Oral Viral DNA Profiling in Obesity, Adenomatous Polyposis, and Colorectal Cancer Identifies Human β-Papillomavirus Types as Potentially Sex-Related and Modifiable Cancer Risk Indicators

<b>Background/Objectives</b>: Colorectal cancer (CRC) is the third most common cancer and a leading cause of death worldwide. Identifying non-invasive, early indicators of CRC risk remains essential and could help reduce its health burden. Excess adiposity and chronic inflammation are major predisposing factors for precancerous adenomatous polyposis (AP) and CRC, while diet- or surgery-induced weight loss was associated with a reduced risk. Viral infections also represent cancer risk factors through direct or synergic mechanisms, though no definitive causal link has been established for CRC. Moreover, interest is growing on the role of oral viruses as predictors of disease. <b>Methods</b>: In this study, highly sensitive and specific Luminex-based screening assays were used to perform a comprehensive characterization of oral infections by Human Herpes (HHV), Polyoma (HPyV) and Papilloma (HPV) Viruses in CRC patients (N = 50), healthy controls (N = 46; normal weight, NW = 26; overweight, OW = 20), and high-risk individuals with obesity (N = 35) or adenomatous polyposis (AP, N = 22). <b>Results</b>: We observed increased HPyV prevalence in AP, and higher single and multiple β-HPV infection rates in AP and CRC compared to controls. A panel of β-HPV genotypes, including oncogenic HPV5, was overrepresented in CRC and high-risk groups, and some of them showed an association with the male sex. The prevalence of most infections decreased in the obese cohort following bariatric surgery, alongside weight loss and reduction of inflammatory markers. Furthermore, oral infections by viral types previously detected in CRC tissue and adjacent mucosa also declined after surgery. <b>Conclusions</b>: Altogether, these findings suggested a role for oral β-HPV types as potential sex- and lifestyle-related, modifiable indicators of cancer risk.