Association Between Bacteremia From Specific Microbes and Subsequent Diagnosis of Colorectal Cancer.

BACKGROUND & AIMS: Colorectal cancer (CRC) development has been associated with increased proportions of Bacteroides fragilis and certain Streptococcus, Fusobacterium, and Peptostreptococcus species in the intestinal microbiota. We investigated associations between bacteremia from specific intestinal microbes and occurrence of CRC. METHODS: We performed a retrospective study after collecting data on 13,096 adult patients (exposed group) in Hong Kong hospitalized with bacteremia (identified by blood culture test) without a previous diagnosis of cancer from January 1, 2006 through December 31, 2015. We collected data on intestinal microbes previously associated with CRC (genera Bacteroides, Clostridium, Filifactor, Fusobacterium, Gemella, Granulicatella, Parvimonas, Peptostreptococcus, Prevotella, Solobacterium, and Streptococcus). Clinical information, including patient demographics, comorbid medical conditions, date of bacteremia, and bacterial species identified, were collected. The incidence of biopsy-proved CRC was compared between the exposed and unexposed (patients without bacteremia matched for age, sex, and comorbidities) groups. RESULTS: The risk of CRC was increased in patients with bacteremia from B fragilis (hazard ratio [HR] = 3.85, 95% CI = 2.62-5.64, P = 5.5 × 10-12) or Streptococcus gallolyticus (HR = 5.73, 95% CI = 2.18-15.1, P = 4.1 × 10-4) compared with the unexposed group. In addition, the risk of CRC was increased in patients with bacteremia from Fusobacterium nucleatum (HR = 6.89, 95% CI = 1.70-27.9, P = .007), Peptostreptococcus species (HR = 3.06, 95% CI = 1.47-6.35, P = .003), Clostridium septicum (HR = 17.1, 95% CI = 1.82-160, P = .013), Clostridium perfringens (HR = 2.29, 95% CI = 1.16-4.52, P = .017), or Gemella morbillorum (HR = 15.2, 95% CI = 1.54-150, P = .020). We observed no increased risk in patients with bacteremia caused by microbes not previously associated with colorectal neoplasms. CONCLUSIONS: In a retrospective analysis of patients hospitalized for bacteremia, we associated later diagnosis of CRC with B fragilis and S gallolyticus and other intestinal microbes. These bacteria might have entered the bloodstream from intestinal dysbiosis and perturbed barrier function. These findings support a model in which specific members of the intestinal microbiota promote colorectal carcinogenesis. Clinicians should evaluate patients with bacteremia from these species for neoplastic lesions in the colorectum.

Quantitation of faecal Fusobacterium improves faecal immunochemical test in detecting advanced colorectal neoplasia.

OBJECTIVE: There is a need for an improved biomarker for colorectal cancer (CRC) and advanced adenoma. We evaluated faecal microbial markers for clinical use in detecting CRC and advanced adenoma. DESIGN: We measured relative abundance of Fusobacterium nucleatum (Fn), Peptostreptococcus anaerobius (Pa) and Parvimonas micra (Pm) by quantitative PCR in 309 subjects, including 104 patients with CRC, 103 patients with advanced adenoma and 102 controls. We evaluated the diagnostic performance of these biomarkers with respect to faecal immunochemical test (FIT), and validated the results in an independent cohort of 181 subjects. RESULTS: The abundance was higher for all three individual markers in patients with CRC than controls (p<0.001), and for marker Fn in patients with advanced adenoma than controls (p=0.022). The marker Fn, when combined with FIT, showed superior sensitivity (92.3% vs 73.1%, p<0.001) and area under the receiver-operating characteristic curve (AUC) (0.95 vs 0.86, p<0.001) than stand-alone FIT in detecting CRC in the same patient cohort. This combined test also increased the sensitivity (38.6% vs 15.5%, p<0.001) and AUC (0.65 vs 0.57, p=0.007) for detecting advanced adenoma. The performance gain for both CRC and advanced adenoma was confirmed in the validation cohort (p=0.0014 and p=0.031, respectively). CONCLUSIONS: This study identified marker Fn as a valuable marker to improve diagnostic performance of FIT, providing a complementary role to detect lesions missed by FIT alone. This simple approach may improve the clinical utility of the current FIT, and takes one step further towards a non-invasive, potentially more accurate and affordable diagnosis of advanced colorectal neoplasia.

PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling.

Although expression quantitative trait locus, eQTL, serves as an explicit indicator of gene-gene associations, challenges remain to disentangle the mechanisms by which genetic variations alter gene expression. Here we combined eQTL and molecular analyses to identify an association between two seemingly non-associated genes in brain expression data from BXD inbred mice, namely Ptpn21 and Nrg3. Using biotinylated receptor tracking and immunoprecipitation analyses, we determined that PTPN21 de-phosphorylates the upstream receptor tyrosine kinase ErbB4 leading to the up-regulation of its downstream signaling. Conversely, kinase-dead ErbB4 (K751R) or phosphatase-dead PTPN21 (C1108S) mutants impede PTPN21-dependent signaling. Furthermore, PTPN21 also induced Elk-1 activation in embryonic cortical neurons and a novel Elk-1 binding motif was identified in a region located 1919bp upstream of the NRG3 initiation codon. This enables PTPN21 to promote NRG3 expression through Elk-1, which provides a biochemical mechanism for the PTPN21-NRG3 association identified by eQTL. Biologically, PTPN21 positively influences cortical neuronal survival and, similar to Elk-1, it also enhances neuritic length. Our combined approaches show for the first time, a link between NRG3 and PTPN21 within a signaling cascade. This may explain why these two seemingly unrelated genes have previously been identified as risk genes for schizophrenia.