Oral microbial community composition is associated with pancreatic cancer: A case‐control study in Iran

MoayyedKazemi*, Ali reza and Suman, Shalabh and Vogtmann, Emily and Bokulich, Nicholas and Kamangar, Farin and Hicks, Belynda (2021) Oral microbial community composition is associated with pancreatic cancer: A case‐control study in Iran. cancer medicine.

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Abstract

Background: Oral microbiota may be related to pancreatic cancer risk because periodontal disease, a condition linked to multiple specific microbes, has been associated with increased risk of pancreatic cancer. We evaluated the association between oral microbiota and pancreatic cancer in Iran. Methods: A total of 273 pancreatic adenocarcinoma cases and 285 controls recruited from tertiary hospitals and a specialty clinic in Tehran, Iran provided saliva samples and filled out a questionnaire regarding demographics and lifestyle characteristics. DNA was extracted from saliva and the V4 region of the 16S rRNA gene was PCR amplified and sequenced on the MiSeq. The sequencing data were processed using the DADA2 plugin in QIIME 2 and taxonomy was assigned against the Human Oral Microbiome Database. Logistic regression and MiRKAT models were calculated with adjustment for potential confounders. Results: No association was observed for alpha diversity with an average of 91.11 (standard deviation [SD] 2.59) sequence variants for cases and 89.42 (SD 2.58) for controls. However, there was evidence for an association between beta diversity2 | VOGTMANN eT Al. 1 | INTRODUCTION Microbes living in and on the human body, including bacteria, viruses and archaea, have the potential to impact human health and disease. There is evidence that the microbiota is related to a number of conditions, such as inflammatory bowel disease,1 diabetes,2 and cancer.3 It has been hypothesized that oral microbiota may play a role in the etiology of pancreatic cancer, particularly due to the associations detected between periodontal disease and pancreatic cancer risk.4-9 Oral health and periodontal disease are associated with oral microbial diversity. Distinct oral microbiome communities by gingivitis status10 and dental caries11 have been observed. Clustering by periodontal disease status has also been detected12 and there are multiple specific microbes strongly implicated in periodontal disease etiology, including Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans.13 These data suggest that the relationships between oral health and periodontal disease with pancreatic cancer may be related to changes in the oral microbiota. A limited number of studies have assessed the relationship between the oral microbiota or antibodies to oral bacteria and pancreatic cancer.14-18 However, these studies were conducted within populations in the United States and Europe and many had very small sample sizes. Pancreatic cancer ranks as the 12th most common incident cancer globally, but due to its poor prognosis, it is the seventh most common cause of cancer death.19 Mortality from pancreatic cancer has also been increasing over the past few years, including in Iran,20 unlike trends for many other cancer sites.21 Given the poor prognosis after a diagnosis of pancreatic cancer, identifying new risk factors is essential and changes in the oral microbiota offer a promising new avenue in the search for risk factors. Therefore, we evaluated the association between oral microbiota and pancreatic cancer in a case‐control study in Iran. 2 | METHODS 2.1 | Study population The recruitment of pancreatic cancer cases and controls for this study has been previously described in detail.22 In brief, participants were recruited from patients referred for endoscopic ultrasonography related to suspicion of a mass or cyst in the pancreas or bile ducts, assessment of submucosal lesions found during esophago‐gastro‐duodenal endoscopy, or to rule out bile duct stones at one of three tertiary hospitals or a specialty clinic in Tehran, Iran from January 2011 to January 2015. After providing informed consent, the participant responded to a questionnaire and provided saliva samples which were immediately stored at −70°C. The questionnaire included information related to demographics, tobacco and opium use, and body mass index. Endoscopic ultrasonography was conducted and for those with mass or cystic lesions, fine needle aspirates were obtained. The pancreatic tissues were interpreted by an expert pathologist and those with pancreatic adenocarcinoma defined by histopathology were considered pancreatic cancer cases. Participants who had a normal pancreas at the endoscopic ultrasonography exam, aged 40 years or older, no history of liver or renal failure or cancer, no consumption of a special diet, and did not develop pancreatic disease or any cancer within one year of the initial visit were considered controls. Final diagnoses for the controls were asymptomatic small (<10 mm) submucosal lesions in the esophagus or stomach, or gallbladder or common bile duct stones without cholangitis. A total of 357 pancreatic cancer cases and 328 controls were identified and saliva specimens were available from 287 cases and 300 controls. and case status. The association between the Bray‐Curtis dissimilarity and pancreatic cancer was particularly strong with a MiRKAT P‐value of .000142 and specific principal coordinate vectors had strong associations with cancer risk. Several specific taxa were also associated with case status after adjustment for multiple comparisons. Conclusion: The overall microbial community appeared to differ between pancreatic cancer cases and controls. Whether these reflect differences evident before development of pancreatic cancer will need to be evaluated in prospective studies.

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