The 100 Most Cited Papers About Cancer Epigenetics

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][4][5]. In one of these studies, Feinberg and Vogelstein showed that DNA methylation was linked to tissuespecific 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][7][8][9][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 And 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.

FIGURE 1: Number of publications per year retrieved from the Thomson Reuters Web of Science with the keyword search described in methods
The top 100 articles related to "cancer epigenetics" were identified by the number of times they were cited ( Table 1).

Rank Authors
Year Article title    Table 2).

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][13][14].
Since the first epigenetic abnormality was identified in cancer cells in 1983, multiple advances led to improved knowledge in epigenetics and cancer [3][4][5]. DNA methylation has been defined as an example of epigenetic dysregulation in cancer, with both hypomethylation and hypermethylation 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][18][19][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.