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Article

The Association between Periodontitis and Human Colorectal Cancer: Genetic and Pathogenic Linkage

1
Department of Medicine, Surgery and Dentistry “Schola Medica Salernitana”, University of Salerno, Via S. Allende, 84081 Baronissi (Salerno), Italy
2
Complex Operating Unit of Odontostomatology, Head and Neck Clinical Department, Azienda Ospedaliero-Universitaria San Giovanni di Dio e Ruggi d’Aragona, 84121 Salerno, Italy
3
Private Practice, Via Provinciale 87B, 55041 Camaiore (Lucca), Italy
4
Department of Surgery, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy
5
Complex Operating Unit of General Surgery, Azienda Ospedaliero-Universitaria San Giovanni di Dio e Ruggi d’Aragona, 84121 Salerno, Italy
6
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy
7
Department of Medicine and Surgery, Centre of Neuroscience of Milan, University of Milano-Bicocca, 20126 Milan, Italy
*
Author to whom correspondence should be addressed.
Life 2020, 10(9), 211; https://doi.org/10.3390/life10090211
Submission received: 5 August 2020 / Revised: 8 September 2020 / Accepted: 14 September 2020 / Published: 18 September 2020

Abstract

:
Periodontitis has been associated with an increased risk of and mortality associated with human colorectal cancer (CRC). Current evidence attributes such an association to the direct and indirect effects of virulence factors belonging to periodontal pathogens, to inflammatory mediators and to genetic factors. The aims of the study were to assess the existence of a genetic linkage between periodontitis and human CRC, to identify genes considered predominant in such a linkage, thus named leader genes, and to determine pathogenic mechanisms related to the products of leader genes. Genes linking periodontitis and CRC were identified and classified in order of predominance, through an experimental investigation, performed via computer simulation, employing the leader gene approach. Pathogenic mechanisms relating to leader genes were determined through cross-search databases. Of the 83 genes linking periodontitis and CRC, 12 were classified as leader genes and were pathogenically implicated in cell cycle regulation and in the immune-inflammatory response. The current results, obtained via computer simulation and requiring further validation, support the existence of a genetic linkage between periodontitis and CRC. Cell cycle dysregulation and the alteration of the immuno-inflammatory response constitute the pathogenic mechanisms related to the products of leader genes.

1. Introduction

Periodontitis, as defined by Tonetti et al. and by Lang et al., is a “multifactorial microbially-associated inflammatory disease” affecting tooth-supporting structures and, ultimately, leading to tooth loss [1,2,3].
In the last decade, a growing body of evidence has reported the association between periodontitis and a variety of systemic inflammatory conditions and diseases, including atherosclerosis, diabetes, rheumatoid arthritis, and inflammatory bowel disease (IBD) [4,5,6]. Most notably, recent findings have also associated periodontitis with solid cancers, such as malignant neoplasms of the prostate, breast, lung, pancreas, and kidney [6,7]. Moreover, periodontitis has been associated with an increased risk of colorectal adenoma and colorectal cancer (CRC) development [8,9] and to an increased mortality from CRC [10].
Human colorectal cancer accounts for approximately ten percent of new cancer cases worldwide in males and 9.2% in females [11]. Considering the high mortality rate of CRC (eight percent and nine percent of cases, corresponding to 700,000 estimated deaths/year) [11], together with the associated morbidity, progress in treatment customization [12] and, above all, in primary and secondary prevention, indicates the importance of new insights into CRC etiopathogenesis [13].
Several environmental factors [12] involved in CRC carcinogenesis have been identified: unhealthy behaviors, such as consumption of red meat and alcohol, smoking, reduced physical activity, IBD [14] (comprising Crohn’s disease and ulcerative colitis) [15], and certain diseases and conditions, such as type 2 diabetes and obesity, which are related to systemic inflammation [16,17]. Indeed, it has been suggested that systemic inflammation may be critical to the development of CRC 13,16, and may link CRC with obesity, IBD, and periodontitis [6,7,18]. In particular, inflammatory mediators, which increase locally and systemically in periodontitis [10,19], together with carcinogens (i.e., nitrosamines), as well as microbial-associated virulence factors from periodontal pathogens, may underlie the association between human CRC and periodontitis.
In addition to environmental factors, genetic susceptibility and/or family history [12] have been recognized as important in ten percent of human CRC cases. The role of genetic factors [20] has been also demonstrated in periodontitis. Therefore, a genetic linkage between periodontitis and CRC has been hypothesized and was investigated in this study.
The primary aim of the present study was to assess, through an experimental investigation performed via computer simulation, the genetic linkages between periodontitis and human colorectal cancer, identifying all the genes involved in such an association, ranking them into cluster in descending order of relevance in such an association, and, finally, pointing out those genes presumed to be “leader” in the association between these disorders. Leader genes, which are considered to be predominant in the genetic determination of complex multi-factorial disorders, or in the genetic linkage between two disorders, as in the association between periodontitis and CRC, may reveal molecular targets for further investigations and focused therapies [20,21].
The secondary aim of the study was to characterize, through a review of current scientific evidence, the main function of leader gene products, their involvement in biological processes, and their role in the onset and progression of CRC and periodontitis, and to determine the putative pathogenic mechanisms associating periodontitis and CRC. Those preliminary data may highlight the possible clinical implications of the genetic linkages between periodontitis and human colorectal cancer and pave the way for targeted molecular experimentations [20,21].

2. Experimental Section

The present experimental study, being performed on computer, did not require either ethical approval or informed consent and was concluded on the 3 April 2019.

2.1. Analysis of the Genetic Linkage between Periodontitis and Human Colorectal Cancer (CRC)

A bioinformatic method, called leader gene approach [20], was employed to identify genes potentially involved in the association between periodontitis and CRC and especially those presumed to be predominant or “leader” in the genetic linkage between the two disorders.
The multi-step procedure, requiring freely available databases and a specific software program for each of the steps involved, is detailed in Figure 1 and summarized below.
Preliminarily, an initial set of genes involved in the above-mentioned phenomenon was built up through various integrated cross-search databases (PubMed, OMIM, Medgen, GeneCards, GenBank, Genedx, GenAtlas) using the search engine Entrez (http://www.ncbi.nlm.nih.gov/).
Repeated genes expansions, obtained through the web-available software STRING version 11.0 (https://string-db.org/) ELIXIR infrastructure, Hinxton, UK, and subsequent expanded genes filtrations to eliminate any false positive, through a further search with PubMed, all together defined as “expansion-filtering loops”, were performed.
The following key words, achieved by studies investigating either colorectal cancer or periodontitis or both of them [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20], were employed in the literature search and were logically combined with the Boolean operators AND, OR, NOT.
The name as well as the symbol of each gene, derived by the above-mentioned databases, underwent validation by means of the official Human Genome Organization (HUGO) Gene Nomenclature Committee, or HGNC (available at https://www.genecards.org), in order to eliminate previous symbols or aliases.
The combined predicted associations, characterized by the higher level of confidence (that is a result with a score ≥ 0.9), were computed between each single gene and the complete gene dataset, through the free online software STRING (Version 11.0) [22]. The sum of these combined predicted associations scores provided the so-called the “Weighted Number of Links” (WNL) for each gene.
Automatic computations were performed on the whole data related to the genes included in the study. A k-mean algorithm was applied to the input variable WNL, and a partitioning of the overall dataset of genes into mutually-exclusive clusters was automatically performed and a “gap statistic method” was used to estimate the ideal number of clusters for the clusters from 2 to 12, as reported in Figure 1. Significant differences among WNLs of cluster groups obtained by the gap statistic method, were found by the Kruskal-Wallis test (statistical significance at a level of α = 0.01), verifying the accurate estimate of the number of clusters.
The resulting gene clusters were classified and correspondingly named as A, B, C, etc., based on their respective value of WNL centroid. The first genes cluster was identified as a ”leader” genes cluster, hypothesizing their possible central role in the phenomenon; in contrast, the last genes cluster, identified as ”orphans” genes, included genes without identified predicted associations (WNL = 0).

2.2. Determination of the Putative Pathogenic Mechanisms Associating Periodontitis and CRC

Leader genes characterization was performed, via the free online software STRING (Version 11.0) [22], to assess the main function of leader gene products and their involvement in biological processes. A further literature search, using the keywords reported in Table 1, was conducted on PubMed/MEDLINE and ScienceDirect search engines (using the same key words reported in Table 1), to investigate the role of leader genes in the onset and in the progression of CRC as well as of periodontitis and to highlight their putative pathogenic mechanisms in the genetic linkage between periodontitis and CRC.

3. Results

3.1. Analysis of the Genetic Linkage between Periodontitis and Human Colorectal Cancer

The final set of genes was composed of 137 genes. A complete description of the identified genes, including acronyms, identification numbers, validated names, cluster assignment, and their involvement in biological processes, is shown in Table A1. In compliance with the estimated optimal number of clusters, shown in Figure 2A, the 137 identified genes were divided into 7 clusters, designated as A, B, C, D, E, F, and orphan genes clusters.
WNL computation is reported in Figure 2B. Depending on the WNL score, 54 genes, lacking combined predicted interactions (WNL = 0), were assumed not to be involved in the genetic linkage between periodontitis and CRC, and were, consequently, designated as orphan genes and excluded from the study; the remaining 83 genes, showing a WNL > 0 and the combined predicted interactions mapped in Figure 2C, were hierarchically grouped in descending order of WNL to the six clusters named from A to F, as illustrated in Figure 3.
In particular, the 12 genes, belonging to cluster A and defined as leader genes, were: E3 ubiquitin-protein ligase (CBL), catenin beta-1 (CTNNB1), proto-oncogene c-Fos (FOS), growth factor receptor-bound protein 2 (GRB2), interleukins 1B, 4, 6, 10 (IL1B, IL4, IL6, IL10), transcription factor AP-1 (JUN), phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA), phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1), and RELA proto-Oncogene NFKB subunit or transcription factor p65 (RELA).
CBL encodes for an enzyme targeting substrates for proteasomal degradation.
CTNNB1 encodes for β-catenin, a subunit of the adherens junctions complex, regulating cell growth and adhesion and Wnt responsive genes (i.e., c-Myc) expression, leading to cell cycle progression.
FOS is an oncogene encoding for the c-Fos protein, which heterodimerizes with c-Jun, encoded by JUN (Transcription factor AP-1), to form the transcription factor AP-1, involved in cell proliferation, differentiation, apoptosis, and cancerous transformation.
GRB2 gene encodes for a protein binding the epidermal growth factor (EGF) receptor, activating several signaling pathways.
IL1B, IL4, IL6, IL10 are active in immune-regulation and inflammation, as discussed below.
PIK3CA and PIK3R1 are centrally involved in several cancers.
RELA (p65), along with NFKB1 (p50), make-up the NFKB complex, which regulates the transcription of several genes encoding for pro-inflammatory cytokines https://www.genecards.org) [22].

3.2. Determination of the Putative Pathogenic Mechanisms Associating Periodontitis and CRC

The characterization of the 12 leader genes in the genetic linkage between periodontitis and human colorectal cancer is reported in Table 2. Identified leader genes were involved in cell signaling (i.e., CTNNB1, CBL, GRB2, PIK3CA, PIK3R1), transcriptional pathways (i.e., JUN, RELA), cell proliferation/differentiation (i.e., FOS), and immuno-inflammatory processes (i.e., IL1B, IL4, IL6, IL10). Current evidence of the role of leader genes in CRC and in periodontitis onset and progression, as well as the putative pathogenic mechanisms is reported in Table 2.

4. Discussion

Periodontitis and human colorectal cancer are complex multi-factorial disorders, dealing with a multitude of genes, which are interconnected by several heterogeneous networks, and whose products are involved in a wide range of biological pathways [20]. In view of this fact, the present experimental investigation of the genetic linkages between periodontitis and CRC was conducted through a bioinformatic method, called “leader gene approach” [20]. This multi-step procedure, as described above, is especially useful in identifying the highest priority genes in the investigated phenomenon [20,21] and provides the necessary synthesis and analysis of the overwhelming amount of raw bioinformatic data generated. Ranking genes hierarchically and identifying leader genes consistently revealed those genes, and their related products, which are mainly involved in the genetic linkage between periodontitis and CRC (Table 2). Such bioinformatic data were subsequently integrated with current evidence to reveal cellular functions and biological processes carried out by the gene products, and were interpreted in view of the available clinical and experimental findings to determine the putative pathogenic mechanisms associating periodontitis with CRC.

4.1. Genetic Linkages between Periodontitis and Human Colorectal Cancer: Leader Genes and Putative Pathogenic Mechanisms

Among the 137 genes (complete final gene dataset available as metadata) reported in periodontitis and CRC ethio-pathogenesis, 83 were involved and 12 (“cluster A” or “leader” genes) were considered to play a predominant role in the genetic linkage between both disorders. Notably, four of the cluster A genes, specifically, CBL, GRB2, PIK3R1, and RELA, were also ranked among the five leader genes previously identified in periodontitis [20]. Nuclear factor kappa B p105 subunit (NFKB1), instead, which is considered as a leader gene in periodontitis, was assigned to cluster C in the present study. These results may support the existence of a possible genetic linkage between periodontitis and CRC.
The characterization of the currently identified leader genes, reported in Table 2, revealed their involvement in several biological processes, such as cell signaling (i.e., CTNNB1, CBL, GRB2, PIK3CA, PIK3R1), transcriptional pathways (i.e., JUN, RELA), cell proliferation/differentiation (i.e., FOS) and immuno-inflammatory processes (i.e., IL1B, IL4, IL6, IL10; see Table 2) [22]. Evidence supporting the role exerted by leader genes in both CRC and periodontitis pathogenesis [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41], reported in Table 2, suggested that the pathogenic mechanisms underlying the association between periodontitis and CRC may be mainly related to the effect of the products of the leader genes on cell cycle dysregulation and on alteration of the immuno-inflammatory response.
Leader genes acting in cell cycle regulation, such as CTNNB1, FOS, JUN, GRB2, PIK3CA, and PIK3R1, may affect homeostasis in both colonic cells and periodontal tissues, causing, if dysregulated, colonic cell proliferation and malignant transformation, on the one hand, and periodontitis development and progression, on the other, as described in Table 2 [22,23,24,25,26,27,28,29,30,31,32].
Leader genes affecting the immune-inflammatory response, such as IL1B, IL4, IL6, IL10, CBL, and RELA, may underlie a possible bi-directional relationship between the disorders, as described below [20,33,34,35,36,37,38,39,40]. Moreover, in addition to leader genes affecting the immune-inflammatory response, NFKB, which has been ranked among cluster C genes and is functionally related to RELA, regulates the transcription of several genes, also encoding for pro-inflammatory cytokines. NFKB is constitutively inactivated and its activation, with subsequent immuno-inflammatory response alteration, may be due to a dysregulation in the ubiquitin–proteasome system, which is a mechanism of intracellular protein degradation, occurring in atherogenesis, neurodegenerative and autoimmune diseases, and, possibly, in IBD and CRC [41,42]. Current knowledge about the role of the cellular ubiquitin–proteasome system dysregulation, and subsequent NFKB activation in periodontitis, is still limited, but it may explain the presence of the E3 ubiquitin-protein ligase (CBL) gene among the leader genes in the genetic linkage between periodontitis and CRC, although no evidence is available relating CBL to periodontitis [20].

4.2. Genetic Linkages between Periodontitis and Human Colorectal Cancer: Cytokines and Systemic Inflammation

Periodontal tissue destruction, occurring in periodontitis, is microbially initiated and sustained by the dysregulation of the immune-inflammatory processes [5]. A body of evidence has shown that cytokines produced in inflamed periodontal tissues, together with virulence factors from periodontal pathogens and oral microbial agents, may gain access to the circulation, and, consequently, induce systemic inflammation [5,43]. Accordingly, it has been proposed that non-resolving periodontal inflammation may affect systemic inflammatory diseases and that cytokines may be considered as a possible pathogenic link between periodontitis and various systemic diseases, including IBD and CRC [4,5,6,7,38,44].
It is well known that IBD has oral mucosal manifestations, such as pyostomatitis vegetans and aphthous stomatitis, and it has been reported that subjects suffering from Crohn’s disease show a higher risk of periodontitis compared to non-IBD subjects [8,45]. In addition, evidence suggests that periodontal pathogens, especially Fusobacterium nucleatum, may be involved in IBD [9,10] and colorectal adenomas [46], and that cytokines induced by periodontal pathogens and released in periodontitis may predispose to neoplastic transformation of chronic colitis, favoring colorectal carcinogenesis [12,46,47]. In more detail, oral fusobacterium nucleatum, which is abundant in the oral cavity and increased in periodontal pockets, is mobile and caplable to bind, through the Fusobacterium adhesin A (FadA), both to vascular endothelial-cadherins, gaining access to systemic circulation, and to (E)-cadherin on epithelial cells, stimulating the growth of tumor cells. Binding to (E)-cadherins on colorectal adenoma and cancer cells, FadA, which is only detectable on oral Fusobacterium species, activates the transcriptions of those oncogenes regulated by b-catenin, which is the product of the leader gene CTNNB1, and of some genes involved into the immune-inflammatory response, including IL6, which is presently ranked as a leader gene, and NFKB, belonging to cluster C genes [46]. From this standpoint, periodontitis may be considered as a possible risk factor for CRC genesis in IBD subjects, as it accounts for poor metabolic control in diabetic patients [48]. Such an inter-relationship may rely on the fact that both IBD and periodontitis share a multifactorial etiology, as well as the pathogenic mechanisms affecting the local immuno-inflammatory response, which leads to the genesis of a systemic inflammation [45]. Analogously, it may be supposed that those periodontal cytokines, which are listed among leader genes products, may enhance colonic tumor-associated inflammation, and may subsequently be considered as a risk factor for cancer progression in CRC subjects. As a counterpart, along with the tumor-associated inflammatory environment, CRC cells themselves release inflammatory mediators, which self-sustain neoplastic cell growth and enhance the cancerous cells’ interactions with the surrounding stroma and immune cells, favoring, in turn, CRC progression and invasion [13,49]. Since CRC inflammatory mediators have been identified as leader genes in the present study, it may be hypothesized, as previously proposed for cytokines released in diabetes [43], that CRC cytokines may negatively affect periodontitis onset and development, altering the immune-inflammatory response in periodontal tissues.

4.3. Genetic Linkages between Periodontitis and Human Colorectal Cancer: Possible Clinical Implications

The findings discussed, certainly requiring validation by larger studies, may provide preliminary data for further research, especially considering the beneficial clinical applications potentially offered by the insight into the mechanisms associating periodontitis and CRC. Indeed, if the results presented, which suggest a central role for cytokines and systemic inflammation in the genetic bi-directional linkage between periodontitis and CRC, are validated, periodontitis management may be included in CRC prevention and treatment plans. Complex multi-factorial disorders, such as periodontitis and CRC, significantly impact on the quality of life, present life-threatening risks, and imply a heavy burden on society. Therefore, highlighting the genetic traits of such disorders may pave the way for primary prevention strategies, which are essential to reduce the biological impact as well as the healthcare costs of these disorders. The improved understanding of the putative pathogenic mechanisms associating periodontitis with CRC may encourage a multidisciplinary approach, which is strongly advocated for such complex multifactorial disorders.
From this standpoint, oral health professionals may also become part of CRC screening plans, introducing, in their daily practice, general health promotion and disease prevention goals, and including risk assessment for both oral and systemic diseases. CRC screening might be improved by the provision of broader dental health records, with the potential to identify subjects at risk for CRC development for referral to a physician. In addition, based on the definition of oral health as a component of general health affecting the quality of life [50], oral health professionals may widen their activity in an interprofessional setting, providing oral and periodontal evaluation and necessary treatments, in CRC subjects referred by other health professionals, integrating the patient’s medical care in therapeutic and follow-up plans.
Periodontal treatment may be proposed as a CRC primary prevention strategy, in subjects considered at higher risk for CRC development, such as those suffering from IBD, in order to decrease the systemic inflammation and the related pro-carcinogenic environment. However, threshold values of cytokines in inflamed periodontal tissues, capable of inducing systemic inflammation and subsequently increasing the risk for colorectal cancer genesis, in IBD subjects have not yet been defined. Furthermore, the quantitative assessment of periodontal cytokines is even more complicated than the qualitative one, since it may actually be biased by the accidental detection of inflammatory mediators possibly derived from mucosal inflammation and orally administered drugs, in whole saliva analysis, and by the need for full mouth sampling, in gingival crevicular fluid analysis [51]. For these reasons, identifying those IBD subjects potentially exposed to a higher risk of systemic inflammation induced by periodontitis, and of consequent malignant transformation of chronic colitis, may be impracticable. Thus, periodontitis prevention and treatment, which potentially reduces systemic inflammation and, consequently, decreases the risk for malignant transformation of chronic colitis, may be routinely included in all IBD subjects’ treatment plans. Moreover, periodontal treatment, reducing the periodontal microbial load and the related cytokine levels, may decrease the systemic spread of inflammatory mediators and of Fusobacterium nucleatum, specifically, presumed to be associated with CRC, beyond IBD, lesions [41,46], and to favor tumor-associated environment, and may, therefore, constitute a secondary and/or tertiary prevention strategy in subjects affected by CRC.

5. Conclusions

Four out of the five leader genes previously identified for periodontitis (CBL, GRB2, PIK3R1, and RELA) were also listed as leader genes in the investigated phenomenon, carefully supporting the genetic linkages between CRC and periodontitis, and suggesting the need for a multi-disciplinary approach, also involving oral health professionals, to CRC subject management.
IL1B, IL4, IL6, IL10 were also ranked among leader genes, suggesting a central role for systemic inflammation in the genomic relationship between CRC and periodontitis; in particular, periodontitis may be linked to IBD, and, in turn, to CRC, both affecting the inflammatory pro-carcinogenic and tumor-associated environment and acting in an indirect way in the “inflammation-dysplasia” carcinogenic sequence, favoring colorectal cancer development. In this perspective, periodontitis management may be proposed as a CRC primary prevention strategy, especially in patients considered at higher risk for CRC development, such as IBD subjects. Indeed, periodontal therapy would reduce the periodontal microbial charge, and, consequently, the systemic widespread of bacterial toxins and of periodontal pathogens them-selves, including Porphyromonas gingivalis and Fusobacterium nucleatum, supposed to be associated with IBD and CRC lesions. Moreover, periodontal treatment and healthy periodontal conditions would indirectly decrease the systemic inflammation and the related CRC pro-carcinogenic environment, as a part of the CRC treatment strategy.

Author Contributions

Conceptualization, F.D.S., P.T., V.P., and L.S.; methodology, F.D.S., P.T., V.P., and L.S.; software, P.T.; validation, X.X., Y.Y., and Z.Z.; formal analysis, P.T.; investigation, F.D.S. and P.T.; resources, F.D.S.; data curation, F.D.S., P.T., V.P., F.C., D.L., and L.S.; writing—original draft preparation, F.D.S., P.T., and L.S.; writing—review and editing, F.D.S., P.T., V.P., F.C., D.L., and L.S.; visualization, X.X.; supervision, X.X.; project administration, X.X.; funding acquisition, Y.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

Appendix A

Table A1. Identified genes acronyms, identification numbers, validated names, cluster assignment, and biological process(es) involvement description, as per the free online software STRING (version 11.0) [22].
Table A1. Identified genes acronyms, identification numbers, validated names, cluster assignment, and biological process(es) involvement description, as per the free online software STRING (version 11.0) [22].
Gene AcronymGene Identification NumberGene Official NameProtein Main Function/Biological Process (Es) InvolvementGene Cluster Assignment
CBL12E3 ubiquitin-protein ligase CBLCell signalingA
CTNNB126Catenin beta-1Cell signalingA
FOS43Proto-oncogene c-FosGene (s) transcription, cell signaling, cell proliferation, and differentiationA
GRB246Epidermal Growth Factor Receptor-Binding Protein GRB2Cell signalingA
IL1B52Interleukin 1 betaInflammationA
IL454Interleukin 4Immune responseA
IL656Interleukin 6Immuno-inflammatory processA
IL1058Interleukin 10InflammationA
JUN63Transcription factor AP-1Gene(s) transcriptionA
PIK3CA96Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoformCell proliferation, cell survivalA
PIK3R197Phosphatidylinositol 3-kinase regulatory subunit alphaCell signalingA
RELA109RELA Proto-Oncogene, NF-KB Subunit or Transcription factor p65Sub-unit of the transcription factor NF-kappa-BA
AKT12 RAC-alpha serine/threonine-protein kinaseCell proliferation, cell survival, angiogenesisB
CD1916B-lymphocyte antigen CD19Immune responseB
CD79A19B-cell antigen receptor complex-associated protein alpha chainImmune responseB
CD79B20B-cell antigen receptor complex-associated protein beta chainImmune responseB
EP30035Histone acetyl transferase p300Regulates genes transcription via chromatin remodelingB
IGLL548Immunoglobulin lambda like polypeptide 5Associated with solitary osseous plasmacytomaB
IKBKB50Inhibitor of nuclear factor kappa-B kinase subunit betaCell signaling (NF- kappa-B pathway)B
IL-1a51Interleukin-1 alphaImmuno-inflammatory processB
IL1R153Interleukin-1 receptor type 1Cell signalingB
SRC117Proto-oncogene tyrosine-protein kinase SrcGene(s) transcription, immune response, cell cycle regulation, cell adhesion, and migrationB
TP53134Cellular tumor antigen p53Cell cycle regulationB
CCND113 G1/S-specific cyclin-DCell cycle regulationC
CRK25Adapter molecule crkPhagocytosis of apoptotic cells, cell motilityC
FGFR341Fibroblast growth factor receptor 3Cell proliferation, differentiation, and apoptosis, and skeleton developmentC
IL4R55Interleukin-4 receptor subunit alphaImmune responseC
IL6R60Interleukin-6 receptor subunit alphaImmuno-inflammatory processC
IRF462Interferon regulatory factor 4Immune response, dendritic cell differentiationC
LTA73Lymphotoxin-alphaImmune responseC
NFKB191Nuclear factor NF-kappa-B p105 subunitCell signaling, immuno-inflammatory process, cell cycle regulation, and differentiation, tumorigenesisC
SMAD4115Mothers against decapentaplegic homolog 4Muscle physiologyC
TLR2125Toll-like receptor 2Immune responseC
TLR4126Toll-like receptor 4Immune responseC
TLR6127Toll-like receptor 6Immune responseC
AURKA5Aurora kinase ACell cycle regulationD
B2M10Beta-2-microglobulinImmune responseD
CD3818ADP-ribosylcyclase/cyclic ADP-ribosehydrolase 1Synthesizes the second messengers cyclic ADP-ribose and nicotinate-adenine dinucleotide phosphateD
IGJ49Immunoglobulin J chainImmune responseD
IL6ST61Interleukin-6 receptor subunit betaCell signaling, immune response, hematopoiesis, pain control, bone metabolismD
MMP983Matrix metalloproteinase-9Extracellular matrix degradation, leukocyte migration, bone osteoclastic resorptionD
NFATC190Nuclear factor of activated T-cells, cytoplasmic 1Immuno-inflammatory process, osteoclastogenesisD
PMS199PMS1 protein homolog 1DNA repairD
PMS2100Mismatch repair endonuclease PMS2DNA repairD
POU2AF1103POU domain class 2-associating factorImmune responseD
PTGS2104Prostaglandin G/H synthase 2InflammationD
TNFRSF1A131Tumor necrosis factor receptor superfamily member 1A(Pro) ApoptosisD
APC4Adenomatous polyposis coli proteinTumor suppressor (Wnt pathway)E
AXIN26Axin-2Cell signaling (Wnt pathway)E
BAX7Apoptosis regulator BAX(Pro) ApoptosisE
BMPR1A8Bone morphogenetic protein receptor type-1AChondrocyte differentiation, AdipogenesisE
CALR11CalreticulinCell endoplasmic reticulum formationE
CD2717CD27 antigenImmune responseE
HLA-B47HLA class I histocompatibility antigen, B-7 alpha chainImmune responseE
LTF74LactotransferrinImmuno-inflammatory process, protection against cancer development and metastasisE
MLH177DNA mismatch repair protein Mlh1DNA repairE
MME79NeprilysinOpioid peptides, angiotensin-2, -1, -9 and atrial natriuretic factor degradationE
MMP281Matrix metalloproteinase-2Inflammation, tissue repair, angiogenesis, tumor invasionE
MSH286DNA mismatch repair protein Msh2DNA repairE
MSH687DNA mismatch repair protein Msh6DNA repairE
NRAS96GTPase NRasBinds GDP/GTP and possesses intrinsic GTPase activityE
PDGFRB94Platelet-derived growth factor receptor betaTyrosine-protein kinase acting as cell-surface receptor, playing an essential role in blood vessel developmentE
POLD1102DNA Polymerase Delta 1 Catalytic SubunitPlays a crucial role in high fidelity genome replication, requiring the presence of accessory proteins POLD2, POLD3, and POLD4 for full activityE
SMAD7116Mothers against decapentaplegic homolog 7TGF-beta inhibitionE
TGFBR2123TGF-beta receptor type-2Cell cycle regulation (epithelial and hematopoietic cells), cell proliferation and differentiation (mesenchymal cells) Immune responseE
TLR1124Toll-like receptor 1Immune responseE
TLR9128Toll-like receptor 9Immune responseE
TNFRSF17132Tumor necrosis factor receptor superfamily member 17Immune responseE
TNFSF11133Tumor necrosis factor ligand superfamily member 11Immune responseE
TRAF2135TNF receptor-associated factor 2NF-kappa-B and JNK activation, cell survival and apoptosis regulation, immune responseE
XBP1136X-box-binding protein 1Cardiac, hepatic, and secretory tissue developmentE
BUB1B9Mitotic checkpoint serine/threonine-protein kinase BUB1 betaCell cycle regulationF
CCL1814C-C motif chemokine 18Immune responseF
COL1A123Collagen alpha-1 (I) chainMember of group I collagenF
DCC30Netrin receptor DCCNervous system developmentF
EPCAM34EPCAM Epithelial cell adhesion moleculeImmune responseF
FCRLA38Fc receptor-like AImmune responseF
IL857Interleukin-8Immune responseF
IL2259Interleukin-22InflammationF
MMP180Matrix metalloproteinase-1Types I, II, III, VII, and X collagens degradationF
MMP782Matrix metalloproteinase-7Casein, type I, III, IV, and V gelatins and fibronectin degradationF
MZB185Marginal zone B- and B1-cell-specific proteinImmune responseF
NAMPT89Nicotinamide phosphoribosyl transferaseImmune response, anti-diabetic functionF
ZBP1137Z-DNA-bindin gprotein 1Immune responseF
AEBP11Adipocyte enhancer-binding protein 1Adipocyte proliferation, enhanced macrophage inflammatory responsivenessOrphan
AMPD13AMP deaminase 1Energy metabolismOrphan
CD1415Monocyte differentiation antigen CD14Immune responseOrphan
CEACAM2121Carcinoembryonic Antigen Related Cell Adhesion Molecule 21Immune responseOrphan
CLDN1022Claudin-10Cell adhesionOrphan
CPNE524Copine-5Melanocytes formationOrphan
CTR27Calcitonin receptorReceptor for calcitoninOrphan
C12orf6328Cilia- and flagella-associated protein 54Cilia and flagella assemblyOrphan
C8orf8029Nuclear GTPase, Germinal Center AssociatedGenome stabilityOrphan
DERL331Derlin-3Endoplasmic reticulum stress-induced pre-emptive quality controlOrphan
DLC132Rho GTPase-activating protein 7Cell proliferation and migrationOrphan
DPEP133Dipeptidase 1Immuno-inflammatory processOrphan
FAM46C36Nucleotidyl transferase FAM46CRNA polymerizationOrphan
FAM92B37Protein FAM92BCiliogenesisOrphan
FCRL239Fc receptor-like protein 2Immune response, B-cells tumorigenesisOrphan
FCRL540Fc receptor-like protein 5Immune responseOrphan
FLCN42FolliculinTumor suppressionOrphan
GALNT1244Polypeptide N-acetylgalactosaminyl transferase 12Oligosaccharide biosynthesisOrphan
GPR11445Adhesion G-protein coupled receptor G5Cell signalingOrphan
KCNA364Potassium voltage-gated channel subfamily A member 3Mediates the voltage-dependent potassium ion permeability of excitable membranesOrphan
KCNN365Small conductance calcium-activated potassium channel protein 3Forms a voltage-independent potassium channel activated by intracellular calciumOrphan
KLHL666Kelch-like protein 6Immune responseOrphan
LAX167Lymphocyte trans membrane adapter 1Immune responseOrphan
LBP68Lipopolysaccharide-binding proteinImmune responseOrphan
LGALS769Galectin-7Cell growth controlOrphan
LILRA370Leukocyte Immunoglobulin Like Receptor A3Immune responseOrphan
LY971T-lymphocyte surface antigen Ly-9Immune responseOrphan
LRMP72Lymphoid-restricted membrane proteinImmune responseOrphan
MCC75Colorectal mutant cancer proteinTumor suppressionOrphan
MEI176Meiosis inhibitor protein 1MeiosisOrphan
MLH378DNA mismatch repair protein Mlh3DNA repairOrphan
MMP1284Macrophage metalloelastaseTissue remodelingOrphan
MUTYH88Adenine DNA glycosylaseDNA repairOrphan
ODC193 Ornithine decarboxylaseDNA replication, cell proliferation, and apoptosisOrphan
PDGFRL95Platelet-derived growth factor receptor-like proteinAssociated with colorectal cancer and other malignanciesOrphan
PIM298Serine/threonine-protein kinase pim-2Cell proliferation, cell survivalOrphan
PNOC107PrepronociceptinNociception, neuronal developmentOrphan
PTPN12105Tyrosine-protein phosphatase non-receptor type 12Cell signalingOrphan
PTPRJ106Receptor-type tyrosine-protein phosphatase etaCell proliferation and differentiation, cell adhesion and migration, platelet activation, and thrombosisOrphan
P2RX1107P2X purinoceptor 1Synaptic transmissionOrphan
RAD54B108DNA repair and recombination protein RAD54BDNA repairOrphan
RPS11110Ribosomal protein S1140S sub-unit ribosomal proteinOrphan
SAA1111Serumamyloid A-1 proteinInflammationOrphan
SIRT2112NAD-dependent protein deacetylase sirtuin-2Cell cycle regulationOrphan
SLAMF7113SLAM family member 7Immune responseOrphan
SLC17A9114Solute carrier family 17 member 9ATP storage and exocytosisOrphan
SPAG118RNA polymerase II-associated protein 3RNA polymerizationOrphan
SSR4119Translocon-associated protein subunit deltaRetention of ER resident proteins regulationOrphan
STK11120Serine/threonine-protein kinase STK11Tumor suppressionOrphan
ST6GAL1121Beta-galactoside alpha-2,6-sialyltransferase 1Transfers sialic acid from CMP-sialic acid to galactose-containing acceptor substratesOrphan
TAS1R3122Taste receptor type 1 member 3Umami taste stimulus responseOrphan
TMEM156129Transmembrane protein 156Transmembrane proteinOrphan
TNFa130Tumor necrosis factorCell proliferation and differentiation, tumor cells deathOrphan

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Figure 1. Step by step description of the gene clustering analysis procedure, performed via computer simulation, to investigate the existence of a genetic linkage between periodontitis and human colorectal cancer, and to identify leader genes.
Figure 1. Step by step description of the gene clustering analysis procedure, performed via computer simulation, to investigate the existence of a genetic linkage between periodontitis and human colorectal cancer, and to identify leader genes.
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Figure 2. AC. Data analysis for colorectal cancer and periodontal disease: (A) plot of the gap statistic method for estimating the number of clusters; (B) WNL for genes involved in the phenomenon. Black arrows are the centroids of the cluster groups: leader genes (in red); cluster B genes (in light blue); cluster C genes (in yellow); cluster D genes (in green); cluster E genes (in purple); cluster F genes (in orange); and ‘orphan’ genes (in clear); (C) final map of interactions of 137 genes involved in the genetic linkage between periodontitis and CRC according to STRING: leader genes are red; the lines that connect single genes represent predicted functional associations among proteins in the confidence view.
Figure 2. AC. Data analysis for colorectal cancer and periodontal disease: (A) plot of the gap statistic method for estimating the number of clusters; (B) WNL for genes involved in the phenomenon. Black arrows are the centroids of the cluster groups: leader genes (in red); cluster B genes (in light blue); cluster C genes (in yellow); cluster D genes (in green); cluster E genes (in purple); cluster F genes (in orange); and ‘orphan’ genes (in clear); (C) final map of interactions of 137 genes involved in the genetic linkage between periodontitis and CRC according to STRING: leader genes are red; the lines that connect single genes represent predicted functional associations among proteins in the confidence view.
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Figure 3. Gene classification in the seven clusters, designated from A to F, based on the number of predicted interactions of genes, excluding the last orphan genes cluster with no predicted interactions.
Figure 3. Gene classification in the seven clusters, designated from A to F, based on the number of predicted interactions of genes, excluding the last orphan genes cluster with no predicted interactions.
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Table 1. The following key words, achieved by studies investigating either colorectal cancer or periodontitis or both of them [16,18,19,21,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41], were employed in the literature search and were logically combined with the boolean operators AND, OR, NOT.
Table 1. The following key words, achieved by studies investigating either colorectal cancer or periodontitis or both of them [16,18,19,21,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41], were employed in the literature search and were logically combined with the boolean operators AND, OR, NOT.
Key Words
(1)gene AND human
(2)cancer
(3)carcinoma
(4)2 OR 3
(5)colon
(6)colonic
(7)rectal
(8)CRC
(9)5 OR 6 OR 7 OR 8
(10)periodontitis
(11)periodontal disease
(12)periodontal inflammation
(13)gingivitis
(14)periodontal disruption
(15)10 OR 11 OR 12 OR 13 OR 14
(16)1 AND 4 AND 9 AND 15
Table 2. Description of the leader genes identified in the genetic linkage between periodontitis and human colorectal cancer: leader genes product(s) main function’, as per the free online software STRING (version 11.0) [22]; role in CRC development and progression; role in periodontitis onset and progression; putative pathogenic mechanisms related to the effects of the products of leader genes.
Table 2. Description of the leader genes identified in the genetic linkage between periodontitis and human colorectal cancer: leader genes product(s) main function’, as per the free online software STRING (version 11.0) [22]; role in CRC development and progression; role in periodontitis onset and progression; putative pathogenic mechanisms related to the effects of the products of leader genes.
Leader GenesMain FunctionRole in CRCRole in PeriodontitisPutative Pathogenic Mechanisms
CTNNB1Cell signalingMutated in up to 90% of colonic tumors; responsible for initial tissue dysplastic transformation [22]; encodes for β-catenin, a subunit of the adherens junctions complex, regulating cell growth and adhesion and Wnt responsive genes (i.e., c-Myc) expression, leading to cell cycle progression.Its product, β-catenin, is detectable in periodontal ligament cell nuclei in mice, potentially influencing periodontal ligament homeostasis [23]; regulates Wnt responsive genes. Wnt stimulus induces osteogenic lineage commitment [23], while Wnt depletion is involved in alveolar bone loss.Cell cycle dysregulation
FOSGene(s) transcription, cell signaling, cell proliferation and differentiationrs7101 and rs1063169 FOS single nucleotide polymorphisms are considered at higher risk of CRC onset [24] and its expression increases in CRC lesions [25]. In addition, a different member of the FOS family, named Fra-1, is over-expressed in colonic cancer cells, particularly in those acquiring motility and invasive ability [25]. Moreover, FOS may participate in the inflammatory microenvironment associated with CRC [25].May be implicated in periodontitis development and progression through the interaction with prostaglandin-endoperoxide synthase 2, affecting the T-cell receptor (TCR) signaling [26].Cell cycle dysregulation
JUNGene(s) transcription, cell signaling, cell proliferation, and differentiation inflammationIts product, c-Jun, heterodimerizes with c-Fos protein, encoded by FOS, to form the transcription factor AP-1 (see above). Involved in cell proliferation, differentiation, apoptosis, and malignant transformation [24,27].Its product, c-Jun, heterodimerizes with c-Fos protein, encoded by FOS, to form the transcription factor AP-1 (see above). Involved in cell proliferation, differentiation, apoptosis, and malignant transformation [24,27].Cell cycle dysregulation
GRB2Cell signalingIts products stimulate colonic cell proliferation [28]; in particular, the Grb2-associated binding protein 2 (Gab2) has been found responsible for epithelial mesenchymal transition and consequent CRC metastasis development [29].Its products bind to the epidermal growth factor (EGF) receptor.
EGF signaling in the periodontal tissue, indirectly affected by GRB2 expression, is considered essential in tissue regeneration; thus, its interruption may affect healing and regeneration processes. Indeed, EGF ligand alterations, secondary to the effect of the peptidylarginine deiminase enzyme, released by porphyromonasgingivalis, interfere with EGF signaling, and, potentially, favor periodontitis progression [30].
Cell cycle dysregulation
PIK3CACell proliferation, cell survivalThe most frequently mutated gene in breast cancer and is centrally involved in other malignancies [22].n.a.Cell cycle dysregulation
PIK3R1Cell signalingPhosphorylated by PIK3CA, it is downregulated in CRC cells [31].It is considered as a marker of severe periodontitis [32].Cell cycle dysregulation
IL6InflammationInduces CRC cell growth and invasion; and higher levels of IL6 have been detected in the serum from CRC patients compared to controls [33]. Stimulates osteoclastogenesis [34], has been found associated with chronic as well as aggressive periodontitis and, together with IL6R, IL6ST, IL4R, and IL1R1 may link periodontitis to other diseases [20].Immuno-inflammatory response
IL1BImmune responseIn CRC cells it is produced in higher concentrations compared to healthy surrounding tissues, possibly activating the NFKB signaling pathway [35].IL1-889 C/T gene polymorphism has been associated with severe periodontitis [34] and its role in periodontitis pathogenesis has long been advocated [36].Immuno-inflammatory response
IL4Immuno-inflammatory processProduced by activated T helper 2 lymphocytes, may reduce cancer-directed response operated by the immune system, encouraging cancer invasion and metastasis. Through its binding to Type II IL-4 receptor α (IL-4Rα) and JAK/STAT signaling activation, it favors survival of cancer cells and immunosuppression, so that a dysregulation in IL-4 signaling or IL-4Rα gene polymorphisms may be associated with cancer, including CRC [37].Plays a protective role in periodontitis progression, reducing alveolar bone loss. Consequently, IL4 gingivo-crevicular fluid levels are higher in periodontally healthy subjects and after non-surgical periodontal treatment. In addition, the IL4-590 C/T polymorphism has been reported as potentially associated with an increased risk of periodontitis development [38].Immuno-inflammatory response
IL10Gene(s) transcriptionIts deficiency favors IBD malignant transformation to CRC [4,39], through the so called “inflammation-dysplasia-carcinoma sequence”, an alternative to the well-known “adenoma-carcinoma sequence” [2].Anti-inflammatory cytokine, down-regulating monocyte-macrophage response. Its gene polymorphism has been associated with periodontitis development in Caucasians [34].Immuno-inflammatory response
RELACell signalingIts expression is higher in malignant compared to healthy colonic cells, as well as in breast, liver, pancreatic, and gastric cancers, although its role in cancerogenesis, as well as in periodontitis, is still not fully elucidated [40].It is also classified as leader gene in periodontitis probably because it is functionally related to NFKB pro-inflammatory activity [22]. Immuno-inflammatory response
CBLCell signalingIt may be related to inflammatory bowel disease (IBD) and CRC [41], as well as to atherogenesis, and neurodegenerative and autoimmune diseases, by a de-regulation in the ubiquitin–proteasome system, with subsequent NFKB activation and immuno-inflammatory response enhancement. No evidence is available relating CBL to periodontitis [20].Immuno-inflammatory response

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Di Spirito, F.; Toti, P.; Pilone, V.; Carinci, F.; Lauritano, D.; Sbordone, L. The Association between Periodontitis and Human Colorectal Cancer: Genetic and Pathogenic Linkage. Life 2020, 10, 211. https://doi.org/10.3390/life10090211

AMA Style

Di Spirito F, Toti P, Pilone V, Carinci F, Lauritano D, Sbordone L. The Association between Periodontitis and Human Colorectal Cancer: Genetic and Pathogenic Linkage. Life. 2020; 10(9):211. https://doi.org/10.3390/life10090211

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Di Spirito, Federica, Paolo Toti, Vincenzo Pilone, Francesco Carinci, Dorina Lauritano, and Ludovico Sbordone. 2020. "The Association between Periodontitis and Human Colorectal Cancer: Genetic and Pathogenic Linkage" Life 10, no. 9: 211. https://doi.org/10.3390/life10090211

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