Tooth loss and cancer risk: a dose-response meta analysis of prospective cohort studies.

INTRODUCTION

Cancer has to be the second-leading cause in 2015 that caused over 8.8 million deaths worldwide in 2015 [ 1 ]. Due to countries geographical environment, living habits, cancer incidence is very different. The incidence of cancer in developing countries such as Africa, Asia and South America is the most severe. A total of 14 million cancer cases were added worldwide and 8.2 million people died in 2012. Among them, China added 3.07 million cancer patients and caused about 2.2 million deaths, accounting for 21.9% of the total global deaths. The incidence of cancer in developed countries is still higher than in developing countries. Residents of North America and Europe are the most vulnerable to cancer, but China has a large population base, making it the country with the highest number of cancer deaths throughout the world. As more and more people in developing countries improve their living standards and dietary patterns change, the chances of cancer have increased significantly in developing countries [ 2 ]. The etiology of cancer involves both genetic and environmental factors. Therefore, understanding the impact of environmental factors on cancer will help to prevent cancer.

Oral cavity is an important part of the body, and is starts in the digestive system, mainly by the lip and cheek, tongue and palate, salivary glands, teeth and jaw, with mastication, swallowing, speech and feeling, and other functions, which maintain the normal shape of maxillofacial. Oral health is an important part of human health. The World Health Organization (WHO) identifies dental health as one of the top ten criteria for human health. Poor oral health may increase systemic inflammation, resulting in a local overly aggressive immune response, and thus could have important implications for cancer development. Periodontal disease and tooth loss are two common oral health measures [ 3 ]. Tooth loss has been considered to impact quality of life [ 4 ], and been known to considerably influence food choice, diet, nutrition intake, and esthetics [ 5 ].

Previous studies have examined the correlation between tooth loss and cancer risk [ 6 – 30 ]. However, the result remains controversial. Additionally, no study to quantitative assessed tooth loss in relation to cancer risk. Thus, we performed this dose-response meta-analysis to clarify and quantitative assessed the correlation between tooth loss and cancer risk.

MATERIALS AND METHODS

This meta-analysis was conducted according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklist [ 31 ].

Search strategy

We included eligible studies to investigate the relationship between tooth loss and cancer risk in general adult populations. To develop a flexible, non-linear, r meta-regression model, we required that an eligible study should have categorized into 3 or more levels.

PubMed and EMBASE were searched for studies that contained risk estimates for the outcomes of cancer and were published update to March 2017, with keywords including “dentition” [MeSH] OR ”tooth loss” [MeSH] OR “edentulous” [MeSH] OR “lost of tooth” [MeSH] AND “cancer” [MeSH] OR “tumor” [MeSH] OR “neoplasms” [MeSH]. We refer to the relevant original essays and commentary articles to determine further relevant research.

Study selection

Two independent researchers investigate information the correlation between tooth loss and cancer risk: outcome was cancer. Moreover, we precluded non-human studies, reviews, meta-analyses, editorials and published letters.

Data extraction

Use standardized data collection tables to extract data. Each eligible article information was extracted by two independent researchers. We extracted the following information: first author; publication year; age; country; sex; cases and participants; the categories of tooth loss; relative risk or odds ratio (OR). We collect the risk estimates with multivariable-adjusted [ 32 ]. According to the Newcastle-Ottawa scale, quality assessment was performed for non-randomized studies [ 33 ]. The disagreements were resolved through consensus by all the authors.

Statistical analysis

We pooled relative risk estimates to measure the association between tooth loss and cancer; the hazard ratio were considered equivalent to the relative risk [ 34 ]. Results in different subgroups of tooth loss and cancer risk were treated as two separate reports.

Due to different definitions cut-off points in the included studies for categories, we performed a relative risk estimates by the method recommended by Greenland, Longnecker and Orsini and colleagues [ 35 ]. Dose of tooth loss used the median tooth loss. If the median tooth loss category was not available, the midpoint of the upper and lower boundaries was considered the dose of each category. In addition, using restricted cubic splines to evaluate the non-linear association between tooth loss and cancer risk, with three knots at the 10th, 50th, and 90th percentiles of the distribution. A flexible meta-regression based on restricted cubic spline (RCS) function was used to fit the potential non-linear trend, and generalized least-square method was used to estimate the parameters. This procedure treats tooth loss (continuous data) as an independent variable and logRR of diseases as a dependent variable, with both tails of the curve restricted to linear. A P value is calculated for linear or non-linear by testing the null hypothesis that the coefficient of the second spline is equal to zero [ 32 ].

The between-study heterogeneity was assessed by Q -statistic (signifcance level at P ≤ 0.10) and the I 2 -statistic. STATA software 14.0 (STATA Corp, College Station, TX, USA) was using in all analyses. P < 0.05 was considered signifcant for all tests.

RESULTS

Literature search results

We identifed 3088 relevant citations after removing duplicates. Reviewing their titles and abstracts, 3021 citations were excluded. The remaining 67 citations were assessed in more detail for eligibility by reading the full text. Among them, 43 were excluded, after review reference, one articles was included. Finally, 25 studies were used for the final data synthesis [ 6 – 30 ]. The flow chart of literature searching was presented in Figure 1 , and the data were extracted. These studies were published update to March 2017.

Study characteristics

The characteristics of the included studies of tooth loss and cancer risk are shown in the Table 1 and Supplementary Table 1 . Among the selected studies, nine focused on esophageal cancer [ 6 – 13 , 24 ], five focused on gastric cancer [ 6 , 7 , 12 , 13 , 15 ], eleven focused on head and neck cancer [ 11 – 13 , 16 – 20 , 23 , 25 , 26 ], four focused on colorectal cancer [ 12 , 13 , 28 , 29 ], five focused on pancreas cancer [ 12 – 14 , 21 , 30 ], two focused on lung cancer [ 12 , 13 ], two focused on prostate cancer [ 12 , 13 ] and two focused on bladder cancer [ 12 , 13 ]. Results in different subgroups were treated as two separate reports. Finally, Eighty-one independent reports from twenty five studies investigated the association between tooth loss and cancer.

Tooth loss and overall cancer risk

Eighty-one independent reports from twenty five studies investigated the association between tooth loss and cancer [ 6 – 30 ]. Compared with the lowest tooth loss, tooth loss is significantly associated with a higher risk of cancer risk (RR:1.06; 95% CI, 1.02–1.09; P < 0.001) (Table 2 ). Additionally, a dose-response analysis revealed that each 10 tooth loss was associated with a 9% incremental in cancer risk (RR: 1.09; 95% CI, 1.05–1.13) (Figure 2 ). A cubic spline model revealed an positive non-linear correlation between tooth loss and cancer ( P < 0.001 for non-linearity; Figure 2 ).

Tooth loss and esophageal cancer

Ten independent reports from nine studies investigated the association between tooth loss and esophageal cancer [ 6 – 13 , 24 ]. Compared with the lowest tooth loss, tooth loss is significantly associated with a higher risk of esophageal cancer (RR:1.18; 95% CI, 1.04–1.31; P < 0.001) (Table 2 ). Furthermore, tooth loss is significantly associated with esophageal cancer risk in Caucasia (RR:1.12; 95% CI, 1.02–1.21; P < .001) (Table 2 ) and Asia (RR:1.26; 95% CI, 1.08–1.44; P < .001) (Table 2 ). Additionally, a dose-response analysis revealed that each 10 tooth loss was associated with a 14% incremental in esophageal cancer risk (RR: 1.14; 95% CI, 1.05–1.25) (Figure 3 ). A cubic spline model revealed an positive non-linear correlation between tooth loss and esophageal cancer ( P < 0.001 for non-linearity; Figure 3 ).

Tooth loss and gastric cancer

Nine independent reports from five studies investigated the association between tooth loss and gastric cancer [ 6 , 7 , 12 , 13 , 15 ]. The results of tooth loss and gastric cancer risk are shown in Table 2 . Compared with lowest the tooth loss, tooth loss is significantly associated with a higher risk of gastric cancer (RR: 1.09; 95% CI, 1.03–1.16; P < 0.001) (Table 2 ). Furthermore, tooth loss is significantly associated with gastric cancer risk in Caucasia (RR:1.25; 95% CI, 1.11–1.36; P < 0.001) (Table 2 ) and Asia (RR:1.04; 95% CI, 1.01–1.09; P < 0.001) (Table 2 ). Additionally, a dose-response analysis revealed that each 10 tooth loss was associated with a 9% incremental in gastric cancer risk (RR: 1.09; 95% CI, 1.01–1.18; P < 0.001) (Figure 3 ). A cubic spline model revealed an positive non-linear correlation between tooth loss and gastric cancer ( P < 0.001 for non-linearity; Figure 3 ).

Tooth loss and head and neck cancer

Nineteen independent reports from eleven studies investigated the association between tooth loss and head and neck cancer [ 11 – 13 , 16 – 20 , 23 , 25 , 26 ]. Compared with the lowest tooth loss, tooth loss is significantly associated with head and neck cancer risk (RR:1.52; 95% CI, 1.14–1.90; P < 0.001) (Table 2 ). Furthermore, tooth loss is significantly associated with a higher risk of head and neck cancer in Caucasia (RR:1.15; 95% CI, 1.04–1.26; P < 0.001) (Table 2 ) and Asia (RR:1.82; 95% CI, 1.52–2.12; P < 0.001) (Table 2 ). Also, tooth loss is significantly associated with oral cancer (RR:1.80; 95% CI, 1.30–2.30; P < 0.001) (Table 2 ), Pharynx cancer (RR:1.14; 95% CI, 1.05–1.23; P < 0.001) (Table 2 ) and Larynx cancer (RR:1.08; 95% CI, 1.02–1.15; P < 0.001) (Table 2 ). Additionally, a dose-response analysis revealed that each 10 tooth loss was associated with a 31% incremental in head and neck cancer risk (RR: 1.31; 95% CI, 1.15–1.50; P < 0.001) (Figure 3 ). A cubic spline model revealed an positive non-linear correlation between tooth loss and head and neck cancer cancer ( P < 0.001 for non-linearity; Figure 3 ).

Tooth loss and colorectal cancer

Thirteen independent reports from four studies investigated the association between tooth loss and colorectal cancer [ 12 , 13 , 28 , 29 ]. Compared with the lowest tooth loss, tooth loss is significantly associated with a higher risk of colorectal cancer (RR:1.07; 95% CI, 1.02–1.14; P < 0.001) (Table 2 ). Furthermore, tooth loss is significantly associated with colorectal cancer risk in Caucasia (RR:1.17; 95% CI, 1.07–1.27; P < 0.001) (Table 2 ) and Asia (RR:1.05; 95% CI, 1.01–1.09; P < 0.001) (Table 2 ). Also, tooth loss is significantly associated with a higher risk of colon cancer (RR: 1.09; 95% CI, 1.02–1.17; P < 0.001) (Table 2 ) and rectal cancer (RR:1.08; 95% CI, 1.01–1.17; P < 0.001) (Table 2 ). Additionally, a dose-response analysis revealed that each 10 tooth loss was associated with a 4% incremental in colorectal cancer risk (RR:1.04; 95% CI, 1.01–1.08; P < 0.001) (Figure 3 ). A cubic spline model revealed an positive non-linear correlation between tooth loss and colorectal cancer ( P < 0.001 for non-linearity; Figure 3 ).

Tooth loss and pancreas cancer

Five independent reports from five studies investigated the association between tooth loss and pancreas cancer [ 12 – 14 , 21 , 30 ]. Compared with the lowest tooth loss, tooth loss is significantly associated with a higher risk of pancreas cancer (RR:1.15; 95% CI, 1.05–1.19; P < 0.001) (Table 2 ). Additionally, a dose-response analysis revealed that each 10 tooth loss was associated with a 7% incremental in pancreas cancer risk (RR:1.07; 95% CI, 1.01–1.15; P < 0.001) (Figure 4 ). A cubic spline model revealed an positive non-linear correlation between tooth loss and pancreas cancer ( P < 0.001 for non-linearity; Figure 4 ).

Tooth loss and lung cancer

Five independent reports from two studies investigated the association between tooth loss and lung cancer [ 12 , 13 ]. Compared with lowest tooth loss, tooth loss is significantly associated with a higher risk of lung cancer (RR: 1.66; 95% CI, 1.34-1.97; P < 0.001) (Table 2 ). Additionally, a dose-response analysis revealed that each 10 tooth loss was associated with a 19% incremental in lung cancer risk (RR:1.19; 95% CI, 1.04–1.35; P < 0.001) (Figure 4 ). A cubic spline model revealed an positive non-linear correlation between tooth loss and lung cancer ( P < 0.001 for non-linearity; Figure 4 ).

Tooth loss and bladder cancer

Two independent reports from two studies investigated the association between tooth loss and bladder cancer [ 12 , 13 ]. Compared with lowest tooth loss, tooth loss is significantly associated with a higher risk of bladder cancer (RR: 1.23; 95% CI, 1.12–1.35; P < 0.001) (Table 2 ). Additionally, a dose-response analysis revealed that each 10 tooth loss was associated with a 2% incremental in bladder cancer risk (RR: 1.02; 95% CI, 1.01–1.03; P < 0.001) (Figure 4 ). A cubic spline model revealed an positive non-linear correlation between tooth loss and bladder cancer ( P < 0.001 for non-linearity; Figure 4 ).

Tooth loss and hematopoietic cancer

Two independent reports from two studies investigated the association between tooth loss and hematopoietic cancer [ 12 , 13 ]. Compared with the lowest tooth loss, tooth loss is significantly associated with a higher risk of hematopoietic cancer (RR: 1.07; 95% CI, 1.02–1.13; P < 0.001) (Table 2 ). Additionally, a dose-response analysis revealed that each 10 tooth loss was associated with a 3% incremental in hematopoietic cancer risk (RR: 1.03; 95% CI, 1.01–1.07; P < 0.001) (Figure 4 ). A cubic spline model revealed an positive non-linear correlation between tooth loss and hematopoietic cancer ( P < 0.001 for non-linearity; Figure 4 ).

Subgroup analyses

Subgroup analysis was performed to check the stability of the primary outcome. Subgroup meta-analyses in study design and study quality showed consistent findings (Table 2 ).

Sensitivity analysis

Sensitivity analysis was conducted to assess the stability of the results. The results show the results were stable in Supplementary Figure 1 .

Publication bias

Each studies in this meta-analysis were performed to evaluate the publication bias by both Begg’s funnel plot and Egger’s test. P > 0.05 was considered no publication bias. The results show no obvious evidence of publication bias was found in the associations between tooth loss and cancer risk ( Supplementary Table 2 ).

DISCUSSION

Cancer affects millions of people in developed and developing countries that is now a public health crisis. Despite the decline in the mortality rate of developed countries, cancer is still the main cause of death and has caused serious social and economic distress on a global scale over the past few decades. In low and middle-income countries, the incidence of cancer has risen sharply [ 2 ]. To date, there are a few identified risk factors for acute pancreatitis, including smoking, infection, occupational exposure, environmental pollution, unreasonable diet and genetic factors. Previous studies indicated that tooth loss may be a risk factors in cancer, but presented controversial results.

In the current meta-analysis was based on 25 case-control or cohort study, with more than 1.3 million participants and 32925 cases from eleven countries. Thus, this meta analysis provides the most up-to-date epidemiological evidence supporting tooth loss is harmful for cancer. A dose-response analysis revealed that a per 10 of tooth loss increase was associated with a 9% increment of cancer risk, 14% increment of esophageal cancer risk, 9% increment of gastric cancer risk, 31% increment of head and neck cancer risk, 4% increment of colorectal cancer risk, 7% increment of pancreas cancer risk, 19% increment of lung cancer risk, 3% increment of prostate cancer risk, 2% increment of bladder cancer risk and 3% increment of hematopoietic cancer risk. Subgroup meta-analyses by various factors also showed consistent findings.

Several plausible pathways may reasonable for the relationship between tooth loss and cancer. The influence of chronic inflammation on cancer development is one possible pathway. Chronic systemic inflammation linked to periodontal disease [ 36 , 37 ], which is a major cause of tooth loss in adults that can increase the risk of cancer by inhibiting apoptosis and stimulating tumor cell proliferation [ 38 ]. Secondly, the main cause of teeth loss is dental caries [ 39 , 40 ], and carbohydrate intake is the dental caries cause. Carbohydrate intake was associated with increased risk cancer [ 41 , 42 ]. Third, the progress of tooth damage destroys normal periodontal tissue, allowing oral microbial accumulation deep into oral tissue, thereby promoting its growth [ 43 ]. Thus, tooth loss and cancer seems to be closely related.

To our knowledge, this is the first study to identify and quantify the potential dose-response association between tooth loss and cancer risk in a large cohort of both men and women. Although, we performed this meta-analysis very carefully, however, some limitations must be considered in the current meta-analysis. First, different sex of population should be included in this meta-analysis to explore the impact of different sex of population on tooth loss and cancer risk. Second, we only select literature that written by English, which may have resulted in a language or cultural bias, other language should be chosen in the further. Third, in the subgroup analysis in cancer type, there might be insufficient statistical power to check an association. Fourth, Though some data were obtained from retrospective studies, most of retrospective studies only to identify the relationship between tooth loss and cancer risk, and we also add more study to identify and quantify the potential dose-response association between tooth loss and cancer risk.

In conclusion, our findings underscore the notion that tooth loss was associated with cancer risk increment. In the future, large-scale and population based association studies must be performed in the future to validate the risk identified in the current meta-analysis.

SUPPLEMENTARY MATERIALS FIGURE AND TABLES

CONFLICTS OF INTEREST

Authors have disclosed no conflicts of interest.

FINANCIAL SUPPORT

This work was partially supported by the Initial Project for Post-Graduates of HuBei University of Medicine (K1228901).

REFERENCES

1 GBD 2015 Mortality and Causes of Death Collaborators Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015 Lancet 2016 388 1459 544 27733281 10.1016/S0140-6736(16)31012-1 PMC5388903

2 Fitzmaurice C Allen C Barber RM Barregard L Bhutta ZA Brenner H Dicker DJ Chimed-Orchir O Dandona R Dandona L Fleming T Forouzanfar MH Hancock J Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study JAMA Oncol 2016 3 524 548 10.1001/jamaoncol.2016.5688 PMC6103527 27918777

3 Pihlstrom BL Michalowicz BS Johnson NW Periodontal diseases Lancet 2005 366 1809 20 https://doi.org/10.1016/s0140-6736(05)67728-8 16298220 10.1016/S0140-6736(05)67728-8

4 Gerritsen AE Allen PF Witter DJ Bronkhorst EM Creugers NH Tooth loss and oral health-related quality of life: a systematic review and meta-analysis Health Qual Life Outcomes 2010 8 126 21050499 10.1186/1477-7525-8-126 PMC2992503

5 Adegboye AR Twetman S Christensen LB Heitmann BL Intake of dairy calcium and tooth loss among adult Danish men and women Nutrition 2012 28 779 84 22459555 10.1016/j.nut.2011.11.011

6 Abnet CC Qiao YL Mark SD Dong ZW Taylor PR Dawsey SM Prospective study of tooth loss and incident esophageal and gastric cancers in China Cancer Causes Control 2001 12 847 54 11714113 10.1023/a:1012290009545

7 Abnet CC Kamangar F Dawsey SM Stolzenberg-Solomon RZ Albanes D Pietinen P Virtamo J Taylor PR Tooth loss is associated with increased risk of gastric non-cardia adenocarcinoma in a cohort of Finnish smokers Scand J Gastroenterol 2005 40 681 7 16036528 10.1080/00365520510015430

8 Abnet CC Kamangar F Islami F Nasrollahzadeh D Brennan P Aghcheli K Merat S Pourshams A Marjani HA Ebadati A Sotoudeh M Boffetta P Malekzadeh R Tooth loss and lack of regular oral hygiene are associated with higher risk of esophageal squamous cell carcinoma Cancer Epidemiol Biomarkers Prev 2008 17 3062 8 18990747 10.1158/1055-9965.EPI-08-0558 PMC2586052

9 Dar NA Islami F Bhat GA Shah IA Makhdoomi MA Iqbal B Rafiq R Lone MM Abnet CC Boffetta P Poor oral hygiene and risk of esophageal squamous cell carcinoma in Kashmir Br J Cancer 2013 109 1367 72 23900216 10.1038/bjc.2013.437 PMC3778293

10 Dye BA Wang R Lashley R Wei W Abnet CC Wang G Dawsey SM Cong W Roth MJ Li X Qiao Y Using NHANES oral health examination protocols as part of an esophageal cancer screening study conducted in a high-risk region of China BMC Oral Health 2007 7 10 17640341 10.1186/1472-6831-7-10 PMC1993835

11 Guha N Boffetta P Wunsch Filho V Eluf Neto J Shangina O Zaridze D Curado MP Koifman S Matos E Menezes A Szeszenia-Dabrowska N Fernandez L Mates D Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case-control studies Am J Epidemiol 2007 166 1159 73 17761691 10.1093/aje/kwm193

12 Hiraki A Matsuo K Suzuki T Kawase T Tajima K Teeth loss and risk of cancer at 14 common sites in Japanese Cancer Epidemiol Biomarkers Prev 2008 17 1222 7 18483345 10.1158/1055-9965.EPI-07-2761

13 Michaud DS Liu Y Meyer M Giovannucci E Joshipura K Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study Lancet Oncol 2008 9 550 8 18462995 10.1016/S1470-2045(08)70106-2 PMC2601530

14 Michaud DS Joshipura K Giovannucci E Fuchs CS A prospective study of periodontal disease and pancreatic cancer in US male health professionals J Natl Cancer Inst 2007 99 171 5 17228001 10.1093/jnci/djk021

15 Shakeri R Malekzadeh R Etemadi A Nasrollahzadeh D Abedi-Ardekani B Khoshnia M Islami F Pourshams A Pawlita M Boffetta P Dawsey SM Kamangar F Abnet CC Association of tooth loss and oral hygiene with risk of gastric adenocarcinoma Cancer Prev Res (Phila) 2013 6 477 82 23503651 10.1158/1940-6207.CAPR-12-0491 PMC3644330

16 Balaram P Sridhar H Rajkumar T Vaccarella S Herrero R Nandakumar A Ravichandran K Ramdas K Sankaranarayanan R Gajalakshmi V Munoz N Franceschi S Oral cancer in southern India: the influence of smoking, drinking, paan-chewing and oral hygiene Int J Cancer 2002 98 440 5 11920597 10.1002/ijc.10200

17 Bundgaard T Wildt J Frydenberg M Elbrond O Nielsen JE Case-control study of squamous cell cancer of the oral cavity in Denmark Cancer Causes Control 1995 6 57 67 7718736 10.1007/BF00051681

18 Divaris K Olshan AF Smith J Bell ME Weissler MC Funkhouser WK Bradshaw PT Oral health and risk for head and neck squamous cell carcinoma: the Carolina Head and Neck Cancer Study Cancer Causes Control 2010 21 567 75 20049634 10.1007/s10552-009-9486-9 PMC2925153

19 Garrote LF Herrero R Reyes RM Vaccarella S Anta JL Ferbeye L Munoz N Franceschi S Risk factors for cancer of the oral cavity and oro-pharynx in Cuba Br J Cancer 2001 85 46 54 11437401 10.1054/bjoc.2000.1825 PMC2363910

20 Lissowska J Pilarska A Pilarski P Samolczyk-Wanyura D Piekarczyk J Bardin-Mikollajczak A Zatonski W Herrero R Munoz N Franceschi S Smoking, alcohol, diet, dentition and sexual practices in the epidemiology of oral cancer in Poland Eur J Cancer Prev 2003 12 25 33 12548107 10.1097/00008469-200302000-00005

21 Talamini R Vaccarella S Barbone F Tavani A La Vecchia C Herrero R Munoz N Franceschi S Oral hygiene, dentition, sexual habits and risk of oral cancer Br J Cancer 2000 83 1238 42 11027440 10.1054/bjoc.2000.1398 PMC2363583

22 Bertrand KA Shingala J Evens A Birmann BM Giovannucci E Michaud DS Periodontal disease and risk of non-Hodgkin lymphoma in the Health Professionals Follow-Up Study Int J Cancer 2017 140 1020 6 27861844 10.1002/ijc.30518 PMC5243178

23 Chen F He BC Yan LJ Qiu Y Lin LS Cai L Influence of oral hygiene and its interaction with standard of education on the risk of oral cancer in women who neither smoked nor drank alcohol: a hospital-based, case-control study Br J Oral Maxillofac Surg 2017 55 260 5 27908460 10.1016/j.bjoms.2016.11.316

24 Chen X Yuan Z Lu M Zhang Y Jin L Ye W Poor oral health is associated with an increased risk of esophageal squamous cell carcinoma - a population-based case-control study in China Int J Cancer 2017 140 626 35 27778330 10.1002/ijc.30484

25 Zuo C Zhu Y Wang X Zeng X Huang C Tooth loss and risk of oral squamous cell carcinoma in Chinese Han population Int J Clin Exp Med 2015 8 21893 7 26885159 PMC4724005

26 Huang J Roosaar A Axell T Ye W A prospective cohort study on poor oral hygiene and pancreatic cancer risk Int J Cancer 2016 138 340 7 26235255 10.1002/ijc.29710

27 Liu Z Chang ET Liu Q Cai Y Zhang Z Chen G Xie SH Cao SM Shao JY Jia WH Zheng Y Liao J Chen Y Oral Hygiene and Risk of Nasopharyngeal Carcinoma-A Population-Based Case-Control Study in China Cancer Epidemiol Biomarkers Prev 2016 25 1201 7 27197279 10.1158/1055-9965.EPI-16-0149 PMC4970945

28 Momen-Heravi F Babic A Tworoger SS Zhang L Wu K Smith-Warner SA Ogino S Chan AT Meyerhardt J Giovannucci E Fuchs C Cho E Michaud DS Periodontal disease, tooth loss and colorectal cancer risk: Results from the Nurses’ Health Study Int J Cancer 2017 140 646 52 27778343 10.1002/ijc.30486 PMC5159274

29 Ren HG Luu HN Cai H Xiang YB Steinwandel M Gao YT Hargreaves M Zheng W Blot WJ Long JR Shu XO Oral health and risk of colorectal cancer: results from three cohort studies and a meta-analysis Ann Oncol 2016 27 1329 36 27217540 10.1093/annonc/mdw172 PMC4922320

30 Stolzenberg-Solomon RZ Dodd KW Blaser MJ Virtamo J Taylor PR Albanes D Tooth loss, pancreatic cancer, and Helicobacter pylori Am J Clin Nutr 2003 78 176 81 12816788 10.1093/ajcn/78.1.176

31 Stroup DF Berlin JA Morton SC Olkin I Williamson GD Rennie D Moher D Becker BJ Sipe TA Thacker SB Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group JAMA 2000 283 2008 12 10789670 10.1001/jama.283.15.2008

32 Durrleman S Simon R Flexible regression models with cubic splines Stat Med 1989 8 551 61 2657958 10.1002/sim.4780080504

33 Stang A Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses Eur J Epidemiol 2010 25 603 5 20652370 10.1007/s10654-010-9491-z

34 Xu C Zeng XT Liu TZ Zhang C Yang ZH Li S Chen XY Fruits and vegetables intake and risk of bladder cancer: a PRISMA-compliant systematic review and dose-response meta-analysis of prospective cohort studies Medicine (Baltimore) 2015 94 e759 25929912 10.1097/MD.0000000000000759 PMC4603065

35 Orsini N Li R Wolk A Khudyakov P Spiegelman D Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software Am J Epidemiol 2012 175 66 73 22135359 10.1093/aje/kwr265 PMC3244608

36 Moutsopoulos NM Madianos PN Low-grade inflammation in chronic infectious diseases: paradigm of periodontal infections Ann N Y Acad Sci 2006 1088 251 64 17192571 10.1196/annals.1366.032

37 Loos BG Systemic markers of inflammation in periodontitis J Periodontol 2005 76 2106 15 10.1902/jop.2005.76.11-S.2106 16277583

38 Kaaks R Lukanova A Energy balance and cancer: the role of insulin and insulin-like growth factor-I Proc Nutr Soc 2001 60 91 106 11310428 10.1079/pns200070

39 Chauncey HH Glass RL Alman JE Dental caries. Principal cause of tooth extraction in a sample of US male adults Caries Res 1989 23 200 5 2661000 10.1159/000261178

40 Saunders RH Jr Meyerowitz C Dental caries in older adults Dent Clin North Am 2005 49 293 308 15755406 10.1016/j.cden.2004.10.004

41 Sanders TA How important is the relative balance of fat and carbohydrate as sources of energy in relation to health? Proc Nutr Soc 2016 75 147 53 26564394 10.1017/S0029665115004188

42 Brand-Miller JC Postprandial glycemia, glycemic index, and the prevention of type 2 diabetes Am J Clin Nutr 2004 80 243 4 15277141 10.1093/ajcn/80.2.243

43 Abnet CC Qiao YL Dawsey SM Dong ZW Taylor PR Mark SD Tooth loss is associated with increased risk of total death and death from upper gastrointestinal cancer, heart disease, and stroke in a Chinese population-based cohort Int J Epidemiol 2005 34 467 74 15659476 10.1093/ije/dyh375