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

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.