Erratum: Author Correction: High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia.

[This corrects the article DOI: 10.1038/s41522-017-0040-3.].

High-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia.

Colorectal cancer (CRC) remains the third most common cancer worldwide, with a growing incidence among young adults. Multiple studies have presented associations between the gut microbiome and CRC, suggesting a link with cancer risk. Although CRC microbiome studies continue to profile larger patient cohorts with increasingly economical and rapid DNA sequencing platforms, few common associations with CRC have been identified, in part due to limitations in taxonomic resolution and differences in analysis methodologies. Complementing these taxonomic studies is the newly recognized phenomenon that bacterial organization into biofilm structures in the mucus layer of the gut is a consistent feature of right-sided (proximal), but not left-sided (distal) colorectal cancer. In the present study, we performed 16S rRNA gene amplicon sequencing and biofilm quantification in a new cohort of patients from Malaysia, followed by a meta-analysis of eleven additional publicly available data sets on stool and tissue-based CRC microbiota using Resphera Insight, a high-resolution analytical tool for species-level characterization. Results from the Malaysian cohort and the expanded meta-analysis confirm that CRC tissues are enriched for invasive biofilms (particularly on right-sided tumors), a symbiont with capacity for tumorigenesis (Bacteroides fragilis), and oral pathogens including Fusobacterium nucleatum, Parvimonas micra, and Peptostreptococcus stomatis. Considered in aggregate, species from the Human Oral Microbiome Database are highly enriched in CRC. Although no detected microbial feature was universally present, their substantial overlap and combined prevalence supports a role for the gut microbiota in a significant percentage (>80%) of CRC cases.

Lack of correlation between X-ray repair cross-complementing group 1 gene polymorphisms and the susceptibility to colorectal cancer in a Malaysian cohort.

X-ray repair cross-complementing group 1 (XRCC1) is one of the key components in the base excision repair pathway that repairs erroneous DNA lesions and removes nonbulky base adducts for the maintenance of genome integrity. Studies have revealed that differences in individual DNA repair capacity can impact the interindividual variation in cancer susceptibility, tumour aggressiveness and treatment response. The relationship between XRCC1 and sporadic colorectal cancer (CRC) susceptibility, which is hitherto inconclusive, has been explored in many association studies of different populations. In view of the conflicting findings generated, we aimed to investigate the association between XRCC1 and genetic predisposition to CRC among Malaysians. The present case-control association study was conducted on 130 CRC patients and 212 age-matched healthy controls. The genotyping of XRCC1 Arg194Trp, Arg280His and Arg399Gln single nucleotide polymorphisms was performed with allele-specific real-time PCR approach. This was followed by basic statistical analysis on the single nucleotide polymorphisms and haplotype data obtained. No significant difference in the allele and genotype frequencies was observed between CRC patients and healthy controls (P>0.05). There was also no association observed between XRCC1 haplotypes and CRC (P>0.05). In conclusion, a positive association between XRCC1 gene polymorphisms and CRC risk was not established in our Malaysian population.

Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis.

IL17-producing Th17 cells, generated through a STAT3-dependent mechanism, have been shown to promote carcinogenesis in many systems, including microbe-driven colon cancer. Additional sources of IL17, such as γδ T cells, become available under inflammatory conditions, but their contributions to cancer development are unclear. In this study, we modeled Th17-driven colon tumorigenesis by colonizing Min(Ap) (c+/-) mice with the human gut bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to investigate the link between inflammation and colorectal cancer. We found that ablating Th17 cells by knocking out Stat3 in CD4(+) T cells delayed tumorigenesis, but failed to suppress the eventual formation of colonic tumors. However, IL17 blockade significantly attenuated tumor formation, indicating a critical requirement for IL17 in tumorigenesis, but from a source other than Th17 cells. Notably, genetic ablation of γδ T cells in ETBF-colonized Th17-deficient Min mice prevented the late emergence of colonic tumors. Taken together, these findings support a redundant role for adaptive Th17 cell- and innate γδT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources. Cancer Res; 76(8); 2115-24. ©2016 AACR.

Microbiota organization is a distinct feature of proximal colorectal cancers.

Environmental factors clearly affect colorectal cancer (CRC) incidence, but the mechanisms through which these factors function are unknown. One prime candidate is an altered colonic microbiota. Here we show that the mucosal microbiota organization is a critical factor associated with a subset of CRC. We identified invasive polymicrobial bacterial biofilms (bacterial aggregates), structures previously associated with nonmalignant intestinal pathology, nearly universally (89%) on right-sided tumors (13 of 15 CRCs, 4 of 4 adenomas) but on only 12% of left-sided tumors (2 of 15 CRCs, 0 of 2 adenomas). Surprisingly, patients with biofilm-positive tumors, whether cancers or adenomas, all had biofilms on their tumor-free mucosa far distant from their tumors. Bacterial biofilms were associated with diminished colonic epithelial cell E-cadherin and enhanced epithelial cell IL-6 and Stat3 activation, as well as increased crypt epithelial cell proliferation in normal colon mucosa. High-throughput sequencing revealed no consistent bacterial genus associated with tumors, regardless of biofilm status. However, principal coordinates analysis revealed that biofilm communities on paired normal mucosa, distant from the tumor itself, cluster with tumor microbiomes as opposed to biofilm-negative normal mucosa bacterial communities also from the tumor host. Colon mucosal biofilm detection may predict increased risk for development of sporadic CRC.

Development of a risk score to stratify symptomatic adults referred for colonoscopy.

BACKGROUND AND AIM: With an increasing burden on overstretched colonoscopy services, a simple risk score for significant pathology in symptomatic patients may aid in the prioritization of patients. METHODS: A derivative study of a risk score model for colonic neoplasia (colorectal carcinoma [CRC] and advanced adenoma) and CRC alone was conducted in symptomatic adults referred for an index colonoscopy. The accuracy of the final model was assessed by the area under the curve (AUC) of the receiver operating characteristic curve and the Hosmer-Lemeshow goodness-of-fit statistic. RESULTS: A total of 1013 subjects (mean age 59.9 ± 13.7 years, 52.3% females) from a multi-ethnic Asian background (Chinese 56%, Malay 20.4%, Indian 21.5%) were recruited. Colonic neoplasia and CRC were identified in 175 (17.3%) and 114 (11.3%) cases, respectively. Risk scores were assigned to individual factors identified in a logistic regression model of both demographic (age, gender, ethnicity, education level, smoking history, Aspirin use) and clinical symptoms (change in bowel habit, bloody stool, weight loss, appetite loss, lethargy). The risk score for each patient was the sum of their individual risk factors. The AUC of the risk score for colonic neoplasia and CRC was 0.76 (Hosmer-Lemeshow goodness-of-fit statistic of P = 0.745) and 0.83 (Hosmer-Lemeshow goodness-of-fit statistic of P = 0.982), respectively. CONCLUSION: A simple risk score for colonic neoplasia and CRC may be able to prioritize colonoscopy referrals in symptomatic subjects from a multi-ethnic background. A further study to validate this scoring system is required.

Prevalence of faecal incontinence and its related factors among patients in a Malaysian academic setting.

BACKGROUND: Prevalence data is essential for planning of healthcare services. The prevalence of faecal incontinence (FI) varies worldwide, and in Malaysia is not known. We sought to estimate its prevalence among patients with various conditions in a Malaysian academic setting. METHOD: A questionnaire-based survey was conducted among a convenience sample of adult patients and relatives who visited the Obstetrics and Gynaecology and General Surgery Clinics of University of Malaya Medical Centre (UMMC) from June 2009 to February 2010. Data collected included patient demographics and pre-existing medical conditions known to be FI risk factors. Severity of FI was assessed using the Wexner Continence Scale (WCS). RESULTS: Among the 1000 subjects recruited into the study, 760 (76%) were female and the median age was 38 years with an inter-quartile range of 24 years. The prevalence of FI among the study subjects was found to be 8.3%. Among them, 63 subjects (75.9%) were determined to have mild FI as measured by the WCS. The proportions of patients with moderate and severe FI were 18.3% and 6.0%, respectively. FI was found to be significantly associated with older age, presence of diabetes mellitus and increased duration of defaecation. There was no statistically significant association between FI and sex, defaecation frequency, or history of surgery. CONCLUSION: FI in our setting is prevalent enough to warrant targeted healthcare interventions, including the need to improve general public awareness of the condition in order to counter social stigma and embarrassment that may be faced by patients.

Is laparoscopic colectomy as cost beneficial as open colectomy?

BACKGROUND: Laparoscopic colectomy has yet to gain widespread acceptance in cost-conscious health-care institutions. The aim of the present study was to define the cost-benefit relationship of laparoscopic versus open colectomy. METHODS: Thirty-two consecutive patients undergoing elective laparoscopic colectomy (LC) by a single colorectal surgeon between August 2004 and September 2005 were reviewed. Cases were matched with a historical cohort undergoing elective open colectomy (OC) between June 2003 and July 2004. Demography, perioperative data, histopathology and cost were compared. RESULTS: Both groups had similar demographics. Most resections (90.6%) were for cancer. Operative time was significantly longer for LC compared to OC (180 min vs 110 min, P < 0.001). Four patients (12.5%) in the LC group required conversion. LC patients, however, had lower median pain scores (3, 2 and 1 vs 6, 4 and 2 at 24, 48 and 72 h postoperatively, P < 0.001), faster resolution of ileus (3 vs 4 days, P < 0.001) and earlier discharge (6 vs 9 days, P < 0.001) compared to the OC group. As a result, overall hospital cost for both procedures was not significantly different (US$7943 vs US$7253, P = 0.41). CONCLUSION: Laparoscopic colectomy is as cost-beneficial in the short term as open colectomy.