Microbiota-based SCReening of Anal Cancer in HIV-infected individuals (SCRAtCH)

The risk of anal cancer is markedly increased in HIV-infected subjects, in part due to high prevalence of human papilloma virus (HPV) among men who have sex with men (MSM). The current screening strategy is based on detection of early stages of cancer or cancer precursors using anal cytology. While this approach is highly sensitive, the specificity is poor, leading to an excess number of invasive procedures. Emerging evidence supports that gut bacteria might amplify HPV-associated cancers and contribute to impairment of mucosal immunity during HIV-infection. Our hypothesis is that the diagnostic value of anal cytology for the diagnosis of early stages of anal cancer can be improved by measuring bacterial biomarkers derived from anal cytologies. In this project we have identified specific bacterial metabolites that with high specificity predict early stages of anal cancer in people living with HIV. We expect to improve the diagnosis of early stages of anal cancer, reduce the incidence of anal cancer, reduce the harms and costs associated with the screening of anal cancer, and to gain insight into the potential mechanisms of gut bacteria fuelling anal cancer.

I dette prosjektet har vi identifisert spesifikke metabolitter fra tarmbakterier som med høy presisjon kan identifiser forstadier til analcancer blant HIV positive. Funnene kan bane veien for tidligere og mer presis påsvisning av forstadier til analcancer uten invasive undersøkelser. Dette kan potensielt gi grunnlag for bedre screening metoder, behandling og overlevelse.

The risk of anal cancer is markedly increased (40-130 fold) in HIV-infected subjects, especially among men who have sex with men (MSM) and in women with history of anogenital HPV disease. The current screening strategy is based on detection of high-degree squamous intraepithelial lesions (HSIL), a cancer precursor, using anal cytology. While this approach is highly sensitive, the specificity is poor, leading to an excess number of invasive procedures. Emerging evidence supports that epithelial-adherent bacteria amplify HPV-associated cancers and contribute to impairment of mucosal immunity since the early stage of HIV-infection. Our hypothesis is that the diagnostic value of anal cytology for the diagnosis of HSIL can be improved by measuring bacterial biomarkers derived from anal cytologies. The primary aim is to identify a set of anal-associated bacterial biomarkers to improve the accuracy of anal cytology for the diagnosis of biopsy-proven HSIL in MSM. We will include 250 HIV-infected MSM undergoing screening for anal cancer by anal cytology and high-resolution anoscopy. We will extract the DNA/RNA from the anal bacteria and sequence the 16S ribosomal genes to infer the composition of dead, dormant, inactive and active bacteria. Mass spectrometry will be used to examine proteins and metabolites produced by active bacteria. Direct relationships between species abundance, protein synthesis and metabolic alterations will be studied by integrative models and multivariate logistic regression to identify predictors of HSIL. External validation will be performed in independent cohorts of 100 HIV-infected MSM and 50 HIV-infected women. We expect to improve the diagnosis of HSIL, reduce the incidence of anal cancer, reduce the harms and costs associated with the screening of anal cancer, and to gain insight into the potential mechanisms of microbiota fuelling anal cancer. A consortium of 2 clinical sites and 3 academic partners has been established to achieve this.