Impact of the faecal immunochemical test on colorectal cancer survival.

BACKGROUND: There is already evidence that the faecal immunochemical test (FIT) is a useful tool for the diagnosis of colorectal cancer (CRC) that helps to identify symptomatic patients requiring early colonoscopy. Although the recommendation to use FIT is widely accepted, there are no data concerning whether this strategy improves patient survival.The objective was to assess whether the survival is higher if CRC patients have been first diagnosed by FIT (as compared with the rest of patients with CRC). METHODS: We identified all cases of CRC diagnosed between 2009 and 2016 in Donostialdea (Spain), excluding all the CRC detected in population screening. We focused on symptomatic patients. One thousand five hundred twenty-seven cases of CRC were divided into two groups based on the route to diagnosis: group 1: individuals who tested positive in a FIT during the year before diagnosis, and group 2: others.Survival was assessed by Kaplan-Meier estimation, and with the log-rank test. A Cox regression model was used to adjust for differences between groups due to other variables associated with survival. RESULTS: One thousand nine hundred sixty-seven cases of invasive CRC were identified, of which 22.4% were detected in population screening. Of the 1527 cases diagnosed in symptomatic patients, 317 patients had undergone a FIT in the year before the diagnosis of CRC. In 279 cases(18.3%), the result had been positive and this was the first step towards their CRC diagnosis (group 1). Group 2 was composed of the 1248 cases of CRC (81.7%). Considering these cases, 1210 patients with CRC did not undergo any FIT while 38 patients presented a negative result in the year before the diagnosis. The rate of early-stage disease (stage I or II) was higher in group 1 (51.3% vs 45.5% in group 2) (p = 0.04). Furthermore, the 3-year survival was longer in group 1 (72% vs 59% in group 2) (HR 1.50; 95% CI 1.22-1.84).The variables independently associated with worse survival were: group 2, age > 70 years and stage at the moment of diagnosis. CONCLUSIONS: The use of FIT as a diagnostic strategy in symptomatic patients may improve survival in CRC. Nonetheless,FIT is still not widely used in our region

Value of Serum NEUROG1 Methylation for the Detection of Advanced Adenomas and Colorectal Cancer

Aberrant DNA methylation detected in liquid biopsies is a promising approach for colorectal cancer (CRC) detection, including premalignant advanced adenomas (AA). We evaluated the diagnostic capability of serum NEUROG1 methylation for the detection of AA and CRC. A CpG island in NEUROG1 promoter was assessed by bisulfite pyrosequencing in a case-control cohort to select optimal CpGs. Selected sites were evaluated through a nested methylation-specific qPCR custom assay in a screening cohort of 504 asymptomatic family-risk individuals. Individuals with no colorectal findings and benign pathologies showed low serum NEUROG1 methylation, similar to non-advanced adenomas. Contrarily, individuals bearing AA or CRC (advanced neoplasia-AN), exhibited increased NEUROG1 methylation. Using >1.3518% as NEUROG1 cut-off (90.60% specificity), 33.33% of AN and 32.08% of AA were identified, detecting 50% CRC cases. Nonetheless, the combination of NEUROG1 with fecal immunochemical test (FIT), together with age and gender through a multivariate logistic regression resulted in an AUC = 0.810 for AN, and 0.796 for AA, detecting all cancer cases and 35-47% AA (specificity 98-95%). The combination of NEUROG1 methylation with FIT, age and gender demonstrated a convenient performance for the detection of CRC and AA, providing a valuable tool for CRC screening programs in asymptomatic individuals

Increased Th17-Related Cytokine Serum Levels in Patients With Multiple Polyps of Unexplained Origin

OBJECTIVES: Most patients with multiple colonic polyps do not have a known genetic or hereditary origin. Our aim was to analyze the presence of inflammatory cytokines and levels of glucose, insulin, and C-reactive protein (CRP) in patients with multiple colonic polyps. METHODS: Eighty-three patients with 10 or more adenomatous or serrated polyps and 53 control people with normal colonoscopy were included. Smoking habits were registered, and glucose, CRP, and basal insulin in the serum/blood were measured. Quantification of IL-2, IL-4, IL-6, IL-10, IL-11, IL-17A, and IL-23 cytokine levels in the serum was performed by a high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Smoking and diabetes were more prevalent in those with colonic polyps than in the control people (67% vs 16%, P = 0.001; 11% vs 2%, P = 0.048). In addition, the cytokine serum levels were higher, i.e., IL-2 (P = 0.001), IL-4 (P = 0.001), IL-6 (P = 0.001), IL-17A (P = 0.001), IL-23 (P = 0.014), and CRP (P = 0.003). Adjusting for sex, smoking, and diabetes in a multivariate analysis, IL-2, IL-4, IL-6, IL-17A, and IL-23 remained independently elevated in cases with multiple polyps. DISCUSSION: These results indicate that immune responses mediated by Th17 cells may be involved in the pathogenesis of multiple colonic polyps

Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer

Colorectal cancer (CRC) shows aggregation in some families but no alterations in the known hereditary CRC genes. We aimed to identify new candidate genes which are potentially involved in germline predisposition to familial CRC. An integrated analysis of germline and tumor whole-exome sequencing data was performed in 18 unrelated CRC families. Deleterious single nucleotide variants (SNV), short insertions and deletions (indels), copy number variants (CNVs) and loss of heterozygosity (LOH) were assessed as candidates for first germline or second somatic hits. Candidate tumor suppressor genes were selected when alterations were detected in both germline and somatic DNA, fulfilling Knudson's two-hit hypothesis. Somatic mutational profiling and signature analysis were also performed. A series of germline-somatic variant pairs were detected. In all cases, the first hit was presented as a rare SNV/indel, whereas the second hit was either a different SNV (3 genes) or LOH affecting the same gene (141 genes). BRCA2, BLM, ERCC2, RECQL, REV3L and RIF1 were among the most promising candidate genes for germline CRC predisposition. The identification of new candidate genes involved in familial CRC could be achieved by our integrated analysis. Further functional studies and replication in additional cohorts are required to confirm the selected candidates