We evaluate potential contributors to the development of autoimmunity and other phenotypes consistent with immune dysregulation in individuals with germline mutations in the tumor suppressor gene PTEN in this observational report.
Materials and methods: Illumina sequencing of bacterial and fungal microbes was carried out on patient-donated fecal samples in a cohort of 67 patients with pathogenic germline PTEN mutations, including 41 individuals with autoimmunity and/or phenotypes consistent with immune dysregulation (cases) and 26 individuals without (controls). From these data, we measured differences in alpha and beta diversity between cases and controls and identified differentially abundant bacterial and fungal taxa using phyloseq and MicrobiomeSeq packages in R. We analyzed correlations between these taxa and specific HLA genotypes, along with correlations between HLA diversity and microbial diversity, by conducting high-resolution HLA genotyping at four class II loci (DRB1, DRB345, DQA1, and DQB1).
Results: We found that alpha diversity distributions for both bacterial and fungal genera were statistically different between cases and controls. We identified differentially abundant bacterial and fungal taxa between cases and controls. Network analysis of differentially abundant bacterial taxa revealed some co-varying bacterial genera. We additionally found significant correlations between certain HLA genotypes and certain taxa and significant correlations between HLA diversity and alpha diversity.
Conclusion: PTEN-associated immune phenotypes might be influenced by the gut microbiome, and class II HLA molecules, in part, crosstalk with the gut microbiome. These preliminary observations should lay the groundwork for future studies to ultimately derive clinical measures, which could use gut microbiome and HLA molecule biomarkers to predict, and perhaps prevent, immunity and inflammation in patients predisposed to cancer because of germline PTEN mutations.
© 2021 by American Society of Clinical Oncology.