Holistic paradigm in carcinogenesis: Genetics, epigenetics, immunity, inflammation and oral infections

Table 1 Cancer pathogenesis literature metrics stratified by risk factor categories

Risk factor category	No. of articles published
Genetics	379694
Infections	85420
Immunity	52889
Epigenetics	43505
Inflammation	37930
Oral infections and periodontitis	5612

Not all publications report causal relationship.

Table 2 Summary of inflammation and cancer relationship

Basic observations	Interpretation
Chronic inflammation increases cancer risk	Causality is not proven[47]
	Inflammation from psoriasis actually reduces cancer risk
AIs decrease cancer	AIs are proven to decrease cancer risk as shown in Coley’s toxin[93]
	AIs may mobilize strong immune responses and create cancer resisting environment[94,95]
Metabolic inflammation may be an important risk factor	Causality is quite possible, via IGF, VEGF
Various type of immune, inflammatory cells are present in cancer loci	They can be innocent bystanders
Immune cells affect malignant cells through cytokines, chemokines, growth factors, prostaglandins, and reactive oxygen and nitrogen species	This fact proves that there is an interaction between immune cells and cancer cells but causal relationship is yet to be established
Inflammation is present from tumor initiation to metastasis	It does not mean inflammation causes cancer. Inflammation may be a part of disease processes in cancer
NF-κB signaling pathway can be two-way street: NF-κB from immune system can suppress cancer progress; also NF-κB from cancer cells to resist immune action	NF-κB is universal biologic transcription factor and difficult to prove its involvement as a causal factor in carcinogenesis
Certain immune/inflammatory actions are dispensable in some stages and indispensable in others

AIs: Acute infections; IGF: Insulin-like growth factor; VEGF: Vascular endothelial growth factor.

Table 3 Longitudinal studies on the association of oral infections with cancer

	Design/sample size/f-u	Predictor	Outcome	Methods	Results	Comments
Ahn et al[62], 2012	Prospective follow-up study: (n = 105)	Serum P. gingivalis antibody and periodontitis status	ODC mortality	Cox proportional hazards regression analysis	Periodontitis increase CRC risk RR = 3.58, 95%CI: 1.15-11.16)	No adjustment of alcohol consumption and genetics
	Approximately 12 yr f-u			Controlled age, sex, smoking status, education, race/ethnicity and BMI	Greater serum P. gingivalis IgG → non-significant increase in risk for ODC mortality	Cox regression n = event number
						May be underpowered
Michaud[63], 2013	Nested case-control study: n = 405 cases and 416 matched controls	Plasma antibodies to 25 oral bacteria	Pancreatic cancer	Conditional logistic regression: Matched on centre, sex, follow-up time, age collection, date and time of blood collection, fasting status and use of exogenous hormones among women	High antibody level to P. gingivalis double the risk (non-significant) → OR = 2.11 (0.97-4.59), P > 0.05	No adjustment of genetics
	Approximately 10 yr f-u			Additional adjustment of smoking and BMI	High antibody levels to commensals → 45% lower cancer risk (significant): OR = 0.55, 95%CI: 0.36-0.83, P < 0.05	No adjustment of metabolic oncogenes, i.e., k-ras
Hwang et al[65], 2014	Age, sex matched case-control (1:2), n = 116706	Periodontal treatment by insurance claims	Death, withdrawal from the NHI system, or any cancer diagnosis	Cox proportional hazards regression	HR = 0.72, 95%CI: 0.68-0.76, P < 0.05	No adjustment of smoking, alcohol consumption or genetics
	Approximately 13 yr f-u			Age, sex, occupation, T2D hypertension, hyperlipidemia
Chang et al[64], 2016	Prospective cohort study, n = 214890	PD diagnosis by insurance claims	Censored or diagnosed with pancreatic cancer	Cox proportional hazards regression	HR = 1.55 (1.02-2.33), P = 0.04 in the whole cohort	Proxies for smoking and alcohol consumption adjusted
	Approximately 12 yr f-u			Adjusted for age, sex, diabetes, hypelipidemia, allergies, viral hepatitis, peptic ulcer, pancreatitis, COPD, and alcohol-related conditions	Age ≥ 65 (HR = 2.17, 95%CI: 1.03-5.47)	Viral hepatitis, gastric ulcer and pancreatitis adjustment is positive
					Age < 65 yr (HR = 0.83, 95%CI: 0.52-1.34)
					Men (HR = 1.72, 95%CI: 1.01-2.93; women HR = 1.33, 95%CI: 0.69-2.55)	Genetics was not adjusted
Bertrand et al[67], 2016	Prospective cohort, 26 yr f-u, n = 51529	History of periodontitis assessed by questionnaire	Non-Hodgkin’s lymphoma including	Lymphoma in general has strong correlation to hereditary immune suppression and chemical usage, i.e., pesticides → lymphoma is prevalent in agricultural workers	Overall NHL HR = 1.30 (95%CI: 1.11-1.51)	Lymphoma → lower immunity→ periodontitis may be a marker for suppressed immunity
			CLL; SLL; diffuse large B-cell lymphomas; follicular lymphomas		CLL/SLL HR = 1.41 (95%CI: 1.08-1.84)	Chemical exposure was not controlled
						Reverse causation is possible due to long asymptomatic latency

CLL: Chronic lymphocytic leukemia; SLL: Small lymphocytic lymphomas; ODC: Orodigestive cancer; f-u: Follow-up; COPD: Chronic obstructive pulmonary disease; CRC: Colorectal cancer; PD: Periodontitis.