The Interplay among Wnt/β-catenin Family Members in Colorectal Adenomas and Surrounding Tissues.

Background: The colorectal adenoma undergoes neoplastic progression via the normal epithelium-adenoma-adenocarcinoma sequence as reported in the Vogelgram. The hazard of developing a tumor is deeply associated with the number and size of adenomas and their subtype. Adenomatous polyps are histologically categorized as follows: approximately 80-90% are tubular, 5-15% are villous, and 5-10% are tubular/villous.

let-7e downregulation characterizes early phase colonic adenoma in APCMin/+ mice and human FAP subjects.

The crypt-villus axis represents the essential unit of the small intestine, which integrity and functions are fundamental to assure tissue and whole-body homeostasis. Disruption of pathways regulating the fine balance between proliferation and differentiation results in diseases development. Nowadays, it is well established that microRNAs (miRNAs) play a crucial role in the homeostasis maintenance and perturbation of their levels may promote tumor development.

Gastric and duodenal polyps in familial adenomatous polyposis patients: Conventional endoscopy virtual chromoendoscopy (fujinon intelligent color enhancement) in dysplasia evaluation.

Aim: To test the fujinon intelligent color enhancement (FICE) in identifying dysplastic or adenomatous polyps in familial adenomatous polyposis (FAP) patients.

Methods: Seventy-six consecutive FAP patients, already treated by colectomy and members of sixty-five families, were enrolled. A FICE system for the upper gastro-intestinal tract with an electronic endoscope system and a standard duodenoscope (for side-viewing examination) were used by two expert examiners.

Correlation between mutations and mRNA expression of APC and MUTYH genes: new insight into hereditary colorectal polyposis predisposition.

Background: Transcript dosage imbalance may influence the transcriptome. To gain insight into the role of altered gene expression in hereditary colorectal polyposis predisposition, in the present study we analyzed absolute and allele-specific expression (ASE) of adenomatous polyposis coli (APC) and mutY Homolog (MUTYH) genes.

Methods: We analyzed DNA and RNA extracted from peripheral blood mononuclear cells (PBMC) of 49 familial polyposis patients and 42 healthy blood donors selected according similar gender and age.

The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.

Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R.

Ileal pouch adenomas and carcinomas after restorative proctocolectomy for familial adenomatous polyposis.

Background: Restorative proctocolectomy and IPAA has become the treatment of choice in familial adenomatous polyposis. However, several cases of adenomas and carcinomas arising in the ileal pouch were reported.

Objective: The aim of this study was to evaluate the prevalence and natural history of ileal pouch adenomas and the development of carcinomas in patients with restorative proctocolectomy for familial adenomatous polyposis.

High resolution melting analysis for a rapid identification of heterozygous and homozygous sequence changes in the MUTYH gene.

Background: MUTYH-associated polyposis (MAP) is an autosomal recessive form of intestinal polyposis predisposing to colorectal carcinoma. High resolution melting analysis (HRMA) is a mutation scanning method that allows detection of heterozygous sequence changes with high sensitivity, whereas homozygosity for a nucleotide change may not lead to significant curve shape or melting temperature changes compared to homozygous wild-type samples. Therefore, HRMA has been mainly applied to the detection of mutations associated with autosomal dominant or X-linked disorders, while applications to autosomal recessive conditions are less common.

Thymidylate synthase expression and genotype have no major impact on the clinical outcome of colorectal cancer patients treated with 5-fluorouracil.

Background And Objectives: Thymidylate synthase (TS) expression levels appear to be related to response to 5-fluorouracil-(5-FU)-based chemotherapy in colorectal cancer (CRC) patients. Three polymorphisms have been proposed as modulators of TS expression: a tandemly repeated sequence (2R/3R) in the 5' UTR, a SNP (G>C) within the 3R allele and a 6bp deletion in the 3' UTR. To evaluate the influence of TS expression and polymorphisms on clinical outcome of 5-FU-treated patients we performed a comprehensive genetic analysis on 63 CRC patients.

The use of COLD-PCR and high-resolution melting analysis improves the limit of detection of KRAS and BRAF mutations in colorectal cancer.

Fast and reliable tests to detect mutations in human cancers are required to better define clinical samples and orient targeted therapies. KRAS mutations occur in 30-50% of colorectal cancers (CRCs) and represent a marker of clinical resistance to cetuximab therapy. In addition, the BRAF V600E is mutated in about 10% of CRCs, and the development of a specific inhibitor of mutant BRAF kinase has prompted a growing interest in BRAF (V600E) detection.

Identification of potential pharmacogenomic markers of clinical efficacy of 5-fluorouracil in colorectal cancer.

Although adjuvant chemotherapy has significantly increased overall survival in resected Stage III colorectal cancer, disease recurrence is still high (30-40%). 20-25% of Stage II patients also develop recurrent disease. Thus, high-risk patients may benefit from chemotherapy.

The intestinal nuclear receptor signature with epithelial localization patterns and expression modulation in tumors.

Background & Aims: The WNT-adenomatous polyposis coli system controls cell fate in the intestinal epithelium, where compartment-specific genes tightly regulate proliferation, migration, and differentiation. Nuclear receptors are transcription factors functioning as sensors of hormones and nutrients that are known to contribute to colon cancer progression. Here we mapped the messenger RNA (mRNA) abundance and the epithelial localization of the entire nuclear receptor family in mouse and human intestine.

Expression and localisation of insulin receptor substrate 2 in normal intestine and colorectal tumours. Regulation by intestine-specific transcription factor CDX2.

Background And Aims: Self-renewal and differentiation of intestinal epithelium is a tightly regulated process, whose perturbations are implicated in human colorectal tumourigenesis. The insulin/insulin-like growth factor (IGF) signalling pathway may play an important role in intestinal epithelium homeostasis. Insulin receptor substrate 2 (IRS2) is a poorly characterised component in this pathway.

A proteomics approach to identify changes in protein profiles in serum of Familial Adenomatous Polyposis patients.

Familial adenomatous polyposis (FAP) is one of the most important clinical hereditary forms of inherited susceptibility to colorectal cancer and is characterized by a high degree of phenotypic heterogeneity. We used a mass spectrometry driven-proteomic strategy to identify serum molecules differently expressed in FAP patients. The data obtained were subsequently processed by bioinformatic analysis and confirmed by Western blotting.

High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer.

High-resolution melting analysis (HRMA) provides a valid approach to efficiently detect DNA genetic and somatic mutations. In this study, HRMA was used for the screening of 116 colorectal cancers (CRCs) to detect hot-spot mutations in the KRAS and BRAF oncogenes. Mutational hot spots on the PIK3CA gene, exons 9 and 20, were also screened.

Analysis of gene expression profiles reveals novel correlations with the clinical course of colorectal cancer.

In order to discover potential markers of prognosis in colorectal cancer (CRC) we have determined gene expression profiles, using cDNA microarrays in CRC samples obtained from 19 patients in Dukes stages C and D, with favorable clinical course (Dukes C patients, survival >5 years after surgery, group A, n=7) or unfavorable clinical course (Dukes stage C and D patients, survival <5 years after surgery, group B, n=12). Gene expression was measured in RNA from each tumor, using a pool of equal amounts of RNA from all tumors as a reference. To identify and rank differentially expressed genes we used three different analytical methods: (i) Significance Analysis of Microarrays (SAM), (ii) Cox's Proportional Hazard Model, and (iii) Trend Filter (a mathematical method for the assessment of numerical trends).

Balance between endoscopic and genetic information in the choice of ileorectal anastomosis for familial adenomatous polyposis.

Background And Objectives: The number of rectal polyps and the site of mutations in the APC (Adenomatous polyposis coli) gene have been used to guide the surgical management in patients with familial adenomatous polyposis (FAP). The aim of this study is to assess the utility of the APC mutation screening compared to the degree of the rectal polyposis in surgical decision making.

Methods: The post-surgical courses of 25 patients submitted to subtotal colectomy with ileorectal anastomosis (IRA) were reviewed.

Distribution of Tankyrase-1 mRNA expression in colon cancer and its prospective correlation with progression stage.

We tested Tankyrase-1 mRNA expression in colon cancer patients to evaluate the prognostic role of this parameter by real-time RT-PCR in a retrospective group of 82 unselected patients with colon cancer. Paired cancer and corresponding not affected tissues were used. Laser-assisted microdissection was used to measure Tankyrase-1 mRNA in homogeneous cancer cell populations and in normal colon epithelium of the same patients.

[Rectal cancer: locoregional recurrence in relation to surgical and complementary treatment].

Much recent data have been published on the risk of local recurrence (LR) following curative surgery for rectal cancer and the impact of adjuvant therapy. On the other hand, improvements in surgical techniques, as the total mesorectal excision, have apparently reduced the risk of LR. Furthermore, in selected cases, neoadjuvant therapy seems to reduce much more the incidence of LR.

Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancers.

Thymidylate synthase (TS) intratumoural expression may be a prognostic marker and predict outcome of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer patients. The TS gene promoter enhancer region contains two different polymorphisms which can influence TS mRNA transcriptional and translational efficiency: a polymorphic tandem repeat sequence (2 or 3 repeats; 2R and 3R) and a single nucleotide polymorphism (SNP), G > C, within the second repeat of the 3R alleles. We studied the relationship between tumoural TS mRNA expression levels and TS gene polymorphisms in the colonic mucosa of 48 colorectal cancer patients.

Prognostic value of somatostatin receptor subtype 2 expression in colorectal cancer.

The clinical relevance of the somatostatin receptor subtype 2 (sst2) is well defined in neuroendocrine tumors but it is still a matter of debate whether its expression may have a role also in other tumors not arising from the neuroectoderm. We investigated the prognostic value of the expression levels of sst2 mRNA in a consistent group of patients affected by colorectal cancer. Survival analysis of cancer-related death showed that patients with a high sst2 mRNA expression had an unfavourable outcome (p=0.

Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli.

The analysis of APC and MYH mutations in adenomatous polyposis coli patients should provide clues about the genetic heterogeneity of the syndrome in human populations. The entire coding region and intron-exon borders of the APC and MYH genes were analyzed in 60 unrelated Italian adenomatous polyposis coli patients. APC analysis revealed 26 point mutations leading to premature termination, one missense variant and one deletion spanning the entire coding region in 32 unrelated patients.