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pmid:36882493

Differentially expressed discriminative genes and significant meta-hub genes based key genes identification for hepatocellular carcinoma using statistical machine learning.

Md Al Mehedi Hasan · Md Maniruzzaman · Jungpil Shin

Scientific reports · 2023 doi:10.1038/s41598-023-30851-1

Paper

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Experiment

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Data

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Differentially expressed discriminative genes and significant meta-hub genes based key genes identification for hepatocellular carcinoma using statistical machine learning.
doi
10.1038/s41598-023-30851-1
pmid
36882493
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[0]
Md Al Mehedi Hasan
[1]
Md Maniruzzaman
[2]
Jungpil Shin
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Scientific reports
year
2023
abstract
Hepatocellular carcinoma (HCC) is the most common lethal malignancy of the liver worldwide. Thus, it is important to dig the key genes for uncovering the molecular mechanisms and to improve diagnostic and therapeutic options for HCC. This study aimed to encompass a set of statistical and machine learning computational approaches for identifying the key candidate genes for HCC. Three microarray datasets were used in this work, which were downloaded from the Gene Expression Omnibus Database. At first, normalization and differentially expressed genes (DEGs) identification were performed using limma for each dataset. Then, support vector machine (SVM) was implemented to determine the differentially expressed discriminative genes (DEDGs) from DEGs of each dataset and select overlapping DEDGs genes among identified three sets of DEDGs. Enrichment analysis was performed on common DEDGs using DAVID. A protein-protein interaction (PPI) network was constructed using STRING and the central hub genes were identified depending on the degree, maximum neighborhood component (MNC), maximal clique centrality (MCC), centralities of closeness, and betweenness criteria using CytoHubba. Simultaneously, significant modules were selected using MCODE scores and identified their associated genes from the PPI networks. Moreover, metadata were created by listing all hub genes from previous studies and identified significant meta-hub genes whose occurrence frequency was greater than 3 among previous studies. Finally, six key candidate genes (TOP2A, CDC20, ASPM, PRC1, NUSAP1, and UBE2C) were determined by intersecting shared genes among central hub genes, hub module genes, and significant meta-hub genes. Two independent test datasets (GSE76427 and TCGA-LIHC) were utilized to validate these key candidate genes using the area under the curve. Moreover, the prognostic potential of these six key candidate genes was also evaluated on the TCGA-LIHC cohort using survival analysis.
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SVM with RBF kernel was applied on the identified DEGs (699 DEGs for GSE36376; 428 DEGs for GSE39791; and 413 DEGs for GSE57957) of each dataset in order to identify the DEDGs of HCC patients.
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sections[4] "Identification of common DEDGs using SVM" paragraph 2
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SVM with RBF kernel was applied on the identified DEGs (699 DEGs for GSE36376; 428 DEGs for GSE39791; and 413 DEGs for GSE57957) of each dataset in order to identify the DEDGs of HCC patients.
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sections[31] "Data availability" paragraph 2
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The datasets generated and/or analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository with accession numbers: GSE36376, GSE39791, GSE57957, and GSE76427 with GPL10558 platforms. One can easily download these datasets from the link: www.ncbi.nlm.nih.gov/geo/.
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The study identified six key candidate genes for hepatocellular carcinoma: TOP2A, CDC20, ASPM, PRC1, UBE2C, and NUSAP1.
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Finally, six key candidate genes (TOP2A, CDC20, ASPM, PRC1, NUSAP1, and UBE2C) were determined by intersecting shared genes among central hub genes, hub module genes, and significant meta-hub genes.
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open
state
resolved
reader
null
reader_status
reader_required
identifier
GSE39791
version
null
note
The datasets generated and/or analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository with accession numbers: GSE36376, GSE39791, GSE57957, and GSE76427 with GPL10558 platforms. One can easily download these datasets from the link: www.ncbi.nlm.nih.gov/geo/.
structure object · 15 fields
repository
GEO
access_route
GEO accession URL
access_statement_verbatim
The datasets generated and/or analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository with accession numbers: GSE36376, GSE39791, GSE57957, and GSE76427 with GPL10558 platforms. One can easily download these datasets from the link: www.ncbi.nlm.nih.gov/geo/.
access_statement_kind
data_availability_statement
sample_accessions array · 144 items
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[35]
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[40]
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[41]
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[42]
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[43]
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[44]
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[45]
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[46]
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[47]
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[48]
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[49]
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[50]
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[51]
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[52]
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[53]
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[54]
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[55]
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[56]
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[57]
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[58]
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[60]
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[61]
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[62]
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[63]
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[64]
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[65]
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[66]
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[67]
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[68]
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[69]
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[70]
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[71]
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[72]
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[73]
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[74]
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[75]
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[76]
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[77]
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[78]
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[79]
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[80]
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[81]
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[82]
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[83]
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[84]
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[85]
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[86]
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[87]
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[88]
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[89]
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[90]
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[91]
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[92]
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[93]
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[94]
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[95]
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[96]
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[97]
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[98]
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[99]
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[100]
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[101]
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[102]
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[103]
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[104]
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[105]
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[106]
GSM979157
[107]
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[108]
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[109]
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[110]
GSM979161
[111]
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[112]
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[113]
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[114]
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[115]
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[116]
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[117]
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[118]
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[119]
GSM979170
[120]
GSM979171
[121]
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[122]
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[123]
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[124]
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[125]
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[126]
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[127]
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[128]
GSM979179
[129]
GSM979180
[130]
GSM979181
[131]
GSM979182
[132]
GSM979183
[133]
GSM979184
[134]
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[135]
GSM979186
[136]
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[137]
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[138]
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[139]
GSM979190
[140]
GSM979191
[141]
GSM979192
[142]
GSM979193
[143]
GSM979194
sample_count
144
group_sizes
null
group_sizes_basis
null
platform
10558
taxon
Homo sapiens
title
Hepatic regeneration gene expression signature predicts late recurrence of hepatocellular carcinoma
resolution_checked_at
2026-11-01T15:39:54Z
resolution_check
identifier_resolution_only_no_download_no_licence_read
downloaded
false
licence_read
false
[3] object · 15 fields
id
data:geo:GSE57957
role
raw
format
geo-series
media_type
application/vnd.ncbi.geo-series+json
uri
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE57957
sha256
null
bytes
null
access
open
state
resolved
reader
null
reader_status
reader_required
identifier
GSE57957
version
null
note
The datasets generated and/or analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository with accession numbers: GSE36376, GSE39791, GSE57957, and GSE76427 with GPL10558 platforms. One can easily download these datasets from the link: www.ncbi.nlm.nih.gov/geo/.
structure object · 15 fields
repository
GEO
access_route
GEO accession URL
access_statement_verbatim
The datasets generated and/or analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository with accession numbers: GSE36376, GSE39791, GSE57957, and GSE76427 with GPL10558 platforms. One can easily download these datasets from the link: www.ncbi.nlm.nih.gov/geo/.
access_statement_kind
data_availability_statement
sample_accessions array · 78 items
[0]
GSM1398645
[1]
GSM1398646
[2]
GSM1398647
[3]
GSM1398648
[4]
GSM1398649
[5]
GSM1398650
[6]
GSM1398651
[7]
GSM1398652
[8]
GSM1398653
[9]
GSM1398654
[10]
GSM1398655
[11]
GSM1398656
[12]
GSM1398657
[13]
GSM1398658
[14]
GSM1398659
[15]
GSM1398660
[16]
GSM1398661
[17]
GSM1398662
[18]
GSM1398663
[19]
GSM1398664
[20]
GSM1398665
[21]
GSM1398666
[22]
GSM1398667
[23]
GSM1398668
[24]
GSM1398669
[25]
GSM1398670
[26]
GSM1398671
[27]
GSM1398672
[28]
GSM1398673
[29]
GSM1398674
[30]
GSM1398675
[31]
GSM1398676
[32]
GSM1398677
[33]
GSM1398678
[34]
GSM1398679
[35]
GSM1398680
[36]
GSM1398681
[37]
GSM1398682
[38]
GSM1398683
[39]
GSM1398684
[40]
GSM1398685
[41]
GSM1398686
[42]
GSM1398687
[43]
GSM1398688
[44]
GSM1398689
[45]
GSM1398690
[46]
GSM1398691
[47]
GSM1398692
[48]
GSM1398693
[49]
GSM1398694
[50]
GSM1398695
[51]
GSM1398696
[52]
GSM1398697
[53]
GSM1398698
[54]
GSM1398699
[55]
GSM1398700
[56]
GSM1398701
[57]
GSM1398702
[58]
GSM1398703
[59]
GSM1398704
[60]
GSM1398705
[61]
GSM1398706
[62]
GSM1398707
[63]
GSM1398708
[64]
GSM1398709
[65]
GSM1398710
[66]
GSM1398711
[67]
GSM1398712
[68]
GSM1398713
[69]
GSM1398714
[70]
GSM1398715
[71]
GSM1398716
[72]
GSM1398717
[73]
GSM1398718
[74]
GSM1398719
[75]
GSM1398720
[76]
GSM1398721
[77]
GSM1398722
sample_count
78
group_sizes
null
group_sizes_basis
null
platform
10558
taxon
Homo sapiens
title
Expression profile of Hepatocellular Carcinoma
resolution_checked_at
2026-11-01T15:39:54Z
resolution_check
identifier_resolution_only_no_download_no_licence_read
downloaded
false
licence_read
false
[4] object · 15 fields
id
data:geo:GSE76427
role
raw
format
geo-series
media_type
application/vnd.ncbi.geo-series+json
uri
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE76427
sha256
null
bytes
null
access
open
state
resolved
reader
null
reader_status
reader_required
identifier
GSE76427
version
null
note
The datasets generated and/or analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository with accession numbers: GSE36376, GSE39791, GSE57957, and GSE76427 with GPL10558 platforms. One can easily download these datasets from the link: www.ncbi.nlm.nih.gov/geo/.
structure object · 15 fields
repository
GEO
access_route
GEO accession URL
access_statement_verbatim
The datasets generated and/or analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository with accession numbers: GSE36376, GSE39791, GSE57957, and GSE76427 with GPL10558 platforms. One can easily download these datasets from the link: www.ncbi.nlm.nih.gov/geo/.
access_statement_kind
data_availability_statement
sample_accessions array · 167 items
[0]
GSM2011285
[1]
GSM2011286
[2]
GSM2011287
[3]
GSM2011288
[4]
GSM2011289
[5]
GSM2011290
[6]
GSM2011291
[7]
GSM2011292
[8]
GSM2011293
[9]
GSM2011294
[10]
GSM2011295
[11]
GSM2011296
[12]
GSM2011297
[13]
GSM2011298
[14]
GSM2011299
[15]
GSM2011300
[16]
GSM2011301
[17]
GSM2011302
[18]
GSM2011303
[19]
GSM2011304
[20]
GSM2011305
[21]
GSM2011306
[22]
GSM2011307
[23]
GSM2011308
[24]
GSM2011309
[25]
GSM2011310
[26]
GSM2011311
[27]
GSM2011312
[28]
GSM2011313
[29]
GSM2011314
[30]
GSM2011315
[31]
GSM2011316
[32]
GSM2011317
[33]
GSM2011318
[34]
GSM2011319
[35]
GSM2011320
[36]
GSM2011321
[37]
GSM2011322
[38]
GSM2011323
[39]
GSM2011324
[40]
GSM2011325
[41]
GSM2011326
[42]
GSM2011327
[43]
GSM2011328
[44]
GSM2011329
[45]
GSM2011330
[46]
GSM2011331
[47]
GSM2011332
[48]
GSM2011333
[49]
GSM2011334
[50]
GSM2011335
[51]
GSM2011336
[52]
GSM2011337
[53]
GSM2011338
[54]
GSM2011339
[55]
GSM2011340
[56]
GSM2011341
[57]
GSM2011342
[58]
GSM2011343
[59]
GSM2011344
[60]
GSM2011345
[61]
GSM2011346
[62]
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[63]
GSM2011348
[64]
GSM2011349
[65]
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[66]
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[67]
GSM2011352
[68]
GSM2011353
[69]
GSM2011354
[70]
GSM2011355
[71]
GSM2011356
[72]
GSM2011357
[73]
GSM2011358
[74]
GSM2011359
[75]
GSM2011360
[76]
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[77]
GSM2011362
[78]
GSM2011363
[79]
GSM2011364
[80]
GSM2011365
[81]
GSM2011366
[82]
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[83]
GSM2011368
[84]
GSM2011369
[85]
GSM2011370
[86]
GSM2011371
[87]
GSM2011372
[88]
GSM2011373
[89]
GSM2011374
[90]
GSM2011375
[91]
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[92]
GSM2011377
[93]
GSM2011378
[94]
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[95]
GSM2011380
[96]
GSM2011381
[97]
GSM2011382
[98]
GSM2011383
[99]
GSM2011384
[100]
GSM2011385
[101]
GSM2011386
[102]
GSM2011387
[103]
GSM2011388
[104]
GSM2011389
[105]
GSM2011390
[106]
GSM2011391
[107]
GSM2011392
[108]
GSM2011393
[109]
GSM2011394
[110]
GSM2011395
[111]
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[112]
GSM2011397
[113]
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[114]
GSM2011399
[115]
GSM2011400
[116]
GSM2011401
[117]
GSM2011402
[118]
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[119]
GSM2011404
[120]
GSM2011405
[121]
GSM2011406
[122]
GSM2011407
[123]
GSM2011408
[124]
GSM2011409
[125]
GSM2011410
[126]
GSM2011411
[127]
GSM2011412
[128]
GSM2011413
[129]
GSM2011414
[130]
GSM2011415
[131]
GSM2011416
[132]
GSM2011417
[133]
GSM2011418
[134]
GSM2011419
[135]
GSM2011420
[136]
GSM2011421
[137]
GSM2011422
[138]
GSM2011423
[139]
GSM2011424
[140]
GSM2011425
[141]
GSM2011426
[142]
GSM2011427
[143]
GSM2011428
[144]
GSM2011429
[145]
GSM2011430
[146]
GSM2011431
[147]
GSM2011432
[148]
GSM2011433
[149]
GSM2011434
[150]
GSM2011435
[151]
GSM2011436
[152]
GSM2011437
[153]
GSM2011438
[154]
GSM2011439
[155]
GSM2011440
[156]
GSM2011441
[157]
GSM2011442
[158]
GSM2011443
[159]
GSM2011444
[160]
GSM2011445
[161]
GSM2011446
[162]
GSM2011447
[163]
GSM2011448
[164]
GSM2011449
[165]
GSM2011450
[166]
GSM2011451
sample_count
167
group_sizes
null
group_sizes_basis
null
platform
10558
taxon
Homo sapiens
title
Microarray expression data for tumor and adjacent non-tumor tissues from hepatocellular carcinoma patients
resolution_checked_at
2026-11-01T15:39:55Z
resolution_check
identifier_resolution_only_no_download_no_licence_read
downloaded
false
licence_read
false
gaps array · 8 items
[0]
asset:data:geo:GSE36376 not downloaded
[1]
asset:data:geo:GSE36376 licence not read
[2]
asset:data:geo:GSE39791 not downloaded
[3]
asset:data:geo:GSE39791 licence not read
[4]
asset:data:geo:GSE57957 not downloaded
[5]
asset:data:geo:GSE57957 licence not read
[6]
asset:data:geo:GSE76427 not downloaded
[7]
asset:data:geo:GSE76427 licence not read
analysis object · 4 fields
state
partial
methods array · 4 items
[0] object · 10 fields
id
method-1
family
machine_learning
specific
support_vector_machine
label
Machine learning
dsl_operations array · 3 items
[0]
train_classifier
[1]
cross_validate
[2]
roc_auc
missing_operations array · 0 items
parameters object · 0 fields
data_shapes array · 1 item
[0]
labelled_feature_matrix
evidence object · 3 fields
score
1
band
verbatim
quote
SVM with RBF kernel was applied on the identified DEGs (699 DEGs for GSE36376; 428 DEGs for GSE39791; and 413 DEGs for GSE57957) of each dataset in order to identify the DEDGs of HCC patients.
[1] object · 10 fields
id
method-2
family
differential_expression
specific
limma_voom
label
Differential expression analysis
dsl_operations array · 3 items
[0]
normalise_counts
[1]
differential_expression_fit
[2]
fdr_bh
missing_operations array · 0 items
parameters object · 0 fields
data_shapes array · 1 item
[0]
count_matrix_with_condition
evidence object · 3 fields
score
0.7
band
medium
quote
limma
[2] object · 10 fields
id
method-3
family
network_analysis
specific
ppi_network
label
Network / pathway analysis
dsl_operations array · 3 items
[0]
build_graph
[1]
centrality_scores
[2]
pathway_enrich
missing_operations array · 0 items
parameters object · 0 fields
data_shapes array · 1 item
[0]
edge_list
evidence object · 3 fields
score
0.7
band
medium
quote
protein-protein interaction
[3] object · 10 fields
id
method-4
family
network_analysis
specific
centrality
label
Network / pathway analysis
dsl_operations array · 3 items
[0]
build_graph
[1]
centrality_scores
[2]
pathway_enrich
missing_operations array · 0 items
parameters object · 0 fields
data_shapes array · 1 item
[0]
edge_list
evidence object · 3 fields
score
0.7
band
medium
quote
centrality
targets array · 0 items
gaps array · 1 item
[0]
method.reader_differs_from_extractor
capability object · 3 fields
state
complete
requirements array · 1 item
[0] object · 6 fields
capability_id
capability:computational_analysis
label
Computational analysis platform
assay_families array · 9 items
[0]
meta_analysis
[1]
machine_learning
[2]
survival_analysis
[3]
statistical_regression
[4]
pca
[5]
molecular_docking
[6]
network_analysis
[7]
differential_expression
[8]
gwas
candidate
Automated Assays Laravel application and simulated adapters
gaps array · 0 items
readiness object · 8 fields
state
complete
tier
R1
blocked_on
nothing:replicable_now
axes object · 3 fields
method object · 5 fields
tier
R1
expressible
true
required_operations array · 3 items
[0]
train_classifier
[1]
cross_validate
[2]
roc_auc
missing_operations array · 0 items
basis
The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: support_vector_machine.
capability object · 4 fields
tier
R1
capability_id
capability:computational_analysis
availability_state
owned
basis
The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here.
data object · 6 fields
tier
R1
reachable
true
accessions array · 4 items
[0]
GSE36376
[1]
GSE39791
[2]
GSE57957
[3]
GSE76427
resolved_accessions array · 4 items
[0]
GSE36376
[1]
GSE39791
[2]
GSE57957
[3]
GSE76427
statements array · 1 item
[0]
The datasets generated and/or analyzed during the current study are available in the Gene Expression Omnibus (GEO) repository with accession numbers: GSE36376, GSE39791, GSE57957, and GSE76427 with GPL10558 platforms. One can easily download these datasets from the link: www.ncbi.nlm.nih.gov/geo/.
basis
The paper names GSE36376, GSE39791, GSE57957, GSE76427 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read.
can_run object · 3 fields
dsl_operations array · 3 items
[0]
train_classifier
[1]
cross_validate
[2]
roc_auc
assets array · 2 items
[0]
source:pmid:36882493
[1]
data:geo:GSE36376
steps array · 1 item
[0]
run_analysis
must_build object · 5 fields
dsl_operations array · 0 items
converters array · 0 items
readers array · 0 items
capabilities array · 0 items
data_gaps array · 1 item
[0]
data:geo:GSE36376
gaps array · 0 items
review object · 5 fields
state
partial
machine_critique object · 5 fields
kind
extraction_review
reader object · 5 fields
model
MiniMax-M3.1-Flash
provider
minimax
provider_family
minimax
read_at
2026-11-01T18:32:55Z
independence
single_reader
evidence_check object · 2 fields
method
verbatim
availability
verbatim
calls
5
usage object · 3 fields
prompt_tokens
19161
completion_tokens
1687
cached_tokens
256
stages array · 1 item
[0] object · 4 fields
id
extraction
state
complete
reader
MiniMax-M3.1-Flash
provider
minimax
gaps array · 3 items
[0]
review.independent_reader
[1]
review.machine_critique
[2]
review.human_critique
execution object · 5 fields
state
absent
status
not_run
mode
null
runs array · 0 items
gaps array · 1 item
[0]
execution.not_run
provenance object · 7 fields
entities array · 3 items
[0] object · 3 fields
id
pmid:36882493
type
paper
label
pmid:36882493
[1] object · 3 fields
id
source:pmid:36882493
type
manuscript
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PMID 36882493 full text
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fying the key candidate genes for HCC. Three microarray datasets were used in this work, which were
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SVM with RBF kernel was applied on the identified DEGs (699 DEGs for GSE36376; 428 DEGs for GSE39791; and 413 DEGs for GSE57957) of each dataset in order to identify the DEDGs of HCC patients.
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Complete file
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Thus, it is important to dig the key genes for uncovering the molecular mechanisms and to improve diagnostic and therapeutic options for HCC. This study aimed to encompass a set of statistical and machine learning computational approaches for identifying the key candidate genes for HCC. Three microarray datasets were used in this work, which were downloaded from the Gene Expression Omnibus Database. At first, normalization and differentially expressed genes (DEGs) identification were performed using limma for each dataset. Then, support vector machine (SVM) was implemented to determine the differentially expressed discriminative genes (DEDGs) from DEGs of each dataset and select overlapping DEDGs genes among identified three sets of DEDGs. Enrichment analysis was performed on common DEDGs using DAVID. A protein-protein interaction (PPI) network was constructed using STRING and the central hub genes were identified depending on the degree, maximum neighborhood component (MNC), maximal clique centrality (MCC), centralities of closeness, and betweenness criteria using CytoHubba. Simultaneously, significant modules were selected using MCODE scores and identified their associated genes from the PPI networks. Moreover, metadata were created by listing all hub genes from previous studies and identified significant meta-hub genes whose occurrence frequency was greater than 3 among previous studies. Finally, six key candidate genes (TOP2A, CDC20, ASPM, PRC1, NUSAP1, and UBE2C) were determined by intersecting shared genes among central hub genes, hub module genes, and significant meta-hub genes. Two independent test datasets (GSE76427 and TCGA-LIHC) were utilized to validate these key candidate genes using the area under the curve. 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