Many existing studies have demonstrated that p16 promoter methylation might be correlated with the clinicopathologic features of colorectal cancer (CRC), but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationships between p16 promoter methylation and the clinicopathologic features of CRC. We searched the CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through August 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under fixed- or random-effects models. Twenty-seven clinical cohort studies were included with a total of 3311 CRC patients. Our meta-analysis results revealed that p16 promoter methylation was associated with pathological characteristics of CRC (tumor, nodes, metastasis stage: OR=1.55, 95% CI: 1.14–2.13, p=0.006; lymph node metastasis: OR=2.40, 95% CI: 1.37–4.19, p=0.002; histologic grade: OR=2.72, 95% CI: 1.63–4.54, p<0.001; Dukes stage: OR=2.06, 95% CI: 1.57–2.71, p=0.002; tumor size: OR=1.99, 95% CI: 1.03–3.85, p=0.041; location: OR=2.49, 95% CI: 1.95–3.18, p<0.001, respectively). Subgroup analysis by ethnicity suggested that there were also significant correlations between p16 gene promoter methylation and pathological characteristics of CRC among both Caucasian and Asian populations (all p<0.05). Our meta-analysis suggests that promoter methylation of the p16 gene may be strongly correlated with the clinicopathologic features of CRC. Thus, p16 gene promoter methylation may be a potential biomarker for CRC.
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References
1.
AbbaszadeganM.R., MoavenO., SimaH.R., GhafarzadeganK., A'RabiA., ForghaniM.N., et al. (2008). p16 promoter hypermethylation: a useful serum marker for early detection of gastric cancer. World J Gastroenterol, 14, 2055–2060.
2.
AoyagiH., IidaS., UetakeH., IshikawaT., TakagiY., KobayashiH., et al. (2011). Effect of classification based on combination of mutation and methylation in colorectal cancer prognosis. Oncol Rep, 25, 789–794.
3.
ArimaY., HayashiN., HayashiH., SasakiM., KaiK., SugiharaE., et al. (2012). Loss of p16 expression is associated with the stem cell characteristics of surface markers and therapeutic resistance in estrogen receptor-negative breast cancer. Int J Cancer, 130, 2568–2579.
4.
ChanA.T., and GiovannucciE.L. (2010). Primary prevention of colorectal cancer. Gastroenterology, 138, 2029–2043.e2010.
5.
ChengS.Q., LiuJ.W., MaH.T., H., Z.Z., and CaoJ. (2003). Study of aberrant methylation of p16 gene in patients with colorectal cancer. Med J Chin People's Liberat Army, 28, 616–617.
6.
DaiW., ZellerC., MasrourN., SiddiquiN., PaulJ., and BrownR. (2013). Promoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in high-grade serous ovarian cancer. Clin Cancer Res, 19, 5788–5797.
7.
DelmerA., TangR., Senamaud-BeaufortC., PaterliniP., BrechotC., and ZittounR. (1995). Alterations of cyclin-dependent kinase 4 inhibitor (p16INK4A/MTS1) gene structure and expression in acute lymphoblastic leukemias. Leukemia, 9, 1240–1245.
8.
DupontW.D., and PlummerW.D.Jr. (1990). Power and sample size calculations. A review and computer program. Control Clin Trials, 11, 116–128.
9.
FukushimaN., SatoN., UekiT., RostyC., WalterK.M., WilentzR.E., et al. (2002). Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol, 160, 1573–1581.
10.
Gonzalez-ZuluetaM., BenderC.M., YangA.S., NguyenT., BeartR.W., Van TornoutJ.M., et al. (1995). Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res, 55, 4531–4535.
11.
GotoT., MizukamiH., ShirahataA., SakataM., SaitoM., IshibashiK., et al. (2009). Aberrant methylation of the p16 gene is frequently detected in advanced colorectal cancer. Anticancer Res, 29, 275–277.
12.
GoyetteM.C., ChoK., FaschingC.L., LevyD.B., KinzlerK.W., ParaskevaC., et al. (1992). Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. Mol Cell Biol, 12, 1387–1395.
13.
HaradaH., NakagawaK., IwataS., SaitoM., KumonY., SakakiS., et al. (1999). Restoration of wild-type p16 down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human gliomas. Cancer Res, 59, 3783–3789.
14.
HasegawaM., NelsonH.H., PetersE., RingstromE., PosnerM., and KelseyK.T. (2002). Patterns of gene promoter methylation in squamous cell cancer of the head and neck. Oncogene, 21, 4231–4236.
15.
HibiK., NakayamaH., KoikeM., KasaiY., ItoK., AkiyamaS., et al. (2002). Colorectal cancers with both p16 and p14 methylation show invasive characteristics. Jpn J Cancer Res, 93, 883–887.
16.
HibiK., TaguchiM., NakayamaH., TakaseT., KasaiY., ItoK., et al. (2001). Molecular detection of p16 promoter methylation in the serum of patients with esophageal squamous cell carcinoma. Clin Cancer Res, 7, 3135–3138.
17.
HiramaT., and KoefflerH.P. (1995). Role of the cyclin-dependent kinase inhibitors in the development of cancer. Blood, 86, 841–854.
18.
HoldtL.M., and TeupserD. (2012). Recent studies of the human chromosome 9p21 locus, which is associated with atherosclerosis in human populations. Arterioscler Thromb Vasc Biol, 32, 196–206.
19.
HuxleyR.R., Ansary-MoghaddamA., CliftonP., CzernichowS., ParrC.L., and WoodwardM. (2009). The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. Int J Cancer, 125, 171–180.
20.
IacopettaB., GrieuF., LiW., RuszkiewiczA., CarusoM., MooreJ., et al. (2006). APC gene methylation is inversely correlated with features of the CpG island methylator phenotype in colorectal cancer. Int J Cancer, 119, 2272–2278.
21.
IidaS., KatoS., IshiguroM., MatsuyamaT., IshikawaT., KobayashiH., et al. (2012). PIK3CA mutation and methylation influences the outcome of colorectal cancer. Oncol Lett, 3, 565–570.
22.
IshiguroA., TakahataT., SaitoM., YoshiyaG., TamuraY., SasakiM., et al. (2006). Influence of methylated p15 and p16 genes on clinicopathological features in colorectal cancer. J Gastroenterol Hepatol, 21, 1334–1339.
23.
JemalA., BrayF., CenterM.M., FerlayJ., WardE., and FormanD. (2011). Global cancer statistics. CA Cancer J Clin, 61, 69–90.
24.
JeongY.J., JeongH.Y., LeeS.M., BongJ.G., ParkS.H., and OhH.K. (2013). Promoter methylation status of the FHIT gene and Fhit expression: Association with HER2/neu status in breast cancer patients. Oncol Rep, 30, 2270–2278.
25.
JonesP.A., and BaylinS.B. (2002). The fundamental role of epigenetic events in cancer. Nat Rev Genet, 3, 415–428.
26.
KazamaY., WatanabeT., KanazawaT., TanakaJ., TanakaT., and NagawaH. (2008). Poorly differentiated colorectal adenocarcinomas show higher rates of microsatellite instability and promoter methylation of p16 and hMLH1: a study matched for T classification and tumor location. J Surg Oncol, 97, 278–283.
27.
KondoE., GuZ., HoriiA., FukushigeS. (2005). The thymine DNA glycosylase MBD4 represses transcription and is associated with methylated p16(INK4a) and hMLH1 genes. Mol Cell Biol, 25, 4388–4396.
28.
KrieglL., NeumannJ., ViethM., GretenF.R., ReuS., JungA., et al. (2011). Up and downregulation of p16(Ink4a) expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer. Mod Pathol, 24, 1015–1022.
29.
KrtolicaK., KrajnovicM., Usaj-KnezevicS., BabicD., and JovanovicD., DimitrijevicB. (2007). Comethylation of p16 and MGMT genes in colorectal carcinoma: correlation with clinicopathological features and prognostic value. World J Gastroenterol, 13, 1187–1194.
30.
LeeJ.J., KoE., ChoJ., ParkH.Y., LeeJ.E., NamS.J., et al. (2012). Methylation and immunoexpression of p16(INK4a) tumor suppressor gene in primary breast cancer tissue and their quantitative p16(INK4a) hypermethylation in plasma by real-time PCR. Korean J Pathol, 46, 554–561.
31.
LevineA.J. (1993). The tumor suppressor genes. Annu Rev Biochem, 62, 623–651.
32.
LiG., QianX.L., CuiJ., WangZ.Q., YeY.P., YangX.Y., et al. (2006). Role of DNA methylation in control of tumor suppressor gene and oncogene expression in colorectal carcinal. World Chin J Digestol, 14, 1699–1703.
33.
LiY., NicholsM.A., ShayJ.W., and XiongY. (1994). Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res, 54, 6078–6082.
34.
LiangJ.T., ChangK.J., ChenJ.C., LeeC.C., ChengY.M., HsuH.C., et al. (1999). Hypermethylation of the p16 gene in sporadic T3N0M0 stage colorectal cancers: association with DNA replication error and shorter survival. Oncology, 57, 149–156.
35.
LimsuiD., VierkantR.A., TillmansL.S., WangA.H., WeisenbergerD.J., LairdP.W., et al. (2010). Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J Natl Cancer Inst, 102, 1012–1022.
36.
LiuY., LanQ., SiegfriedJ.M., LuketichJ.D., and KeohavongP. (2006). Aberrant promoter methylation of p16 and MGMT genes in lung tumors from smoking and never-smoking lung cancer patients. Neoplasia, 8, 46–51.
37.
LopesE.C., VallsE., FigueroaM.E., MazurA., MengF.G., ChiosisG., et al. (2008). Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines. Cancer Res, 68, 7258–7263.
38.
MalesciA., LaghiL., BianchiP., DelconteG., RandolphA., TorriV., et al. (2007). Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res, 13, 3831–3839.
39.
MasS., LafuenteM.J., CrescentiA., TriasM., BallestaA., MolinaR., et al. (2007). Lower specific micronutrient intake in colorectal cancer patients with tumors presenting promoter hypermethylation in p16(INK4a), p4(ARF) and hMLH1. Anticancer Res, 27, 1151–1156.
40.
MatsudaY., WakaiT., KubotaM., TakamuraM., YamagiwaS., AoyagiY., et al. (2013). Clinical significance of cell cycle inhibitors in hepatocellular carcinoma. Med Mol Morphol, 46, 185–192.
41.
Miladi-AbdennadherI., Abdelmaksoud-DamakR., AyadiL., KhabirA., FrikhaF., KallelL., et al. (2011). Aberrant methylation of hMLH1 and p16INK4a in Tunisian patients with sporadic colorectal adenocarcinoma. Biosci Rep, 31, 257–264.
42.
MirandaE., DestroA., MalesciA., BalladoreE., BianchiP., BaryshnikovaE., et al. (2006). Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer. Br J Cancer, 95, 1101–1107.
43.
NakayamaG., HibiK., NakayamaH., KoderaY., ItoK., AkiyamaS., et al. (2007). A highly sensitive method for the detection of p16 methylation in the serum of colorectal cancer patients. Anticancer Res, 27, 1459–1463.
44.
NakayamaH., HibiK., TaguchiM., TakaseT., YamazakiT., KasaiY., et al. (2002). Molecular detection of p16 promoter methylation in the serum of colorectal cancer patients. Cancer Lett, 188, 115–119.
45.
NakayamaH., HibiK., TakaseT., YamazakiT., KasaiY., ItoK., et al. (2003). Molecular detection of p16 promoter methylation in the serum of recurrent colorectal cancer patients. Int J Cancer, 105, 491–493.
46.
NorrieM.W., HawkinsN.J., ToddA.V., MeagherA.P., O'ConnorT.W., and WardR.L. (2003). Inactivation of p16INK4a by CpG hypermethylation is not a frequent event in colorectal cancer. J Surg Oncol, 84, 143–150.
47.
PajciniK.V., CorbelS.Y., SageJ., PomerantzJ.H., and BlauH.M. (2010). Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle. Cell Stem Cell, 7, 198–213.
48.
PazM.F., FragaM.F., AvilaS., GuoM., PollanM., HermanJ.G., et al. (2003). A systematic profile of DNA methylation in human cancer cell lines. Cancer Res, 63, 1114–1121.
49.
PetersJ.L., SuttonA.J., JonesD.R., AbramsK.R., and RushtonL. (2006). Comparison of two methods to detect publication bias in meta-analysis. JAMA, 295, 676–680.
50.
RadpourR., BarekatiZ., KohlerC., LvQ., BurkiN., DieschC., et al. (2011). Hypermethylation of tumor suppressor genes involved in critical regulatory pathways for developing a blood-based test in breast cancer. PLoS One, 6, e16080.
51.
RoccoJ.W., and SidranskyD. (2001). p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp Cell Res, 264, 42–55.
52.
SameerA.S., AbdullahS., NissarS., RasoolR., ShahZ.A., AfrozeD., et al. (2012). The blues of P(16)INK(4a): aberrant promoter methylation and association with colorectal cancer in the Kashmir valley. Mol Med Rep, 5, 1053–1057.
53.
Sanz-CaslaM.T., MaestroM.L., VidaurretaM., MaestroC., ArroyoM., and CerdanJ. (2005). p16 Gene methylation in colorectal tumors: correlation with clinicopathological features and prognostic value. Dig Dis, 23, 151–155.
54.
SemczukA., and JakowickiJ.A. (2004). Alterations of pRb1-cyclin D1-cdk4/6-p16(INK4A) pathway in endometrial carcinogenesis. Cancer Lett, 203, 1–12.
55.
ShapiroG.I. (2006). Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol, 24, 1770–1783.
56.
ShimaK., NoshoK., BabaY., CantorM., MeyerhardtJ.A., GiovannucciE.L., et al. (2011). Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers: Cohort study and literature review. Int J Cancer, 128, 1080–1094.
57.
ShinC.M., KimN., JungY., ParkJ.H., KangG.H., KimJ.S., et al. (2010). Role of Helicobacter pylori infection in aberrant DNA methylation along multistep gastric carcinogenesis. Cancer Sci, 101, 1337–1346.
58.
SøreideK., NedrebøB.S., KnappJ.C., GlomsakerT.B., SøreideJ.A., and KørnerH. (2009). Evolving molecular classification by genomic and proteomic biomarkers in colorectal cancer: potential implications for the surgical oncologist. Surg Oncol, 18, 31–50.
59.
StangA. (2010). Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol, 25, 603–605.
60.
TaioliE., GarzaM.A., AhnY.O., BishopD.T., BostJ., BudaiB., et al. (2009). Meta- and pooled analyses of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer: a HuGE-GSEC review. Am J Epidemiol, 170, 1207–1221.
TsouJ.A., HagenJ.A., CarpenterC.L., and Laird-OffringaI.A. (2002). DNA methylation analysis: a powerful new tool for lung cancer diagnosis. Oncogene, 21, 5450–5461.
63.
van RijnsoeverM., GrieuF., ElsalehH., JosephD., and IacopettaB. (2002). Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands. Gut, 51, 797–802.
64.
Veganzones-de-CastroS., Rafael-FernandezS., Vidaurreta-LazaroM., de-la-OrdenV., Mediero-ValerosB., FernandezC., et al. (2012). p16 gene methylation in colorectal cancer patients with long-term follow-up. Rev Esp Enferm Dig, 104, 111–117.
65.
VerdoodtB., SommererF., PalisaarR.J., NoldusJ., VogtM., NambiarS., et al. (2011). Inverse association of p16 INK4a and p14 ARF methylation of the CDKN2a locus in different Gleason scores of prostate cancer. Prostate Cancer Prostatic Dis, 14, 295–301.
66.
WangZ.W., R., Z., ZouH.Z., WangH., YuB.M., and TangX.M. (2001). P16 CpG region methylation of colorectal cancer and its association with dukes stages. Acta Univers Med Sec Shanhai, 21, 307–309.
67.
WardR.L., CheongK., KuS.L., MeagherA., O'ConnorT., and HawkinsN.J. (2003). Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol, 21, 3729–3736.
68.
WettergrenY., OdinE., NilssonS., CarlssonG., and GustavssonB. (2008). p16INK4a gene promoter hypermethylation in mucosa as a prognostic factor for patients with colorectal cancer. Mol Med, 14, 412–421.
69.
WienckeJ.K., ZhengS., LafuenteA., LafuenteM.J., GrudzenC., WrenschM.R., et al. (1999). Aberrant methylation of p16INK4a in anatomic and gender-specific subtypes of sporadic colorectal cancer. Cancer Epidemiol Biomarkers Prev, 8, 501–506.
70.
XingX., CaiW., ShiH., WangY., LiM., JiaoJ., and ChenM. (2013) The prognostic value of CDKN2A hypermethylation in colorectal cancer: a meta-analysis. Br J Cancer, 108, 2542–2548.
71.
YangY.H., HeX.B., zhangF.Y., ZhangJ.Q., and XieW. (2003). Relationship between CpG methylationi of p16 gene and spporatic colorectal cancer. Acta Genet Sin, 30, 1061–1064.
72.
YiJ., WangZ.W., CangH., ChenY.Y., ZhaoR., YuB.M., et al. (2001). p16 gene methylation in colorectal cancers associated with Duke's staging. World J Gastroenterol, 7, 722–725.
73.
ZennamiK., YoshikawaK., KondoE., NakamuraK., UpsilonamadaY., De VelascoM.A., et al. (2011). A new molecular targeted therapeutic approach for renal cell carcinoma with a p16 functional peptide using a novel transporter system. Oncol Rep, 26, 327–333.
74.
ZhaoP., HuY.C., and TalbotI.C. (2003). Expressing patterns of p16 and CDK4 correlated to prognosis in colorectal carcinoma. World J Gastroenterol, 9, 2202–2206.
75.
ZintzarasE., and IoannidisJ.P. (2005). HEGESMA: genome search meta-analysis and heterogeneity testing. Bioinformatics, 21, 3672–3673.
76.
ZouH.Z., YuB.M., R., Z., WangZ.W., CangH., LiG.D., et al. (2002). Detection of aberrant p16 methylation in the serum of colorectal cancer patients. Chin J Surg, 40, 499–501.
