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Original article
peer-reviewed

The 100 Most Cited Papers About Cancer Epigenetics



Abstract

Introduction

Although bibliometric analyses have been performed in the past on cancer and genomics, little is known about the most frequently cited articles specifically related to cancer epigenetics. Therefore, the purpose of this study is to use citation count to identify those papers in the scientific literature that have made key contributions in the field of cancer epigenetics and identify key driving forces behind future investigations.

Materials and methods

The Thomas Reuters Web of Science services was queried for the years 1980-2018 without language restrictions. Articles were sorted in descending order of the number of times they were cited in the Web of Science database by other studies, and all titles and abstracts were screened to identify the research areas of the top 100 articles. The number of citations per year was calculated.

Results

We identified the 100 most-cited articles on cancer epigenetics, which collectively had been cited 147,083 times at the time of this writing. The top-cited article was cited 7,124 times, with an average of 375 citations per year since publication. In the period 1980-2018, the most prolific years were the years 2006 and 2010, producing nine articles, respectively. Twenty-eight unique journals contributed to the 100 articles, with the Nature journal contributing most of the articles (n=22). The most common country of article origin was the United States of America (n=78), followed by Germany (n=4), Switzerland (n=4), Japan (n=3), Spain (n=2), and United Kingdom (n=2).

Conclusions

In this study, the 100 most-cited articles in cancer epigenetics were examined, and the contributions from various authors, specialties, and countries were identified. Cancer epigenetics is a rapidly growing scientific field impacting translational research in cancer screening, diagnosis, classification, prognosis, and targeted treatments. Recognition of important historical contributions to this field may guide future investigations.

Introduction

In 1942, Conrad Hal Waddington was the first to use the Greek word “epigenesis”, to describe how cells differentiated, and thus epigenetics was coined to mean "the causal interactions between genes and their products which bring the phenotype into being" [1]. But it was not until the 1970s when the contemporary definition emerged as “a hereditable change in gene expression that occurred without a change in the DNA sequence” [2]. Broadly speaking, as it applies to modern cancer biology, epigenetics now refers to regulatory mechanisms of DNA transcription that affect gene expression of which DNA methylation is the most widely studied. The relative role of epigenetics in cancer has been attributed to the observation in 1983 by two laboratories that most cancer DNA has fewer methyl groups than non-cancer DNA [3-5]. In one of these studies, Feinberg and Vogelstein showed that DNA methylation was linked to tissue-specific gene silencing in cancer, by finding that a substantial proportion of CpG islands were methylated in normal tissues were unmethylated in cancer cells [3].

Citation analysis is a systematic approach for identifying scientific publications that have a high impact in the scientific or medical community measuring high-impact papers and how they have shaped scientific disciplines [6]. For this purpose, the Institute for Scientific Information collects citation counts for academic journals in the Science Citation Index. Although bibliometric analyses have been performed in the past on cancer and genomics, little is known about the most frequently cited articles specifically related to cancer epigenetics [6-10]. Therefore, the purpose of this study is to use citation count to identify those papers in the scientific literature that have made key contributions in the field of cancer epigenetics and identify key driving forces behind future investigations.

Materials & Methods

The Thomson Reuters Web of Science (WoS) database was used to query for citations of all articles relevant to cancer epigenetics. The basic search tool was selected, the keyword search for the topic to identify the articles of interest was specified as: “(epigenetic OR epigenomic OR methylation OR hypermethylation OR CpG island OR chromatic remodeling OR histone modification OR RNA interference OR gene silencing OR promoter regions OR chromatin assembly and disassembly OR liquid biopsy OR molecular OR biomolecular) AND (cancer OR neoplasm)”. The following search parameters were used: 1) articles published in the years 1980-2018 (since the word "epigenetics" was conceived in 1980); 2) all languages; 3) within the Science Citation Index Expanded. The results were carefully reviewed, and only those relevant to cancer epigenetics were selected. All review articles were excluded from the list. The top 100 articles by the number of citations that matched the search criteria were then further analyzed, and the title, first author, journal, and year of publication, number of citations, country, and the institution of origin were recorded. The articles retrieved were sorted in descending order in terms of times cited, and the number of citations per year was calculated.

Results

Our query retrieved 234,679 papers (Figure 1).

The top 100 articles related to “cancer epigenetics” were identified by the number of times they were cited (Table 1).

WoS Rank Authors Year Article title Total number of citations CY index CY rank
1 Golub et al. 1999 Molecular classification of cancer: class discovery and class prediction by gene expression monitoring 7124 375 6
2 Alizadeh et al. 2000 Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling 6045 336 13
3 Herman et al. 1996 Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands 4600 209 26
4 Barski et al. 2007 High-resolution profiling of histone methylations in the human genome 3849 350 10
5 Hegi et al. 2005 MGMT gene silencing and benefit from temozolomide in glioblastoma 3394 261 21
6 Chin et al. 2008 Comprehensive genomic characterization defines human glioblastoma genes and core pathways 3359 336 12
7 Cerami et al. 2012 The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data 3354 559 2
8 Stupp et al. 2009 Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial 3252 361 8
9 Muzny et al. 2012 Comprehensive molecular characterization of human colon and rectal cancer 3157 526 3
10 Verhaak et al. 2010 Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1 2891 361 7
11 Bell et al. 2011 Integrated genomic analyses of ovarian carcinoma 2725 389 5
12 Gupta et al. 2010 Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis 2637 330 15
13 Forner et al. 2012 Hepatocellular carcinoma 2427 405 4
14 Travis et al. 2011 International association for the study of lung cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of lung adenocarcinoma 2225 318 17
15 Yanaihara et al. 2006 Unique microRNA molecular profiles in lung cancer diagnosis and prognosis 2169 181 27
16 Curtis et al. 2012 The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups 1911 319 16
17 Neve et al. 2006 A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes 1828 152 30
18 Nielsen et al. 2004 Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma 1731 124 42
19 Hammerman et al. 2012 Comprehensive genomic characterization of squamous cell lung cancers 1731 289 19
20 Toyota et al. 1999 CpG island methylator phenotype in colorectal cancer 1701 90 58
21 Takamizawa et al. 2004 Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival 1695 121 43
22 Merlo et al. 1995 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers 1671 73 72
23 Ley et al. 2013 Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia 1656 331 14
24 Varambally et al. 2002 The polycomb group protein EZH2 is involved in progression of prostate cancer 1625 102 50
25 Bhattacharjee et al. 2001 Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses 1624 96 52
26 Esteller et al. 2001 A gene hypermethylation profile of human cancer 1605 94 55
27 Meissner et al. 2008 Genome-scale DNA methylation maps of pluripotent and differentiated cells 1538 154 29
28 Zhang et al. 2007 microRNAs as oncogenes and tumor suppressors 1515 138 36
29 Kandoth et al. 2013 Mutational landscape and significance across 12 major cancer types 1506 301 18
30 Cameron et al. 1999 Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer 1473 78 66
31 Clark et al. 1994 High sensitivity mapping of methylated cytosines. 1464 61 80
32 Herman et al. 1998 Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma 1455 73 71
33 Bass et al. 2014 Comprehensive molecular characterization of gastric adenocarcinoma 1403 351 9
34 Collisson et al. 2014 Comprehensive molecular profiling of lung adenocarcinoma 1372 343 11
35 Brennan et al. 2013 The somatic genomic landscape of glioblastoma 1367 273 20
36 Esteller et al. 2000 Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents 1360 76 69
37 Weinstein et al. 2013 The cancer genome atlas pan-cancer analysis project 1293 259 22
38 Weber et al. 2007 Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome 1289 117 47
39 Figueroa et al. 2010 Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation 1280 160 28
40 Getz et al. 2013 Integrated genomic characterization of endometrial carcinoma 1273 255 23
41 Irizarry et al. 2009 The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores 1267 141 35
42 Herman et al. 1995 Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. 1241 54 88
43 Narita et al. 2003 Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence 1238 83 64
44 Herman et al. 1994 Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. 1226 51 91
45 Swerdlow et al. 2016 The 2016 revision of the World Health Organization classification of lymphoid neoplasms 1201 601 1
46 Noushmehr et al. 2010 Identification of a CpG Island methylator phenotype that defines a distinct subgroup of glioma 1170 146 32
47 Kane et al. 1997 Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines 1164 55 84
48 Weisenberger et al. 2006 CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer 1162 97 51
49 Weber et al. 2005 Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells 1087 84 61
50 Fraga et al. 2005 Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer 1060 82 65
51 Fabbri et al. 2007 MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B 1041 95 54
52 Orom et al. 2010 Long noncoding RNAs with enhancer-like function in human cells 1041 130 39
53 Kleer et al. 2003 EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells 1014 68 77
54 Weinstein et al. 2014 Comprehensive molecular characterization of urothelial bladder carcinoma 1014 254 24
55 Jahr et al. 2001 DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells 1005 59 82
56 Hudson et al. 2010 International network of cancer genome projects 1000 125 40
57 Costello et al. 2000 Aberrant CpG-island methylation has non-random and tumour-type-specific patterns 994 55 85
58 Gaudet et al. 2003 Induction of tumors in mice by genomic hypomethylation 993 66 78
59 Sharma et al. 2010 A Chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations 968 121 44
60 Esteller et al. 1999 Inactivation of the DNA repair gene O-6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia 956 50 92
61 Zuber et al. 2011 RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia 941 134 37
62 Iorio et al. 2007 MicroRNA signatures in human ovarian cancer 937 85 60
63 Dweep et al. 2011 miRWalk - database: prediction of possible miRNA binding sites by "walking" the genes of three genomes 936 134 38
64 Comijn et al. 2001 The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion 933 55 86
65 Issa et al. 1994 Methylation of the oestrogen receptor CpG island links aging and neoplasia in human colon. 925 39 98
66 Kosaka et al. 2010 Secretory mechanisms and intercellular transfer of microRNAs in living cells 920 115 48
67 Saito et al. 2006 Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells 917 76 67
68 Carroll et al. 2006 Genome-wide analysis of estrogen receptor binding sites 911 76 68
69 Valk et al. 2004 Prognostically useful gene-expression profiles in acute myeloid leukemia 907 65 79
70 Weinstein et al. 1997 An information-intensive approach to the molecular pharmacology of cancer 906 43 95
71 Kantarjian et al. 2006 Decitabine improves patient outcomes in myelodysplastic syndromes - resuits of a phase III randomized study 899 75 70
72 Houseman et al. 2012 DNA methylation arrays as surrogate measures of cell mixture distribution 896 149 31
73 Patel et al. 2014 Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma 896 224 25
74 West et al. 2001 Predicting the clinical status of human breast cancer by using gene expression profiles 891 52 90
75 Turchinovich et al. 2011 Characterization of extracellular circulating microRNA 874 125 41
76 McCabe et al. 2012 EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations 861 144 33
77 Dammann et al. 2000 Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3 855 48 94
78 Turcan et al. 2012 IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype 854 142 34
79 Rhee et al. 2002 DNMT1 and DNMT3b cooperate to silence genes in human cancer cells 852 53 89
80 Lapointe et al. 2004 Gene expression profiling identifies clinically relevant subtypes of prostate cancer 849 61 81
81 Eckhardt et al. 2006 DNA methylation profiling of human chromosomes 6, 20 and 22 847 71 73
82 Bos et al. 2009 Genes that mediate breast cancer metastasis to the brain 847 94 56
83 Iliopoulos et al. 2009 An epigenetic switch involving NF-kappa B, lin28, let-7 microRNA, and IL6 links inflammation to cell transformation 845 94 57
84 Bracken et al. 2006 Genome-wide mapping of polycomb target genes unravels their roles in cell fate transitions 842 70 74
85 Campo et al. 2011 The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications 825 118 45
86 Chapman et al. 2011 Initial genome sequencing and analysis of multiple myeloma 824 118 46
87 Murakami et al. 2006 Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues 815 68 76
88 Gregoretti et al. 2004 Molecular evolution of the histone deacetylase family: Functional implications of phylogenetic analysis 806 58 83
89 Li et al. 2002 Causal relationship between the loss of RUNX3 expression and gastric cancer 805 50 93
90 Ng et al. 2009 Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening 794 88 59
91 Bibikova et al. 2011 High density DNA methylation array with single CpG site resolution 762 109 49
92 Yap et al. 2010 Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a 760 95 53
93 Suzuki et al. 2004 Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer 758 54 87
94 Esteller et al. 2000 Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors 756 42 96
95 Schlesinger et al. 2007 Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer 748 68 75
96 Shimono et al. 2009 Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells 745 83 62
97 Doi et al. 2009 Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts 744 83 63
98 Esteller et al. 1999 Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients 741 39 97
99 Belinsky et al. 1998 Aberrant methylation of p16[INK4a] is an early event in lung cancer and a potential biomarker for early diagnosis 723 36 99
100 Rainier et al. 1993 Relaxation of imprinted genes in human cancer. 720 29 100

The articles on this top 100 list were cited between 7,124 times (article rank 1) and 720 times (article rank 100). Collectively, the top 100 articles have been cited 147,083 times with a median of 1,050 for each paper, and an interquartile range of 871 - 1610. The oldest article on the top 100 list was from 1993, and the most recent from 2016. In the period 1980-2018, the two most prolific years were 2006 and 2010, with nine articles each among the top 100 most cited articles. In terms of the number of citations per year, the top article had been cited 375 times per year (CY rank number 6). Likewise, the bottom article has been cited 29 times per year (CY rank number 100). A graph of time vs. publication output (Figure 1) indicates that the field of cancer epigenetics has had publications in the range 1994-2014. The most productive decade was from 2000 to 2009, producing 49 papers in the Top 100 (Table 2).

Decade of publication No. of articles (n=100)
1970-1979 0
1980-1989 0
1990-1999 13
2000-2009 49
2010-2019 27

The top 100 most cited articles were published in 28 different journals, with the journal Nature contributing the most studies with 22 articles (Table 3).

Rank Journal No. of articles (n=100)
1 Nature 22
2 Nature Genetics 15
3 Proceedings of the National Academy of Sciences of the United States of America 10
4 Cancer Research 8
4 Cell 8
5 Cancer Cell 6
6 New England Journal of Medicine 4
6 Science 4
7 Blood 2
7 Molecular Cell 2
7 Nucleic Acids Research 2
8 BMC Bioinformatics 1
8 Cancer 1
8 Cancer Discovery 1
8 Clinical Cancer Research 1
8 Developmental Biology 1
8 Genes Development 1
8 Genomics 1
8 Gut 1
8 Journal of the National Cancer Institute 1
8 Journal of Biological Chemistry 1
8 Journal of Biomedical Informatics 1
8 Journal of Molecular Biology 1
8 Journal of Thoracic Oncology 1
8 Lancet 1
8 Lancet Oncology 1
8 Nature Medicine 1
8 Oncogene 1

Seventy-eight percent of the top 100 most cited papers originated in the United States (n=78). The next five countries with the highest number of articles were Germany (n=4), Switzerland (n=4), Japan (n=3), Spain (n=2), and United Kingdom (n=2). Australia, Belgium, Denmark, Israel, Netherlands, China, and South Korea had one article, each among the top 100. Among the 100 most cited papers, there were a total of 77 unique first authors. Collectively, the two authors with the largest number of articles on the top 100 list were Baylin SB and Herman JG with 26 and 20 papers, respectively (Table 4). The next five authors that followed were Getz G, Laird PW, Meyerson M, Sander C, and Weisenberger DJ, each with 13, 12, 12, 12, and 12 articles, respectively.

Rank Author No. of articles (n=100)
1 Baylin SB 26
2 Herman JG 20
3 Getz G 13
4 Laird PW 12
4 Meyerson M 12
4 Sander C 12
4 Weisenberger DJ 12
5 Ding L 11
5 Hayes DN 11
5 Lander ES 11
5 Perou CM 11

Among the top 100 cited papers, there were three clinical trials, two guidelines or society-based recommendations, 18 cancer classifications, 11 articles related to research tools or methods, 55 articles related to epigenetic cancer mechanism, nine papers related to epigenetic cancer markers/screening/diagnosis and five papers related to epigenetics and cancer treatment (Table 5).

WoS citation rank Authors Year Article title Total number of citations
CLINICAL TRIALS (n=3)
5 Hegi et al. 2005 MGMT gene silencing and benefit from temozolomide in glioblastoma 3394
8 Stupp et al. 2009 Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial 3252
71 Kantarjian et al. 2006 Decitabine improves patient outcomes in myelodysplastic syndromes - Resuits of a Phase III randomized study 899
GUIDELINES OR SOCIETY-BASED RECOMMENDATIONS (n=3)
14 Travis et al. 2011 International association for the study of lung cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of lung adenocarcinoma 2225
56 Hudson et al. 2010 International network of cancer genome projects 1000
CLASSIFICATIONS (n=18)
1 Golub et al. 1999 Molecular classification of cancer: class discovery and class prediction by gene expression monitoring 7124
2 Alizadeh et al. 2000 Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling 6045
10 Verhaak et al. 2010 Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1 2891
16 Curtis et al. 2012 The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups 1911
17 Neve et al. 2006 A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes 1828
18 Nielsen et al. 2004 Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma 1731
20 Toyota et al. 1999 CpG island methylator phenotype in colorectal cancer 1701
23 Ley et al. 2013 Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia 1656
25 Bhattacharjee et al. 2001 Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses 1624
29 Kandoth et al. 2013 Mutational landscape and significance across 12 major cancer types 1506
35 Brennan et al. 2013 The somatic genomic landscape of glioblastoma 1367
39 Figueroa et al. 2010 Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation 1280
45 Swerdlow et al. 2016 The 2016 revision of the World Health Organization classification of lymphoid neoplasms 1201
46 Noushmehr et al. 2010 Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma 1170
48 Weisenberger et al. 2006 CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer 1162
78 Turcan et al. 2012 IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype 854
80 Lapointe et al. 2004 Gene expression profiling identifies clinically relevant subtypes of prostate cancer 849
85 Campo et al. 2011 The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications 825
RESEARCH TOOLS/METHODS (n=11)
3 Herman et al. 1996 Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands 4600
4 Barski et al. 2007 High-resolution profiling of histone methylations in the human genome 3849
7 Cerami et al. 2012 The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data 3354
31 Clark et al. 1994 High sensitivity mapping of methylated cytosines. 1464
37 Weinstein et al. 2013 The cancer genome Atlas Pan-Cancer analysis project 1293
49 Weber et al. 2005 Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells 1087
63 Dweep et al. 2011 miRWalk - database: prediction of possible miRNA binding sites by "walking" the genes of three genomes 936
70 Weinstein et al. 1997 An information-intensive approach to the molecular pharmacology of cancer 906
72 Houseman et al. 2012 DNA methylation arrays as surrogate measures of cell mixture distribution 896
75 Turchinovich et al. 2011 Characterization of extracellular circulating microRNA 874
91 Bibikova et al. 2011 High density DNA methylation array with single CpG site resolution 762
EPIGENETIC CANCER MARKERS/SCREENING/DIAGNOSIS (n=9)
15 Yanaihara et al. 2006 Unique microRNA molecular profiles in lung cancer diagnosis and prognosis 2169
21 Takamizawa et al. 2004 Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival 1695
53 Kleer et al. 2003 EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells 1014
55 Jahr et al. 2001 DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells 1005
69 Valk et al. 2004 Prognostically useful gene-expression profiles in acute myeloid leukemia 907
74 West et al. 2001 Predicting the clinical status of human breast cancer by using gene expression profiles 891
90 Ng et al. 2009 Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening 794
98 Esteller et al. 1999 Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients 741
99 Belinsky et al. 1998 Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis 723
EPIGENETIC CANCER TREATMENT (n=5)
5 Hegi et al. 2005 MGMT gene silencing and benefit from temozolomide in glioblastoma 3394
8 Stupp et al. 2009 Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial 3252
61 Zuber et al. 2011 RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia 941
71 Kantarjian et al. 2006 Decitabine improves patient outcomes in myelodysplastic syndromes - resuits of a phase III randomized study 899
76 McCabe et al. 2012 EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations 861

Discussion

In this study, we sought to identify the most cited 100 articles regarding cancer epigenetics, to gain insight into the history and future directions of this rapidly growing scientific field.

The article that received the most citations on the top 100 list was “Molecular classification of cancer: class discovery and class prediction by gene expression monitoring” [11]. This paper was cited 7,340 times, with an average of 408 citations per year since publication. At the time, the paper was notable for developing the first generalized approach for identifying new cancer classes by applying gene expression profiling to distinguish between acute myeloid leukemia (AML) versus acute lymphoblastic leukemia (ALL). This study marked the beginning of gene expression-based cancer therapy. Currently, the European LeukemiaNet classification in AML uses cytogenetic and molecular data to identify the AML prognostic groups [12-14].

Since the first epigenetic abnormality was identified in cancer cells in 1983, multiple advances led to improved knowledge in epigenetics and cancer [3-5]. DNA methylation has been defined as an example of epigenetic dysregulation in cancer, with both hypomethylation and hyper-methylation having significant roles. DNA hypomethylation can lead to gene activation, and it is linked to chromosomal instability [15, 16]. DNA hypermethylation has been associated with gene silencing as a tumor-suppressor silencing cancer mechanism given that it has been found when genes are rarely mutated but that are frequently DNA hypermethylated and silenced in cancer [17-20]. Histone modification is another epigenetic cancer-linked mechanism that controls chromatin structure [21, 22]. As a result, the detection of epigenetic changes, such as abnormal promoter CpG island DNA hypermethylation, has been studied as a potential biomarker strategy for assessing cancer risk, early detection, prognosis and predicting therapeutic responses [23, 24]. The list of potential marker genes, knowledge of their position in cancer progression, and the development of ever more sensitive epigenetic detection strategies, including nanotechnology approaches, are all expanding [25, 26]. All these landmark discoveries led to the elucidation of novel cancer biomolecular mechanisms, new scientific research tools, and the development of new epigenetic-based targeted therapeutic avenues. As a result of that, “The National Institutes of Health (NIH) Roadmap Epigenomics Mapping Consortium” is accelerating the understanding of epigenomics in human health and disease together with the ENCODE Project (ENCyclopedia Of DNA Elements) [27, 28]. The most immediate future of this new exciting scientific field includes the development of liquid biopsies, personalized medicine, and targeted therapies.

Although citation analysis is a useful tool with the potential benefit of insight into literature trends, it is not without limitations. Over half a century has passed since the Science Citation Index (SCI) was launched as the first systematic effort to track citations in the scientific literature [29]. We recognize that citation counts have inherent biases and that they are not purely quantifiable systems to rank papers by their impact in the scientific literature. In an attempt to control for some of these inherent and potential biases, we utilized the citations per year index in addition to the total number of citations per paper. Despite that, older publications have had a longer timespan to accumulate citations giving them a distinct advantage over newer and potentially more relevant studies. Lastly, one hundred is an arbitrary number since the landmark articles in epigenetic research did not accumulate enough citations such as the paper by Gama-Sosa, Slagel, Trewyn, et al. "The 5-methylcytosine content of DNA from human tumors" that only had 574 citations [30]. Although metrics such as citation counts do have flaws, in the current era, they also serve as one way to measure objectively impact of an article in the scientific community.

Conclusions

In this study, the 100 most cited articles in cancer epigenetics were examined, and the contributions from various authors, specialties, and countries were identified. Cancer epigenetics is a rapidly growing scientific field impacting translational research in cancer screening, diagnosis, classification, prognosis, and targeted treatments. Recognition of important historical contributions to this field may guide future investigations.


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Original article
peer-reviewed

The 100 Most Cited Papers About Cancer Epigenetics


Author Information

Ignacio Jusue-Torres

Neurosurgery, Loyola University Chicago, Stritch School of Medicine, Chicago, USA

Joshua E. Mendoza

Sugery, University of Illinois at Chicago, Chicago, USA

Malcolm V. Brock

Surgery, Johns Hopkins University School of Medicine, Baltimore, USA

Alicia Hulbert Corresponding Author

Surgery, University of Illinois at Chicago, Chicago, USA


Ethics Statement and Conflict of Interest Disclosures

Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.


Original article
peer-reviewed

The 100 Most Cited Papers About Cancer Epigenetics


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