Genetics Research

Research Article

Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis

Table 1

Characteristics of included studies.
No.AuthorYearRegionSample sizeMale %Sample typeTumor typeClinical stage of tumorTumor side (right %)GeneMethod of gene expressionElevated levels/abnormalityCut-off valueOutcomeNOS rating
1Rafael et al. [21]2014Spain34553.3TissueCRCDuke A-DNAWntSSCPMutationsNAβ-Catenin mutation not associated with OS5
2Yoshida et al. [22]2015Japan20159.7TissueCRCStage 1,2,3NAWntIHCHigh, low>50%Nuclear β-catenin associated with poor OS and DFS6
3Ting et al. [23]2013Taiwan28252.4TissueCRCAJCCNAWntGenomic DNA sequencing, tagger algorithmPolymorphismNAWnt polymorphism associated with high risk in OS6
4Veloudis et al. [24]2017Greece57NATissueColon and rectal adenocarcinomaTNM 1–433.3WntIHCNegative, weak, intermediate, strongMedianNuclear β-catenin associated with poor OS5
5Kim et al. [25]2018Korea19465.5TissueCRCNA22.2Wnt 5AGenomic DNA extractionMethylated/nonmethylatedNAMethylation observed in 32%, not associated with OS7
6Wangefjord et al. [26]2011Austria52747.6TissueCRCTNM 1–4NACyclin D1IHCweak, moderate, strong>0–>75%High Cyclin D1 expression associated with poor survival in men7
7Bazan et al. [27]2005Italy16047.5TissueCRCDuke A-DNATP53PCR-SSCPMutationNAAssociated with poor OS6
8Khan et al. [28]2018USA182556.7TissueCRCNA37.2TP53Genomic sequencingMutation5–10%Associated with poor OS5
CTNNB1
SMAD-4
APC
9Brandstedt et al. [29]2014Sweden3040TissueCRCTNM 1–4NAp53IHC staining and gene sequencingPositive/negativep53: >50%;
β-catenin: 0–2;
Cyclin D1: 0->75%		Associated with poor OS6
10Huemer et al. [30]2018Austria16139.7TissueCRCGrade 1–324TP53Genomic DNA sequencingMutationNATP53 mutation not associated with shorter OS compared with TP53 wild type tumor. TP53 mutation not associated with shorter OS in right-sided tumors5
11Sun et al. [31]2014China19764.4TissueCRCTNM 0–4NATP53IHCHigh/low150Associated with poor OS5
12Theodoropoulos et al. [32]2008Greece16567.8TissueColorectal adeno cancerTNM stage 1–4NATP53Nuclear immunostaining of positive cellsOverexpression>10%p53+: 63.5% tumors.
Advanced T stage associated with p53 expression		4
13Warren et al. [33]2013USA60755.5TissueColon cancerStage 3NATP53Direct sequencing and hybridizationMutationNATP53 mutations- 45%4
14Netter et al. [34]2014France6875TissueColon ca., metastaticNA67.6TP53FASAY and sanger sequencingNA10–15%Associated with poor OS5
15Kandioler et al. [35]2015Austria38951.1TissueColon cancerStage 3NATP53Sanger sequencingMutations<75%Associated with poor OS4
16Chen et al. [36]2013China20342.3TissueCRCAJCCNATP53IHCNegative, positive>10%Associated with poor OS5
17Russo et al. [37]2014USA22226.12TissueCRCStage 1–4NATP53,
APC		Clinical tumor genotypingMutationsNATP53 mutations: 21%
APC mutations: 8%		5
18Oh et al. [38]2019Korea62159.9TissueCRCAJCC 2 and 3NATP53IHC and next generation sequencingWeak, moderate, strong0%Weak expression associated with poor OS6
19Wang et al. [39]2017China12450.8TissueCRCTNM 1–4NATP53IHCExpression>10%P53 positive: 58.8%7
20Zhang et al. [40]2014China18542.7TissueCRCAJCC 1–440TP53IHCNegative/positive<10% cells with +ve nuclei: Negative; >10% cells with +ve nuclei: PositiveAssociated with poor OS7
21Godai et al. [41]2009Japan21157.8TissueCRCDuke stage A-DNATP53Genomic DNA SequencingMutationsNATP53 mutations: 70%6
22Chun et al. [42]2019USA40155.6TissueCRCAJCC24.6TP53
APC
SMAD-4		Next gen sequencingLow or high risk (EAp53 score)NATP53 mutations: 65.6%
APC mutations: 47.4%
SMAD-4 mutations: 11.4%		8
23Tiong et al. [43]2014China and taiwanNANATissueCRCNANATP53,
CTNNB1,
Wnt 5A		IHCOverexpressionNAAssociated with poor survival4
24Li et al. [44]2018China31557.1TissueCRCTNMNATP53Next gen mutational analysisMutationNADouble mutated P53 with PIK3CA associated with poor survival6
25Iacopetta et al. [45]2006Multinational358352.3TissueCRCDukes stage A-DNATP53PCRMutationNATP53 mutation associated with distal colon cancer6
26Morikawa et al. [46]2012USA106039TissueColon and rectal cancerStages 1–4NATP53IHCModerate and strongNAAssociated with poor OS8
27Kawaguchi et al. [47]2019USA49058.3TissueCRCAJCC Cat. TNATP53SMAD-4Nextgen sequencingExpression>10%Associated with poor OS7
28Samowitz et al. [48]2002USA146450.2TissueColon cancerAJCCNATP53NANANAAssociated with poor survival7
29Soong et al. [49]2000Australia995NATissueCRCDuke stage B&C34TP53NAMutationNA39% mutations5
30Jurach et al. [50]2006Brazil8356.6TissueRectalAstler Coller B&CNATP53IHCMutation>20%Associated with poor OS5
31Loes et al. [51]2016Norway15160.2TissueCRCNANATP53Sanger sequencingMutationsNATP53 mutations- 60.4%4
32Iacopetta et al. [52]2006Multinational358352.3TissueCRCDukes stage A-DNATP53PCRMutationNATP53 mutation associated with distal colon cancer6
33Salim et al. [53]2013Sweden85NATissueColon cancerNANAβ-CateninIHCLess expression<50%Associated with poor OS4
34Kamposioras et al. [54]2013Greece10661.3TissueCRCNA40% (CRC)β-CateninIHCOverexpressionModerateAssociated with poor OS7
35Gao et al. [55]2014China18158TissueCRCTNM stages 1–4NAβ-CateninIHCOverexpression>50%Associated with poor OS6
36Jang et al. [56]2012Korea21861.4TissueColon cancerNA23.3β-Catenin,
Cyclin D1		IHCOverexpression>30%Associated with poor survival5
37Lee et al. [57]2013Korea30561.9TissueCRCAJCC stages 1–4NAβ-CateninIHCOverexpression>30%Associated with poor OS6
38Wong et al. [58]2003China6065TissueCRCNANAβ-CateninIHCOverexpression>300Associated with poor survival4
39Chung et al. [59]2001USA543NATissueCRCNANAβ-CateninIHCOverexpressionModerateAssociated with poor survival4
40Fernebro et al. [60]2004Sweden25767.3TissueRectal cancerNANAβ-Catenin, p53IHCAbnormal expressionWeakAssociated with poor survival5
41Bondi et al. [61]2004Norway16245.6Tissuecolon cancerNANAβ-CateninIHCoverexpression>1%Associated with poor survival4
42Kim et al. [62]2005Korea124NATissueCRCDuke A-DNAβ-CateninIHCAbnormal expression>5%Associated with poor survival6
43Filiz et al. [63]2010Turkey13860.1TissueCRCNANAβ-CateninIHCExpression levelsWeakAssociated with poor survival5
44Jung et al. [64]2013Korea34959.5TissueCRCNA21.7β-Catenin, p53IHCOverexpression>0%Associated with poor survival7
45Wangefjord et al. [65]2013Sweden52747.4TissueCRCTNM stages 1–4NAβ-CateninIHCOverexpressionModerateAssociated with poor survival5
46Balzi et al. [66]2015Italy32153.2TissueCRCNANAβ-CateninIHCOverexpressionModerateAssociated with poor survival5
47Youssef et al. [67]2015Egypt7248.1TissueCRCTNM stages 1–4 and dukes A-C69.4β-CateninIHCOverexpression>10%Associated with poor survival6
48Togo et al. [68]2008USA18362.8TissueCRCTNM stages 1–433.3β-Catenin, p53IHCOverexpressionModerate/strong expressionAssociated with poor survival5
49Matsuoka et al. [69]2011Japan15663.4TissueCRCTNM stages 1–4NAβ-CateninIHCOverexpression>20%Associated with poor survival7
50Morikawa et al. [70]2011USA95539.9TissueCRCNANAβ-CateninIHCOverexpressionModerate/strong expressionAssociated with poor survival8
51Ozguven et al. [71]2011Turkey6033.3TissueCRCNANAβ-CateninIHCoverexpression>0%Associated with poor survival5
52Stanczak et al. [72]2011Poland6666.66TissueCRCNANAβ-CateninIHCOverexpression>10%Associated with poor survival6
53Toth et al. [73]2012Hungary7950.6TissueCRCNANAβ-CateninIHCOverexpression>10%Associated with poor survival7
54Sun et al. [74]2011China6764.2TissueColon cancerNANAβ-CateninIHCDecreased expression>10%Downregulation associated with increased expression of E-Cadherin8
55Wang et al. [75]2020USA341 (COH)56.3TissueCOADNA30.7APC TP53 CTNNB1DNA sequencingMutationsNAAPC mutations- 74.8%8
934 (MSKCC)52.9TissueNA26.1APC TP53 CTNNB1DNA sequencingMutationsNAAPC mutations- 74.8% 
56Mondaca et al. [76]2020USA471 TissueCRCNA32%APC CTNNB1Tumor genomic profilingExpressionNAAPC associated with poor survival7
57Schell et al. [77]2016USA407NATissueCRCNA41APCTGSMutationNAAssociated with poor survival4
58Gerami et al. [78]2020Iran5777.2Frozen tissueCRCTNM stage 1 to 436.8APCDNA sequencingAG vs. AA genotypeNAAG genotype associated with poor survival5
59Conlin et al. [79]2005Scotland10760.7TissueCRCDuke stage A-D14.9APC p53Genomic DNA extraction and sequencingMutationsNAAPC mutations: 56%; p53 mutations: 61%; not associated4
60Wang et al. [80]2020USA331NAMicrosatellite stable, tissueCRC4NAAPCNext-gen genomic analysisAPC –WT or APC-MTNAAPC-WT associated with poor survival7
61Jorissen et al. [81]2015Australia74655.4CRC MSI (unstable) and MSS (stable); validation cohort, tissueCRCStage 1 to 442.2APC TP53DNA sequencingAPC-WT or APC-MTNATP53: 55.4%; APC-WT associated with poor survival6
62Voorneveld et al. [82]2012Netherlands209NATissueCRCNANASMAD-4IHCExpressionNAAssociated with poor survival5
63Li et al. [83]2011China147NATissueCRCNANASMAD-4IHCExpressionNAAssociated with poor survival5
64Yoo et al. [84]2019Korea1370NATissueCRCNANASMAD-4NASMAD-4 high vs. lowNAAssociated with poor survival5
65Su et al. [85]2016China25157.37TissueCRCStages 1–4NASMAD-4NASMAD-4 positiveNANo association5
66Isaksson et al. [86]2006Sweden8642TissueCRCDuke A-C35SMAD-4IHCNegative – 3+NAAssociated with poor OS6
67Fleming et al. [87]2013Australia74455.6Sporadic CRCs, tissueCRCAJCC stages 1–442.07SMAD-4IHCStroma high, stroma lowNAAssociated with poor survival4
68Roth et al. [88]2012Switzerland1404NATissueCRCStage 2 (18%) and 3 (23%)NASMAD-4IHC detectionLoss of expressionNAAssociated with poor survival6
69Lampropoulos et al. [89]2012Greece195NATissueCRCStage 1 to 4NASMAD-4NANANAAssociated with poor survival4
70Isaksson et al. [90]2011Sweden441NATissueCRCStage 1 to 4NASMAD-4IHCLoss, moderate, high0–5%Loss of SMAD—24%; associated with poor OS5
71Jia et al. [91]2017US20951.7TissueCRCStages 1–4NASMAD-4Genomic DNA sequencingHigh, lowNAHigh cytoplasm and low nuclear SMAD-4 not associated with OS7
72Oyanagi et al. [92]2019Japan201117TissueCRCTNM 1–456SMAD-4IHCWeak, strong>95%SMAD-4 alterations: 28%, associated with poor OS and RFS6
73Ionescu et al. [93]2014Romania3966.6TissueCRCDuke A-D25.6SMAD-3q-RT-PCROverexpression, under-expressionNANo association with OS6
74Fukushima et al. [94]2003Japan100NASporadic CRC and normal tissueSporadic CRCNANASMAD3/SMAD4PCR-SSCPAbnormalNASMAD-3: no abnormality; SMAD-4: abnormal 5 cases4
75Chun et al. [95]2014Korea20165.7TissueRectal cancer3NASMAD4PCRNuclear or cytoplasmic SMAD-4NANo association6
76Bacman et al. [96]2007Germany31061TissueColon cancerStage 2 (57.4%) and 3 (42.6%)NASMAD3/SMAD4PCRSMAD-3 and SMAD-4 in tumor high or lowNASMAD-3 and SMAD-4 in tumor, effects on TGFβ R2 pathway downregulation5
77Meskar et al. [97]2009Netherlands13554.4TissueCRCStage 1 (17.8%), 2 (77.8%) and 3 (4.4%)53.3SMAD4NAStroma high vs. stroma lowNAStroma high SMAD-4 associated with poor prognosis7
78Horst et al. [98]2009Germany14250TissueCRCUICC stage 2ANAβ-CateninIHC stainingNuclear β-cateninNAAssociated with poor survival6
79Bondi et al. [99]2005Norway21947.9TissueColon cancerDuke A-DNACyclin D1Real time q-PCR and IHCLow, highGrade +2Cyclin not associated with survival.6
80Bahnassy et al. [100]2004Egypt6060.0TissueCRCTNM 1–4NACyclin D1DNA extraction and gene amplification, IHCamplification>75%Associated with poor survival7
81Saridaki et al. [101]2010Greece14456.94TissueCRCStages 1–4NACyclin D1DNA extraction and IHCWeak, strong≥50% with weak and ≥20% with strong stainingOverexpression is not associated with poor outcomes6
82Ogino et al. [102]2009USA60243TissueColon cancerAJCC stages 1–4NACyclin D1IHCNo, weak, moderate, strongStrong staining in any fractionOverexpression not associated with poor survival8
NA: not applicable; CRC: colon rectal cancer; COAD: colon adenocarcinoma; IHC: immunohistochemical; OS: overall survival.