Background Adenomatous polyps are the most common precursor to colorectal cancer (CRC), the second leading cause of cancer death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas. Methods We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n=233) and without (n=547). Results Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, pro-inflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Our findings were consistent with previously reported shifts in the gut microbiota of CRC patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism. Conclusions These data hint that increased sugar, protein, and lipid metabolism along with increased bile acid production could promote a colonic environment that supports the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio. In turn, these microbes may produce genotoxic or inflammatory metabolites such as H2S and secondary bile acids, which could play a role in catalyzing adenoma development and eventually CRC. Impact This study suggests a plausible biological mechanism to explain the links between shifts in the microbiota and CRC. This represents a first step toward resolving the complex interactions that shape the adenoma-carcinoma sequence of CRC and may facilitate personalized therapeutics focused on the microbiota.
Nucleosome occupancy plays a key role in regulating access to eukaryotic genomes. Although various chromatin regulatory complexes are known to regulate nucleosome occupancy, the role of DNA sequence in this regulation remains unclear, particularly in mammals. To address this problem, we measured nucleosome distribution at high temporal resolution in human cells at hundreds of genes during the reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV). We show that nucleosome redistribution peaks at 24 h post-KSHV reactivation and that the nucleosomal redistributions are widespread and transient. To clarify the role of DNA sequence in these nucleosomal redistributions, we compared the genes with altered nucleosome distribution to a sequence-based computer model and in vitro-assembled nucleosomes. We demonstrate that both the predicted model and the assembled nucleosome distributions are concordant with the majority of nucleosome redistributions at 24 h post-KSHV reactivation. We suggest a model in which loci are held in an unfavorable chromatin architecture and ''spring'' to a transient intermediate state directed by DNA sequence information. We propose that DNA sequence plays a more considerable role in the regulation of nucleosome positions than was previously appreciated. The surprising findings that nucleosome redistributions are widespread, transient, and DNA-directed shift the current perspective regarding regulation of nucleosome distribution in humans.
Peripheral blood telomere length has been associated with age-related conditions including Alzheimer’s disease (AD). This suggests that telomere length may identify subjects at increased risk of AD. Thus, we investigated the associations of peripheral blood telomere length with amnestic mild cognitive impairment (aMCI), a putative precursor of AD, among Mayo Clinic Study of Aging participants who were prospectively followed for incident aMCI. We matched 137 incident aMCI cases (mean age 81.1 years, [range 70.9–90.8]; 49.6% men) by age and sex to 137 cognitively normal controls. We measured telomere length (T/S ratio) at baseline and follow-up using quantitative PCR. Compared to the middle T/S quintile (Q3), the risk of aMCI was elevated for subjects with the shortest (Q1: HR, 2.85, 95% Confidence interval [CI] 0.98, 8.25; p = 0.05) and the longest telomere lengths (Q5: HR, 5.58, 95%CI, 2.21, 14.11; p = 0.0003). In this elderly cohort, short and long telomeres were associated with increased risk of aMCI. Our findings suggest that both long and short telomere lengths may play a role in the pathogenesis of aMCI, and may be markers of increased risk of aMCI.
The majority of colorectal cancer (CRC) arises from precursor lesions known as polyps. The molecular determinants that distinguish benign from malignant polyps remain unclear. To molecularly characterize polyps, we utilized Cancer Adjacent Polyp (CAP) and Cancer Free Polyp (CFP) patients. CAPs had tissues from the residual polyp of origin and contiguous cancer; CFPs had polyp tissues matched to CAPs based on polyp size, histology and dysplasia. To determine whether molecular features distinguish CAPs and CFPs, we conducted Whole Genome Sequencing, RNA-seq, and RRBS on over 90 tissues from 31 patients. CAPs had significantly more mutations, altered expression and hypermethylation compared to CFPs. APC was significantly mutated in both polyp groups, but mutations in TP53, FBXW7, PIK3CA, KIAA1804 and SMAD2 were exclusive to CAPs. We found significant expression changes between CAPs and CFPs in GREM1, IGF2, CTGF, and PLAU, and both expression and methylation alterations in FES and HES1. Integrative analyses revealed 124 genes with alterations in at least two platforms, and ERBB3 and E2F8 showed aberrations specific to CAPs across all platforms. These findings provide a resource of molecular distinctions between polyps with and without cancer, which have the potential to enhance the diagnosis, risk assessment and management of polyps.
Background We studied the role of peripheral Neutrophil to Lymphocyte Ratio (NLR) on survival outcomes in colon and rectal cancer to determine if its inclusion improved prognostication within existing staging systems. Patients and Methods Disease free and overall survival (DFS and OS) Hazard Ratios (HR) of pretreatment NLR were calculated for 2536 stage I-III colon or rectal cancer patients and adjusted for age, positive/total number of nodes, T stage, and grade. The association of NLR with clinicopathologic features and survival was evaluated and compared to American Joint Committee on cancer (AJCC) TNM staging and Memorial Sloan Kettering Cancer Center (MSKCC) models. Results High NLR was significantly associated with worse DFS (HR: 1.36 [95% CI 1.08–1.70] p: 0.009) and OS (HR: 1.65 [95%CI 1.29–2.10] p<0.0005) in all stages for colon, but not rectal cancer patients. High NLR was significantly associated with site-specific worse prognosis which was stronger in the left vs right colon; an inverse relationship with grade was found. The impact of high NLR on DFS and OS occurred early with the majority of deaths within 2 years following surgery. Adjusted HRs for 5-year and 2-year outcomes in colon cancer per each additional 2-unit increase in NLR were 1.15 (95% CI 1.08–1.23) and 1.20 (95% CI 1.10–1.30), respectively. Addition of NLR enhanced prognostic utility of TNM (TNM alone vs. TNM + NLR: C-index 0. 60 vs. 0.68), and MSKCC (MSKCC alone vs MSKCC + NLR: C-index 0.71 vs. 0.73) models for colon cancer patients. Conclusion NLR is an independent prognostic variable for non-metastatic colon cancer that enhances existing clinical staging systems.
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