Margaret Jia1, Naseer Sangwan2, Alice Tzeng1,3, Charis Eng1,3,4,5,6,7. 1. Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH. 2. Center for Microbiome in Health and Disease, Lerner Research Institute, Cleveland Clinic, Cleveland, OH. 3. Cleveland Clinic Lerner College of Medicine, Cleveland, OH. 4. Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. 5. Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care and Population Health, Cleveland, OH. 6. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH. 7. Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH.
Abstract
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.
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.
Authors: M G Butler; M J Dasouki; X-P Zhou; Z Talebizadeh; M Brown; T N Takahashi; J H Miles; C H Wang; R Stratton; R Pilarski; C Eng Journal: J Med Genet Date: 2005-04 Impact factor: 6.318
Authors: Patrick M Smith; Michael R Howitt; Nicolai Panikov; Monia Michaud; Carey Ann Gallini; Mohammad Bohlooly-Y; Jonathan N Glickman; Wendy S Garrett Journal: Science Date: 2013-07-04 Impact factor: 47.728
Authors: Ritika Jaini; Matthew G Loya; Alexander T King; Stetson Thacker; Nicholas B Sarn; Qi Yu; George R Stark; Charis Eng Journal: Hum Mol Genet Date: 2020-08-11 Impact factor: 6.150
Authors: M A Wadud Khan; W Zac Stephens; Ahmed Dawood Mohammed; June Louise Round; Jason Lee Kubinak Journal: PLoS One Date: 2019-05-16 Impact factor: 3.240