Rectal Colorectal Cancer Research Articles

Gut mucosal microbiota profiles linked to development of positional-specific human colorectal cancer

<p>Colorectal cancer (CRC) continuously ranks as the third most common cause of cancer-related deaths worldwide. Based on anatomical classifications and clinical diagnoses, CRC is classified into right-sided, left-sided, and rectal CRC. Importantly, the three types of positional-specific CRC affect the prognosis outcomes, thus indicating that positional-specific treatments for CRC are required. Emerging evidence suggests that besides host genetic and epigenetic alterations, gut mucosal microbiota is linked to gut inflammation, CRC occurrence, and prognoses. However, gut mucosal microbiota associated with positional-specific CRC are poorly investigated. Here, we report the gut mucosal microbiota profiles associated with these three types of CRC. Our analysis showed that the unique composition and biodiversity of bacterial taxa are linked to positional-specific CRC. We found that a combination of bacterial taxa can serve as potential biomarkers to distinguish the three types of CRC. Further investigations of the physiological roles of bacteria associated with positional-specific CRC may help understand the mechanism of CRC progression in different anatomical locations under the impact of gut mucosal microbiota.</p>

Mucinous and Signet-Ring Cell Colonic Adenocarcinoma in Inflammatory Bowel Disease: A Case-Control Study.

A higher frequency of mucinous and signet-ring cell colonic adenocarcinoma has been reported in inflammatory bowel disease (IBD). The primary aim was to investigate the frequency of mucinous and signet-ring cell colorectal adenocarcinoma in patients with IBD (Cases) versus age-matched non-IBD Controls. The secondary aims were to compare the characteristics of these two histotypes of colorectal cancer (CRC) in IBD patients vs. Controls and to search for specific risk factors in IBD. In a case-control study, all IBD patients with CRC diagnosed from 2000 to 2022 were enrolled and matched for age (1:2) with non-IBD Controls with CRC. The study population included 120 CRC patients (40 IBD, 80 Controls). In IBD, CRC included standard adenocarcinoma in 23 (57.5%) patients mucinous/signet-ring cell adenocarcinoma in 17 (42.5%) patients. The proportion of mucinous/signet-ring cell adenocarcinoma was higher in IBD than in Controls (17 [42.5%] vs. 18 [22.5%]; p = 0.03). In rectal CRC, the proportion of mucinous/signet-ring cell adenocarcinoma was higher than standard adenocarcinoma in IBD (8 [47.1%] vs. 4 [17.4%]; p = 0.04) but not in Controls (4 [22.2%] vs. 20 [32.2%]; p = 0.59). In rectal CRC, the proportion of these two histotypes was higher in Cases than in Controls (8/12 [66.6%] vs. 4/24 [16.6%]; p = 0.008), with no risk factors identified in IBD. CRC was more frequently represented by mucinous/signet-ring cell adenocarcinoma in IBD than in age-matched non-IBD Controls. In IBD, these two CRC histotypes were more frequent in the rectum.

Faecal haemoglobin concentrations in women and men diagnosed with colorectal cancer in a national screening programme

ObjectiveThere is evidence that colorectal cancer screening using faecal haemoglobin is less effective in women than men. The faecal haemoglobin concentrations were therefore examined in women and men with screen-detected colorectal cancer.SettingScottish Bowel Screening Programme, following the introduction of a faecal immunochemical test from November 2017, to March 2020.MethodsData were collated on faecal haemoglobin concentrations, pathological stage and anatomical site of the main lesion in participants who had colorectal cancer detected. The data in women and men were compared.ResultsFor the faecal haemoglobin concentrations studied (>80 µg Hb/g faeces), the distributions indicated lower concentrations in women. Marked differences were found between women and men diagnosed with colorectal cancer. The median faecal haemoglobin concentration for women (n = 720) was 408 µg Hb/g faeces compared to 473 µg Hb/g faeces for men (n = 959) (p = 0.004) and 50.6% of the results were >400 µg Hb/g faeces in women; in men, this was 57.8%. The difference in faecal haemoglobin concentrations in women and men became less statistically significant as stage advanced from stages I–IV. For right-sided, left-sided and rectal colorectal cancer, a similar gender difference persisted in all sites. Differences in faecal haemoglobin between the genders were significant for left-sided cancers and stage I and approached significance for rectal cancers and stage II, but all sites and stages showed lower median faecal haemoglobin concentrations for women.ConclusionsTo minimise gender inequalities, faecal immunochemical test-based colorectal cancer screening programmes should evaluate a strategy of using different faecal haemoglobin concentration thresholds in women and men.

Survival of patients with resected primary colorectal mucinous adenocarcinoma: A competing risk nomogram analysis.

The aim of the present study was to use a competing risk model to analyze the prognostic value of mucinous adenocarcinoma (MAC) in patients with colorectal cancer (CRC). An additional aim was to construct nomograms for estimating the 3- and 5-year overall survival (OS) and cancer specific survival (CSS) rates of patients with primary CRC with MAC. The data were extracted from the Surveillance, Epidemiology, and End Results database, and a Multivariate Cox model and competing risk model were applied to assess the OS and CSS. Cox-based and competing risk-based nomograms were constructed and internally validated by discrimination and calibration, using the bootstrapping method with 1,000 times replicates. A total of 13,035 MAC and 61,958 non-mucinous adenocarcinoma (NMAC) CRC patients were enrolled in the present study. Compared with NMAC, MAC patients had a poorer OS and CSS time in the overall population, and in subgroups that comprised metastatic, non-metastatic, male, site of sigmoid colon, rectosigmoid junction and rectal CRC cases (HR>1; P<0.05). The Cox and competing risk-based nomograms showed effective discrimination and calibration. In conclusion, MAC was associated with poor OS and CSS in patients with CRC of the distal colon and rectum. The nomograms of primary CRC patients with MAC may aid the identification of individual patients with a high risk of overall mortality and cancer-associated mortality within 3 or 5 years.

Epidemiology of Colorectal Cancer in Average Risk Adults 20-39Years of Age: A Population-Based National Study.

While overall rates of colorectal cancer (CRC) have declined in individuals aged above 50years of age, this decline has not been seen in younger individuals who do not benefit from current screening guidelines. We sought to describe the prevalence of CRC in adults 20-39years of age without family history of CRC or inflammatory bowel disease as early-onset CRC (EoCRC), evaluate associated signs and symptoms and medical comorbidities in EoCRC, and compare them with individuals aged 20-39years without CRC (NoCRC). Our secondary aim was to compare EoCRC with individuals aged 40years and above with CRC (LoCRC). Utilizing a commercial database (Explorys Inc, Cleveland, OH), we identified a cohort of patients aged 20-39years with first ever diagnosis of CRC between 2013 and 2018 based on the Systematized Nomenclature of Medicine-Clinical Terms. We calculated the overall prevalence rate of EoCRC, described age, race, and gender-based prevalence rates of EoCRC, and identified associated symptoms and medical comorbidities associated with EoCRC. The overall rate of EoCRC was 18.9/100,000. Compared to NoCRC, EoCRC patients were more likely to be Caucasian and female, with predominant symptoms of hematochezia, anemia, and decreased appetite. EoCRC group had higher prevalence rates of medical comorbidities such as diabetes, smoking, and obesity. Compared to LoCRC, EoCRC group presented more frequently with left-sided CRC and rectal cancers. This is one of the largest studies to date to describe the epidemiology of EoCRC in USA. We found EoCRC to occur predominantly in the Caucasian and female population. EoCRC presented more frequently with left-sided and rectal CRC. We also identified signs/symptoms as well as comorbidities associated with EoCRC. Patients with these features may benefit from earlier screening.

Molecular profiling of patients (pts) with advanced colorectal cancer (CRC): Princess Margaret Cancer Centre experience.

459 Background: The prevalence of somatic mutations other than KRAS, PIK3CA and BRAF in CRC has not been well described. This study reports molecular profiling of pts with advanced CRC in clinical practice. Methods: Pts with advanced CRC are enrolled in an ongoing institution-wide screening program. Molecular profiling is performed on FFPE archival tissues using a customized Sequenom panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ≥ 500x coverage) in our CLIA-certified laboratory. PTEN negative tumor is defined by IHC with H score &lt;1. Demographic and clinical data are collected. Data was analyzed by chi-square test. Results: From March 2012 to August 2013, 132 pts were enrolled. One or more mutations were found in 50% (58/117) and 93%(14/15) of pts using Sequenom and MiSeq platforms respectively. Mutation rate was 40% for KRAS, 9% for PIK3CA, 2% for BRAF, 4% for NRAS, and 1% for each of CTNNB1, ERBB2, FGFR3, and EGFR. Mutations outside of codons 12/13 were found in 8% (4/53) of tumors with KRAS mutations. MiSeq showed additional mutations including ERBB4 (1/15), SMAD4 (1/15), FRXW7 (1/5), APC (5/15), and TP53 (12/15) in CRC. Co-mutation with KRAS was found in 58% (7/12) of pts with PIK3CA mutation and 80% (4/5) of pts with APC mutation. PTEN negative tumor was present in 20% (11/55) of pts. Presence of any mutation was significantly more common for pts with right-sided CRC (73%) compared to those with left-sided CRC (47%) and rectal CRC (38%) (p &lt; 0.01). There was a trend toward increased proportion of KRAS mutation in right-sided CRC (p=0.06). There was no difference in age, ethnicity, gender, smoking status, stage at presentation, pathology grade, and response to first-line chemotherapy between right and left-sided CRC. Conclusions: Somatic alterations are common in advanced CRC. Targeted next-generation DNA sequencing identifies additional clinically relevant alterations than multiplex genotyping. Differences in the mutation profile of right and left-sided CRC tumors should be further investigated. Updated results will be presented at the meeting.

Risk for colorectal cancer in elderly persons and possible methodologies for their screening

Most colorectal cancer (CRC) screening guidelines recommend average-risk screening up to the age of 75 years. However, increasing life span and incidence of proximal CRC could require changes to the age guidelines and adapting screening methodology for the elderly persons. Therefore, we reviewed our CRC epidemiology, international screening age-guidelines, and screening tests for the elderly persons and presented our long-term results of colonoscopy and semi-quantitated immunochemical fecal occult blood tests (I-FOBTs) in individuals that are 75 years or more. We examined the Israel National Cancer Registry (INCR) data to assess the risk of CRC in individuals aged 75 years or more. We re-examined files of patients aged 75 years or more, who underwent both colonoscopy and three I-FOBTs, and followed them through the INCR to identify new cases of CRC. Nationwide, during 2005 and 2007, 41.3% of all CRCs occurred in individuals aged 75 years or more. Both I-FOBT and colonoscopy were performed on 271 individuals (mean age: 78.5 years, standard deviation: 3.1). Both initial colonoscopy and I-FOBT of at least 50 ngHb/ml buffer in either of the first two tests identified six patients with CRC; INCR registered another stage 1 rectal CRC within 1 year. Therefore, the initial sensitivity to CRC of either test was 85.7% (95% confidence interval: 59.8 and 112), valid during a mean of 44.3 months and a standard deviation of 13.4 at INCR follow-up; 14 of 27 advanced adenomatous polyps were identified by I-FOBT, giving a sensitivity of 58.8% (95% confidence interval: 42.3 and 75.4) for CRC or advanced adenomatous polyps. Recently, 41.3% of our CRCs occurred in individuals aged 75 years or more, diagnosed clinically and not by screening. I-FOBT and initial colonoscopic CRC sensitivity were similar, both having false-negative results. Screening age guidelines need reconsideration; our initial results show that semi-quantitated I-FOBT screening is feasible but needs large-scale evaluation in 'healthy' elderly persons.

A Randomized Controlled Trial Comparing Participation and Diagnostic Yield in Colonoscopy and CT-Colonography for Population Based Colorectal Cancer Screening

Background: Semi-quantitative immunochemical fecal occult blood tests (I-FOBT) are increasingly used for colorectal cancer (CRC) screening. Their true performance characteristics have been determined clinically or sometimes by colonoscopy as “gold standard”. However, occasionally colonoscopy has false-negative results for CRC & Cancer Registry follow-up can provide information relevant to both tests. Aims: Evaluate true performance characteristics of both I-FOBT & colonoscopy examinations for detecting CRC & advanced adenomatous polyps (AAP). Methods: We reanalyzed a published file of ambulatory colonoscopy patients who also prepared 3 I-FOBTs processed by OC-MICRO automated instrument (Eiken, Tokyo, Japan) with ≥50ngHb/mL buffer in any test determining positivity (Rozen P, et al Cancer 2010). These patients were followed through the Israel National Cancer Registry (INCR) to identify newly diagnosed CRC. Analyses of sensitivities for CRC & AAP refer to results of I-FOBTs & initial colonoscopy. Results: 1630 persons performed both IFOBT & total colonoscopy, mean age 62.7 years, SD 11.9 & 50.1% males. They were followed through the INCR for mean 44.3 months SD13.4 & during this period 25 CRC patients were identified, 41% in the proximal colon & 86% were Stages 1 or 2. Follow-up Data Within 12 months both colonoscopy & I-FOBTs identified 21/22 CRCs, 2 initially classified as AAPs; neither test identified a Stage 1 rectal CRC. Between 12-24 months 2 more CRCs were diagnosed, both had elevated I-FOBTs & initially been identified as AAPs. Between 25-48 months a CRC was diagnosed after 47 months, it did not have elevated IFOBT & initially been identified as AAP. Analyses: At 1 year, sensitivity for CRC by both I-FOBT & initial colonoscopy was 95.5% (95%CI 86.8, 104) & at 24 months & 36 months it was 95.8% (95%CI 87.8, 104). Within 48 months sensitivity for CRC by I-FOBT was 92% (95%CI 81.4, 103) & 96% by colonoscopy. At 1 year 121 patients were identified as having AAPs, I-FOBT was positive in 70, & so had a sensitivity of 63.6% (95%CI 55.8, 71.5) for all significant neoplasms, CRC or AAP. At 24 months I-FOBT had a sensitivity of 63.2% (95%CI 55.8, 71.5) for all significant neoplasms. Conclusions: In this population, neither initial colonoscopy nor I-FOBTs identified all CRC patients. I-FOBTs examined at 50ngHb/mL buffer threshold identified almost all CRC diagnosed within 36 months. Colonoscopy identified most significant neoplasms, but only by clinical follow-up & repeated colonoscopy were AAPs reclassified correctly as CRCs. From this small but carefully documented study, it would be appropriate to repeat I-FOBTs after 1 year so as to identify any CRC missed initially by either test.

Deciphering the genetics of hereditary non-syndromic colorectal cancer

Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles.