MW,Bai AH,Hui AJ,Chan FK,Sung JJ.Quantitative detection of promoter hypermethylation in multiple genes in the serum of patients with colorectal cancer.Am JGastroenterol 2005;100:2274-2279[PMID:16181380]
88 Wallner M,Herbst A,Behrens A,Crispin A,Stieber P,G?ke B,Lamerz R,Kolligs FT.Methylation of serum DNA is an independent prognostic marker in colorectal cancer.Clin Cancer Res 2006;12:7347-7352[PMID:17189406]
89 Tang D,Liu J,Wang DR,Yu HF,Li YK,Zhang JQ.Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer.Clin Invest Med 2011;34:E88-E95[PMID:21463549]
90 Pack SC,Kim HR,Lim SW,Kim HY,Ko JY,Lee KS,Hwang D,Park SI,Kang H,Park SW,Hong GY,Hwang SM,Shin MG,Lee S.Usefulness of plasma epigenetic changes of five major genes involved in the pathogenesis of colorectal cancer.Int J Colorectal Dis 2013;28:139-147[PMID:22990173 DOI:10.1007/s00384-012-1566-8]
91 Pedersen SK,Mitchell SM,Graham LD,Mc Evoy A,Thomas ML,Baker RT,Ross JP,Xu ZZ,Ho T,La Pointe LC,Young GP,Molloy PL.CAHM,a long non-coding RNA gene hypermethylated in colorectal neoplasia.Epigenetics 2014;9:1071-1082[PMID:24799664 DOI:10.4161/epi.29046]
92 Suzuki H,Yamamoto E,Maruyama R,Niinuma T,Kai M.Biological significance of the Cp G island methylator phenotype.Biochem Biophys Res Commun 2014;455:35-42[PMID:25016183 DOI:10.1016/j.bbrc.2014.07.007]
93 Potter NT,Hurban P,White MN,Whitlock KD,Lofton-Day CE,Tetzner R,Koenig T,Quigley NB,Weiss G.Validation of a realtime PCR-based qualitative assay for the detection of methylated SEPT9 DNA in human plasma.Clin Chem 2014;60:1183-1191[PMID:24938752 DOI:10.1373/clinchem.2013.221044]
94 Lo YM,Tein MS,Lau TK,Haines CJ,Leung TN,Poon PM,Wainscoat JS,Johnson PJ,Chang AM,Hjelm NM.Quantitative analysis of fetal DNA in maternal plasma and serum:implications for noninvasive prenatal diagnosis.Am J Hum Genet 1998;62:768-775[PMID:9529358 DOI:10.1086/301800]
95 Warton K,Lin V,Navin T,Armstrong NJ,Kaplan W,Ying K,Gloss B,Mangs H,Nair SS,Hacker NF,Sutherland RL,Clark SJ,Samimi G.Methylation-capture and Next-Generation Sequencing of free circulating DNA from human plasma.BMC Genomics2014;15:476[PMID:24929644 DOI:10.1186/1471-2164-15-476]
96 Jung M,Klotzek S,Lewandowski M,Fleischhacker M,Jung K.Changes in concentration of DNA in serum and plasma during storage of blood samples.Clin Chem 2003;49:1028-1029[PMID:12766024 DOI:10.1373/49.6.1028]