The association between advanced periodontal disease and cancer risk was examined in a prospective cohort of male never smokers. In this population of never smokers, positive associations with periodontal disease were observed in several cancers, all of which have previously been linked to smoking. We hypothesize that the positive associations are driven by some underlying immune dysregulation associated with bacterial dysbiosis.
Keywords: periodontal disease, cancer risk, never smokers
Abstract
Background
Periodontal disease has a direct impact on the immune response and has been linked to several chronic diseases, including atherosclerosis and stroke. Few studies have examined the association between periodontal disease and cancer.
Patients and methods
A total of 19 933 men reported being never smokers (of cigarette, pipes or cigars) in the Health Professionals' Follow-up Study. Periodontal disease status and teeth number were self-reported at baseline and during follow-up. All cancers were ascertained during 26 years of follow-up. Cox's proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) adjusting for risk factors.
Results
A 13% increase in total cancer was observed among men reporting periodontitis at baseline, and a 45% increase in risk was observed among men with advanced periodontitis (periodontitis with <17 remaining teeth). Periodontitis was not associated with prostate cancer, colorectal cancer or melanoma, the three most common cancers in this cohort of never smokers, but a 33% increase in risk was observed for smoking-related cancers (lung, bladder, oropharnygeal, esophageal, kidney, stomach and liver cancers; HR = 1.33, 95% CI 1.07–1.65). Men with advanced periodontitis had an HR of 2.57 (95% CI 1.56–4.21; P = 0.0002) for smoking-related cancers, compared with men who did not have periodontitis and had 17 teeth or more. Advanced periodontitis was associated with elevated risks of esophageal and head and neck cancers (HR = 6.29, 95% CI 2.13–18.6; based on five cases with advanced periodontitis) and bladder cancer (HR = 5.06, 95% CI 2.32–11.0; based on nine cases with advanced periodontitis).
Conclusions
Advanced periodontitis was associated with a 2.5-fold increase in smoking-related cancers among never smokers. Periodontitis may impact cancer risk through system immune dysregulation. Further studies need to examine the immune impact of advanced periodontitis on cancer, especially for cancers known to be caused by smoking.
introduction
Many of the known risk factors for cancer, including smoking, obesity, diabetes and physical inactivity, share some commonality in that they are all associated with systemic inflammation and immune perturbations, and likely share common pathways to cancer development. Advanced periodontal disease, through local inflammation, bone destruction and tooth loss, can have a major systemic impact on the body, which extends beyond the oral cavity [1]. Recent advances in identifying and quantifying bacteria using new sequencing methodology (e.g. metagenomics) [2] have provided new opportunities to examine the role of microbiota in cancer development [3, 4]. Poor oral health and development of periodontitis are associated with dysbiosis [5], i.e. changes in bacterial communities in the mouth, and changes in the immune status [6], which may well be directly involved in the genesis of cancer.
In a previous analysis, we reported positive associations between periodontal disease and cancer risk in the Health Professionals Follow-up Study (HPFS) [7]. Three other prospective cohort studies with data on periodontal disease, the NHANES I study [8], the NHANES III study [9] and the Women's Health Initiative (WHI) [10], have reported positive associations for periodontitis and cancers, including pancreatic, lung and orodigestive cancers. In addition, antibodies to a periodontal pathogen (Porphyromonas gingivalis) have been associated with elevated risk of pancreatic and orodigestive cancers in two different prospective studies [9, 11]; to date, there are no null studies on this topic. Retrospective studies have examined these associations, especially for head and neck cancers [12, 13], but as these are prone to bias, and reverse causation, they cannot provide strong support for causality. In the previous HPFS analysis [7], and similarly in the WHI [10], periodontal disease associations with lung cancer were not elevated in never smokers, but did remain elevated for all smoking-related cancers in the HPFS (not reported in WHI).
With an additional 8 years of follow-up available in the HPFS cohort (since our last analysis), and substantially more cancer cases among never smokers only, we herein re-examine the association between periodontal disease, tooth number and cancer risk with a focus on never smokers. This analysis also includes a new approach to examining periodontal disease; we combined self-reported history of periodontal disease with a number of teeth lost to better capture severity of periodontitis, given that a great number of teeth lost would indicate more advanced periodontitis
methods
The HPFS is an ongoing prospective cohort study that was initiated in 1986 and is maintained by investigators in the Department of Nutrition, Harvard School of Public Health, Boston, MA. Participants in this cohort were recruited from all US states by mail questionnaires and were eligible if they were registered dentists, veterinarians, pharmacists, optometrists, osteopathic physicians or podiatrists, between ages 40 and 75 years and male; no exclusions were made in the original cohort. Data on behavioral, medical and lifestyle factors were obtained at baseline and subsequently during follow-up through mailed questionnaires (for more details, refer to supplementary Material, available at Annals of Oncology online). The current analysis is restricted to men who reported being never cigarette, cigar or pipe smokers at baseline and consists of 19 933 participants. The follow-up rate for the HPFS cohort is >96%. This study was approved by the Human Subjects Committee of the Harvard School of Public Health.
assessment of dental measures
periodontal disease
At baseline, participants of the HPFS were asked whether they had a history of periodontal disease with bone loss. This question was validated in dentists [14] and non-dentists [15] in the HPFS cohort by obtaining radio graphs from subsets of individuals with and without a self-reported history of periodontal disease (for additional details, refer to supplementary Material, available at Annals of Oncology online). In addition, participants updated their periodontal disease status on each biennial questionnaire during follow-up.
tooth loss
Participants reported a number of natural teeth at baseline, and any tooth loss during the previous 2 years was reported on the follow-up questionnaires. Self-reported number of teeth is highly correlated with the actual number of teeth on clinical assessment in a general population (r = 0.97) [16].
identification of participants with cancer
Medical records were obtained from physicians/hospitals for newly diagnosed cancers as reported by participants on biennial questionnaires (supplementary Material, available at Annals of Oncology online, for more details). Smoking-related cancers are defined as those cancers linked to smoking by IARC [17].
statistical analysis
We computed person-time of follow-up for each participant from the return date of the baseline questionnaire to the date of cancer diagnosis, death from any cause or the end of follow-up (31 January 2012), whichever came first. For the periodontal disease analyses, we examined baseline periodontal disease status and updated periodontal disease status to represent chronic and more recent periodontal disease development, respectively. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) by the use of Cox proportional hazard models adjusting for potential confounders. Additional details on confounders are provided in supplementary Material, available at Annals of Oncology online.
results
At baseline (1986), the prevalence of periodontitis among never smokers in this population was 9.7% which is slightly lower than the overall HPFS population (16% [7]), as expected, given that smoking is strong risk factor for periodontitis. In this highly educated population of health professionals, substantial tooth loss was uncommon (fewer than 17 teeth remaining—due to predefined categories on the questionnaire, we could not use 20 teeth remaining as the cut off; 3% never smokers, 5.5% overall population). Men with fewer teeth were older and had slightly higher BMI, and those with periodontal disease were more likely to have diabetes (Table 1). Alcohol and total caloric intake was similar across exposure groups (Table 1). Men with advanced periodontitis (defined as having fewer than 17 teeth and reported periodontal disease) were more likely to have hypertension (29.7%), were more likely to be non-steroidal anti-inflammatory drug users (38.9%) and a higher percent were non-White (20.8%), compared with men in the other categories (Table 1).
Table 1.
Age-standardized baseline characteristics (mean or %) of participants in the Health Professionals Follow-up Study by periodontal disease and number of teeth among never cigarette, pipe or cigar smokers (n = 19 933)a
| No periodontal disease and 17–32 teeth | No periodontal disease and <17 teeth | Periodontal disease and 17–32 teeth | Periodontal disease and <17 teeth | |
|---|---|---|---|---|
| Participants, n | 17 554 | 434 | 1768 | 177 |
| Age, yearsb | 52.2 (9.56) | 61.3 (9.20) | 56.5 (9.59) | 64.8 (8.06) |
| Height, inb | 70.1 (3.23) | 70.2 (2.89) | 69.9 (4.05) | 70.1 (3.01) |
| Body mass index, kg/m2b | 25.2 (4.81) | 26.0 (5.42) | 25.3 (5.20) | 25.9 (4.48) |
| Physical activity, MET h/weekb | 22.1 (30.1) | 17.6 (20.9) | 21.6 (28.2) | 23.8 (34.6) |
| Ethnic origin, % | ||||
| White | 94.4 | 89.3 | 90.6 | 79.2 |
| Otherc | 5.6 | 10.7 | 9.4 | 20.8 |
| Diabetes (%) | 2.1 | 2.0 | 3.8 | 5.6 |
| High cholesterol (%) | 10.9 | 7.5 | 13.0 | 8.5 |
| High blood pressure (%) | 18.8 | 20.4 | 21.0 | 29.7 |
| NSAID (%) | 32.3 | 35.5 | 31.0 | 38.9 |
| Multivitamin (%) | 41.3 | 46.8 | 37.9 | 29.4 |
| Daily dietary intakeb | ||||
| Calories, kcal | 1997 (617) | 2089 (692) | 1987 (642) | 2132 (666) |
| Vitamin D, IU | 409 (308) | 408 (320) | 413 (336) | 379 (290) |
| Alcohol, g | 7.57 (11.6) | 8.24 (11.8) | 7.36 (11.6) | 7.06 (12.6) |
aAll variables (except age) are age standardized.
bMean (SD) for all such values.
cAll non-White categories combined due to small numbers.
MET, metabolic equivalent; NSAID, non-steroidal anti-inflammatory drug.
Periodontal disease status at baseline was associated with a 13% higher risk of developing cancer [95% CI 1.01–1.27] and a 44% increase in cancer risk was observed among those with periodontal disease and fewer teeth number (Table 2). No associations were observed with either periodontal disease or teeth number and risk of the most common cancers among never smokers in this cohort, i.e. prostate, melanoma and colorectal cancer (Table 2).
Table 2.
Periodontal disease and risk of total cancer and the three most common cancers among never smokers in Health Professionals Follow-up Study 1986–2012 (n = 19 933)
| Baseline periodontal status | Total cancer, 2959 cases |
Prostate cancera, 696 cases |
Colorectal cancer, 461 cases |
Melanoma, 451 cases |
||||
|---|---|---|---|---|---|---|---|---|
| Case no. | HR (95% CI)$b | Case no. | HR (95% CI)b$ | Case no. | HR (95% CI)b$ | Case no. | HR (95% CI)b$ | |
| No history of periodontal disease | 2593 | 1.0 | 598 | 1.0 | 406 | 1.0 | 399 | 1.0 |
| Periodontal disease | 366 | 1.13 (1.01–1.27) | 98 | 1.17 (0.94–1.47) | 65 | 1.03 (0.75–1.39) | 52 | 1.20 (0.89–1.63) |
| 25–32 teeth | 2542 | 1.0 | 584 | 1.0 | 396 | 1.0 | 407 | 1.0 |
| 17–24 teeth | 285 | 0.93 (0.81–1.06) | 77 | 0.91 (0.71–1.18) | 45 | 0.89 (0.63–1.23) | 31 | 0.78 (0.53–1.13) |
| 0–16 teeth | 132 | 1.05 (0.87–1.27) | 35 | 0.89 (0.61–1.30) | 20 | 1.02 (0.63–1.66) | 12 | 0.65 (0.34–1.25) |
| No history periodontal disease with 17–32 teeth | 2512 | 1.0 | 576 | 1.0 | 395 | 1.0 | 392 | 1.0 |
| No history periodontal disease with 0–16 teeth | 81 | 0.96 (0.76–1.21) | 22 | 0.90 (0.57–1.43) | 11 | 0.90 (0.48–1.66) | 7 | 0.61 (0.27–1.38) |
| History of periodontal disease with 17–32 teeth | 315 | 1.09 (0.96–1.23) | 85 | 1.16 (0.92–1.48) | 46 | 0.97 (0.70–1.34) | 47 | 1.15 (0.84–1.58) |
| History of periodontal disease with 0–16 teeth | 51 | 1.45 (1.07–1.96) | 13 | 1.09 (0.61–1.95) | 9 | 1.35 (0.64–2.83) | 5 | 0.95 (0.34–2.63) |
aProstate cancers include only aggressive cancers.
$bHazard ratios (HRs) and 95% confidence intervals (CIs) controlling for age (continuous), race (white, other), alcohol use (0, 0.1–4.9, 5–14.9, 15–29.9, ≥30 g/day), physical activity (quintiles), history of diabetes (yes or no), body mass index (BMI; <22, 22–24.9, 25–29.9, 30+), geographical location (south, west, northeast, midwest), height (quintiles), NSAID use.
Strong associations were observed for periodontitis and smoking-related cancers (lung, bladder, oropharnygeal, esophageal, kidney, stomach and liver [17]). For all smoking-related cancers combined, a 33% increase in risk was observed for those with periodontal disease at baseline, compared with no history of periodontal disease (Table 3). The association was stronger among those who had advanced periodontitis (HR = 2.57, 95% CI 1.56–4.21) when compared with those who had no periodontitis and 17 or more teeth remaining at baseline. For bladder cancer, an HR of 5.06 was observed for men with advanced periodontitis at baseline, and a greater than sixfold increase in risk was observed for oropharyngeal and esophageal cancers (combined because of small numbers) (Table 3). While no associations were observed for periodontal disease status and risk of lung and kidney cancers, elevated risks were noted among those with advanced periodontitis (associations were not statistically significant). Updating periodontal disease status during follow-up years were similar to those observed with baseline periodontal status (Table 3). Similarly, updating tooth loss did not strengthen associations for the advanced periodontitis analyses.
Table 3.
Periodontal disease and cancer risk among never smokers in HPFS 1986–2012 (n = 19 933)
| Smoking-related cancersa, 752 cases |
Bladder cancer, 222 cases |
Lung cancer, 109 cases |
Kidney cancer, 137 cases |
Esophageal and oropharyngeal cancers, 93 cases |
Pancreatic cancer, 141 cases |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Case no. | HR (95% CI)b | Case no. | HR (95% CI)b | Case no. | HR (95% CI)b | Case no. | HR (95% CI)b | Case no. | HR (95% CI)b | Case no. | HR (95% CI)b | |
| Baseline exposures status | ||||||||||||
| No periodontal disease | 644 | 1.0 | 189 | 1.0 | 101 | 1.0 | 120 | 1.0 | 74 | 1.0 | 117 | 1.0 |
| Periodontal disease | 108 | 1.33 (1.07–1.65) | 33 | 1.38 (0.93–2.05) | 13 | 0.92 (0.49–1.71) | 17 | 1.06 (0.61–1.85) | 13 | 2.25 (1.30–3.90) | 24 | 1.57 (0.98–2.50) |
| 25–32 teeth | 628 | 1.0 | 186 | 1.0 | 89 | 1.0 | 115 | 1.0 | 77 | 1.0 | 118 | 1.0 |
| 17–24 teeth | 85 | 1.07 (0.83–1.36) | 24 | 0.97 (0.60–1.54) | 19 | 1.36 (0.76–2.42) | 15 | 1.32 (0.74–2.34) | 8 | 0.96 (0.44–2.06) | 16 | 0.92 (0.52–1.61) |
| 0–16 teeth | 39 | 1.21 (0.85–1.72) | 12 | 1.40 (0.73–2.70) | 6 | 1.47 (0.59–3.68) | 7 | 1.45 (0.64–3.31) | 8 | 1.73 (0.74–4.06) | 7 | 1.10 (0.48–2.51) |
| No periodontal disease and 17–32 teeth | 624 | 1.0 | 186 | 1.0 | 97 | 1.0 | 116 | 1.0 | 71 | 1.0 | 111 | 1.0 |
| No periodontal disease and 0–16 teeth | 20 | 0.83 (0.52–1.35) | 3 | 0.37 (0.09–1.53) | 4 | 1.05 (0.34–3.23) | 4 | 1.14 (0.40–3.27) | 3 | 1.05 (0.30–3.74) | 6 | 1.50 (0.62–3.64) |
| Periodontal disease and 17–32 teeth | 89 | 1.22 (0.96–1.54) | 24 | 1.09 (0.70–1.70) | 11 | 0.86 (0.44–1.67) | 14 | 1.02 (0.56–1.86) | 14 | 1.97 (1.08–3.59) | 23 | 1.68 (1.05–2.70) |
| Periodontal disease and 0–16 teeth | 19 | 2.57 (1.56–4.21) | 9 | 5.06 (2.32–11.0) | 2 | 2.46 (0.53–11.3) | 3 | 2.04 (0.60–6.91) | 5 | 6.29 (2.13–18.6) | 1 | 0.72 (0.10–5.44) |
| Updated periodontal status | ||||||||||||
| No periodontal disease | 595 | 1.0 | 178 | 1.0 | 89 | 1.0 | 113 | 1.0 | 71 | 1.0 | 110 | 1.0 |
| Periodontal disease | 157 | 1.27 (1.05–1.53) | 48 | 1.29 (0.92–1.82) | 25 | 1.27 (0.77–2.10) | 24 | 1.09 (0.68–1.75) | 22 | 1.54 (0.92–2.58) | 31 | 1.26 (0.82–1.93) |
aIncludes lung, bladder, kidney, oropharyngeal, esophagus, pancreatic, stomach and liver. Stomach and liver cancers are not shown individually as the number of cases was too small (46 and 24, respectively).
bHazard ratios (HRs) and 95% CIs controlling for age (continuous), race (white, other), alcohol use (0, 0.1–4.9, 5–14.9, 15–29.9, ≥30 g/day), physical activity (quintiles), history of diabetes (yes or no), body mass index (BMI; <22, 22–24.9, 25–29.9, 30+), geographical location (south, west, northeast, midwest), height (quintiles), NSAID use.
Given that age was significantly higher among those with advanced periodontitis at baseline (Table 1), we were interested in whether the associations would be modified by age. The associations with advanced periodontitis were stronger in men who had these conditions before they were 60 years old than those who were 60 years or older, but there was no statistically significant interaction (for smoking-related cancers, comparing advanced periodontitis with no periodontitis with 17–32 teeth, age <60 years: HR = 3.70, 95% CI 1.45–9.40; age ≥60 years: HR = 2.22, 95% CI 1.24–3.97, P-interaction = 0.89). Periodontal disease associations with smoking-related cancers were not modified by BMI (data and additional analyses are provided in supplementary Material, available at Annals of Oncology online).
discussion
Among never smokers, periodontal disease was associated with a 33% increase in risk of smoking-related cancers, and a 2.5-fold increase in risk among men who had advanced periodontitis (P = 0.0002), compared with men who had no periodontitis and more than 16 teeth remaining. The associations were particularly strong for risk of bladder, esophageal and head and neck cancers, but were also elevated in other smoking-related cancers. No associations were noted for prostate cancer, colorectal cancer or melanoma, the three most common cancers in this population of never smokers.
Known risk factors for cancer were not, for the most part, associated with smoking-related cancers (including BMI, diabetes, physical activity and height; data not shown) in this population; the only statistically significant association observed was for obesity and kidney cancer. Our findings were strongest among men with periodontal disease and few teeth number (16 or less), i.e. with advanced periodontitis; this is a particularly important finding as it supports a biological mechanism, and may provide an opportunity to treat patients with advanced periodontitis to reduce risk of cancer, although confirmation of these findings in other populations will be important.
There is overwhelming evidence that periodontitis results in systemic inflammation and immune dysregulation, and growing evidence for a link with a number of conditions, including atherosclerosis [1, 18, 19]. Although research on periodontal disease and cancer lags behind the work on atherosclerosis, case–control studies have reported positive associations on oral health and risk of head and neck cancer for some time [13]. The real challenge, with cancer as with heart disease, is to evaluate causality in the associations. Prospective cohort studies with long follow-up can begin to address causality, as exposure is ascertained many years, sometimes decades, before cancer diagnosis. In our analysis, we observe persistent elevated risk of cancer 10 years post-periodontal disease, suggesting the association is not likely to be due to reverse causation.
To date, three large cohorts have reported associations with periodontal disease and cancer. In the NHANES I Epidemologic Follow-up Study, individuals with periodontitis at baseline had a higher risk of fatal cancer compared with those with healthy periodontium [odds ratio (OR) = 1.55, 95% CI 1.25–1.92], controlling for age and gender but not smoking [8]. In the NHANES III data, a twofold increase in mortality of orodigestive cancers was observed among those with moderate (RR = 2.22, 95% CI 1.11–4.46) and aggressive periodontitis (RR = 2.64, 95% CI 0.85–8.23; P-trend = 0.01), compared with those with no oral disease [9]. A positive association was also reported for lung cancer in the WHI; periodontitis was associated with a 24% increase in risk (HR = 1.24, 95% CI 1.07–1.45), adjusting for smoking history [10].
In addition, two cohorts examined antibodies to periodontal pathogens and cancer risk [9, 11]. In a large prospective cohort, a greater than twofold increase in risk of pancreatic cancer was observed among those with high levels of antibodies to a pathogenic strain of P. gingivalis (OR = 2.38, 95% CI 1.16–4.90, comparing >200 versus ≤200 ng/ml) after adjusting for known risk factors [11]. In the NHANES III cohort study, elevated antibodies to P. gingivalis (≥69.1 EU, compared with <69.1) were associated with a threefold increase risk of orodigestive cancer mortality (RR = 3.03, 95% CI 0.99–9.31) [9].
Porphyromonas gingivalis, a periodontal disease pathogen, has been shown to trigger oral inflammation and lead to immune dysregulation in mice [20]. A number of biological mechanisms could explain the link between periodontitis and cancer risk and include systemic inflammation [20], immune dysregulation as a result of chronic periodontitis [21, 22] and alteration of cancer signaling pathways by oral pathogens [23]. Elevated systemic markers of inflammation in patients with chronic periodontitis include interleukin 6, tumor necrosis factor-α and fibrinogen [24].
Our finding that only smoking-related cancers appear to increase in risk with periodontitis suggests that alterations in immune pathways may play an important role in mediating these associations, given that smoking is well known to affect the immune response, both the innate and adaptive immune systems [25, 26]. Moreover, smoking has been associated with changes in DNA methylation patterns that are directly linked to the immune response [27]. Recent studies have shown that certain bacterial metabolites can modulate the immune response through epigenetic modification, including the regulatory T cells (Tregs) response [28, 29], which plays an important role in carcinogenesis [30]. More work needs to be done to understand the link between periodontal disease, bacterial dysbiosis and the systemic immune response. Obesity and diabetes were not strongly associated with these cancers in this population of never smokers (with the exception of kidney cancer) and the periodontal disease associations were independent of these factors; given that obesity is well known to cause systemic inflammation, the association with periodontal disease may be driven by other immune components. More research in this area will likely reveal important new insights into critical immune pathways for carcinogenesis. In addition, it is possible that some of the associations observed in this study were due to shared genetic susceptibility among those who developed advanced periodontitis [31].
The strength of the current analysis using the HPFS cohort include restriction to never smokers, 26 years of follow-up with large number of cancer cases and classification of advanced periodontitis by combining self-reported periodontitis with tooth number. There were also limitations, including small number of individuals with advanced periodontitis in this population (as defined in this analysis), self-reported periodontal disease status and number of teeth, no data on pocket depth, gingival attachment loss or periodontal treatment, few numbers of non-White participants and no females.
Among never smokers, we observed a 2.5-fold increase in smoking-related cancers for those with advanced periodontitis. Associations were not modified by age or BMI and remained elevated with a 10-year lag between periodontal status and cancer diagnosis. The impact of advanced periodontal disease on the immune function may be an underlying cause for these observed associations. Further studies need to examine immune perturbations from periodontal disease and biological pathways to address causality.
funding
This study was funded by UM1 CA167552 and R01 CA166150 from the National Cancer Institute of the National Institutes of Health.
disclosure
The authors have declared no conflicts of interest.
Supplementary Material
acknowledgements
We would like to thank the participants and staff of the Health Professionals Follow-up Cohort study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.
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