Abstract
Germline PTEN mutations defining PTEN hamartoma tumor syndrome (PHTS) confer heritable predisposition to breast, endometrial, thyroid and other cancers with known age-related risks, but it remains impossible to predict if any individual will develop cancer. In the general population, gut microbial dysbiosis has been linked to cancer, yet is unclear whether these are associated in PHTS patients. In this pilot study, we aimed to characterize microbial composition of stool, urine, and oral wash from 32 PTEN mutation-positive individuals using 16S rRNA gene sequencing. PCoA revealed clustering of the fecal microbiome by cancer history (P = 0.03, R 2 = 0.04). Fecal samples from PHTS cancer patients had relatively more abundant operational taxonomic units (OTUs) from family Rikenellaceae and unclassified members of Clostridia compared to those from non-cancer patients, whereas families Peptostreptococcaceae, Enterobacteriaceae, and Bifidobacteriaceae represented relatively more abundant OTUs among fecal samples from PHTS non-cancer patients. Functional metagenomic prediction revealed enrichment of the folate biosynthesis, genetic information processing and cell growth and death pathways among fecal samples from PHTS cancer patients compared to non-cancer patients. We found no major shifts in overall diversity and no clustering by cancer history among oral wash or urine samples. Our observations suggest the utility of an expanded study to interrogate gut dysbiosis as a potential cancer risk modifier in PHTS patients.
Highlights
Individuals with germline PTEN mutations have an inherited cancer syndrome known as PTEN hamartoma tumor syndrome (PHTS), which is characterized by increased risk of endocrine cancers including 85% lifetime cancer risk for the female breast, 35% thyroid and 28% endometrium; non-endocrine cancers are components of the syndrome and include renal cancer
A total of 32 unrelated PHTS patients were enrolled in this study, 17 of whom had a history of cancer and 15 of whom had no history of cancer
We found that fecal microbiota yielded structural segregation according to the presence or absence of cancer history
Summary
Individuals with germline PTEN mutations have an inherited cancer syndrome known as PTEN hamartoma tumor syndrome (PHTS), which is characterized by increased risk of endocrine cancers including 85% lifetime cancer risk for the female breast, 35% thyroid and 28% endometrium; non-endocrine cancers are components of the syndrome and include renal cancer (33% lifetime risk), colorectal (9%) and melanoma (6%) (Eng 2001, Tan et al 2012). These data provide evidence for PTEN-enabled cancer risk assessment, surveillance and medical management for PHTS patients as a group. Proposed mechanisms for these links include injection of direct effectors into host cells, induction of a pro-inflammatory microenvironment and altered host–microbiota interactions leading to activation of key cancer-promoting pathways like STAT3 and NF-κB (Rajagopala et al 2017)
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