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PubMed2002

An insight into the genetic pathway of adenocarcinoma of the small intestine.

BACKGROUND: Although the adenoma to carcinoma pathway in colorectal cancer is well described, the mechanisms of carcinogenesis in the small intestine remain unclear. AIMS: The aim of this study was to investigate candidate genes in the genetic pathway of adenocarcinoma of the small intestine. SUBJECTS AND METHODS: A total of 21 non-familial, non-ampullary adenocarcinomas of the small intestine were analysed. DNA was extracted from formalin fixed paraffin wax embedded tissue using standard techniques. The replication error (RER) status was determined by amplification of BAT26. The mutation cluster region (MCR) of the adenomatous polyposis coli (APC) gene was screened using polymerase chain reaction single strand conformational polymorphism and direct sequencing. Immunohistochemistry was performed on formalin fixed paraffin wax embedded tissue using monoclonal antibodies for hMLH1, hMSH2, beta-catenin, E-cadherin, and p53. RESULTS: Fourteen male and seven female patients with a median age of 64 years (range 21-85) presented with adenocarcinoma of the duodenum (10), jejunum (7), and ileum (4). One cancer (5%) was found to be RER+, and all tumours stained positive for hMLH1 and hMSH2. No mutations were detected in the MCR of the APC gene. beta-Catenin showed increased nuclear expression with loss of membranous staining in 10 cancers (48%). Absent or decreased membrane expression of E-cadherin was found in eight cancers (38%). Strong staining of p53 was found in the nucleus of five cancers (24%). CONCLUSION: We did not detect mutations in the MCR of the APC gene, and this suggests that adenocarcinoma of the small intestine may follow a different genetic pathway to colorectal cancer. Abnormal expression of E-cadherin and beta-catenin was common and reflects an early alternative to APC in this pathway in which mutations may be found in adenocarcinoma of the small intestine.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Distributions of substance P- and VIP-immunoreactive nerve fibres in the colonic circular muscle in children.

In children with severe chronic constipation, abnormal distribution of substance P (SP) and vasoactive intestinal peptide (VIP), which represent excitatory and inhibitory nerves, respectively, has been reported. The normal distribution of these neuropeptides, however, is not well known. The aim of this study was to determine the populations of SP- and VIP-immunoreactive nerve fibres in the circular muscle of the colon in children. Surgically resected specimens were collected from a 6-year-old girl with familial polyposis coli (total colon) and nine patients with anorectal malformations aged 0-4 years (sigmoid colon). Double-labelling immunofluorescence was employed using neuron-specific enolase (NSE) with SP and NSE with VIP to count the percentage of SP- or VIP-labelled nerve fibres. These specimens showed normal submucous and myenteric plexuses stained with NSE. The population of SP- immunoreactive fibres was 15%-21% throughout the colon, and VIP was 39% in the caecum and 63%-65% in the transverse, descending, and sigmoid colon. In the four neonatal specimens (day 1 to 4), the SP population was only 1%-6% and the VIP population was also low (22%-33%). After 3 weeks of age, the populations had stabilised at 18%-26% for SP and 52%-62% for VIP. SP-immunoreactive nerve fibres were scarce in the neonatal period, and showed a rapid increase by 3 weeks and a similar though less dramatic increase in VIP-immunoreactive fibres. VIP-immunoreactive fibres were fewer in the caecum that at other colonic levels, where they accounted for 60% of NSE-labelled fibres; the SP population, however, was comparable at all levels of the colon at about 20% of NSE-labelled fibres.

Adenomatous Polyposis Coli↗
PubMed2025

Development of a new flippase-dependent mouse model for red fluorescence-based isolation of KRASG12D oncogene-expressing tumor cells.

Proto-oncogene KRAS, GTPase (KRAS) is one of the most intensively studied oncogenes in cancer research. Although several mouse models allow for regulated expression of mutant KRAS, selective isolation and analysis of transforming or tumor cells that produce the KRAS oncogene remains a challenge. In our study, we present a knock-in model of oncogenic variant KRASG12D that enables the "activation" of KRASG12D expression together with production of red fluorescent protein tdTomato. Both proteins are expressed from the endogenous Kras locus after recombination of a transcriptional stop box in the genomic DNA by the enzyme flippase (Flp). We have demonstrated the functionality of the allele termed RedRas (abbreviated KrasRR) under in vitro conditions with mouse embryonic fibroblasts and organoids and in vivo in the lung and colon epithelium. After recombination with adenoviral vectors carrying the Flp gene, the KrasRR allele itself triggers formation of lung adenomas. In the colon epithelium, it causes the progression of adenomas that are triggered by the loss of tumor suppressor adenomatous polyposis coli (APC). Importantly, cells in which recombination has successfully occurred can be visualized and isolated using the fluorescence emitted by tdTomato. Furthermore, we show that KRASG12D production enables intestinal organoid growth independent of epidermal growth factor (EGF) signaling and that the KRASG12D function is effectively suppressed by specific inhibitor MRTX1133.

Animals↗
PubMed1999

LKB1 somatic mutations in sporadic tumors.

Germline mutations of LKB1/Peutz-Jeghers syndrome gene predispose carriers to hamartomatous polyposis of the gastrointestinal tract as well as to cancer of different organ systems. Although Peutz-Jeghers syndrome patients frequently present with neoplasms of the colon, stomach, small intestine, pancreas, breast, ovaries, and cervix, somatic mutations appear to be rare in the sporadic tumor types thus far studied (colorectal, gastric, testicular, and breast cancers). To evaluate whether somatic mutations of LKB1 contribute to the tumorigenesis of yet unstudied tumor types, we screened 14 cell lines and 129 tumor specimens from different cancers for a genetic defect in LKB1. Six melanoma and eight myeloma cell lines were scrutinized for LKB1 somatic mutations by genomic sequencing. No changes were found in the coding LKB1 sequence and exon/intron boundaries. Next, we analyzed 12 pancreatic, 8 gastric, 12 ovarian granulosa cell, 26 cervical, 28 lung, 24 soft tissue, and 19 renal tumors by single-strand conformational polymorphism analysis. Three changes in LKB1 coding nucleotide sequence were identified. One base pair deletion at A957 and G958 substitution by T occurred in a cervical adenocarcinoma sample, resulting in a frameshift and premature stop codon at position 335. Substitution of A581 by T occurred in a lung adenocarcinoma sample, resulting in the change of aspartic acid at position 194 to valine. A loss of another allele was detected in this sample. One silent change, C1257T, was found in a pancreatic carcinoma sample. The changes were not present in the matched normal tissue DNA samples. Our results suggest that mutational inactivation of LKB1 is a rare event in most sporadic tumor types.

AMP-Activated Protein Kinase Kinases↗
PubMed1998

Intramucosal carcinomas of the stomach: phenotypic expression and loss of heterozygosity at microsatellites linked to the APC gene.

Evaluation of the role of somatic genetic alterations in cancer development is best performed by examining small tumors in the earlier stages of carcinogenesis. We examined the relationship between allelic deletions of 4 microsatellites linked to the adenomatous polyposis coli (APC) gene and differential histogenetical phenotypes in 34 intramucosal carcinomas of the stomach, of which, structurally, 24 cases were the gland-forming type (so-called "intestinal type") and 10 were the diffuse type. Using mucin and immunohistochemical staining techniques specific for gastric- and intestinal-type mucins, the phenotype of each tumor was histogenetically classified as exclusively gastric, predominantly gastric, predominantly intestinal or exclusively intestinal. There was generally a free combination between structural types and phenotypic mucin expression. Allelic deletions were detected in 6 carcinomas of the exclusively intestinal phenotype. The incidence of allelic deletions was significantly higher in the predominantly and exclusively intestinal phenotypes (6/16, 37.5%) than in the predominantly and exclusively gastric phenotypes (0/18) (p = 0.0060, Fisher's test). Taking the high frequency of allelic deletions in 5q in invasive stomach carcinomas, the present study suggests that genetic alteration in this region is a very early event in stomach carcinomas with intestinal differentiation but a relatively late event in those with gastric differentiation.

Adenocarcinoma, Mucinous↗
PubMed2003

Adenomatous polyposis coli gene, beta-catenin, and E-cadherin expression in proximal and distal gastric cancers and precursor lesions: an immunohistochemical study using tissue microarrays.

The aims of this study were (1) to compare protein expression of adenomatous polyposis coli (APC) gene, beta-catenin, and E-cadherin between proximal and distal gastric adenocarcinomas and (2) to investigate their use as markers of cancer risk in intestinal metaplasia (IM). The epidemiology of proximal (cardia and gastroesophageal junction) and distal (antrum and corpus) gastric carcinomas is strikingly different despite similar morphologies. Carcinoma of the distal stomach is decreasing in incidence, whereas proximal carcinomas are increasing in incidence more than any other cancer in the Western world. This phenomenon has so far not been satisfactorily explained. IM is a well-established precursor for adenocarcinoma in the distal stomach but less so in the proximal stomach. However, its specificity as a predictor of gastric carcinoma is very low. Abnormalities of APC, beta-catenin, and E-cadherin are implicated in carcinogenesis of the stomach and may show aberrant expression at early stages of the neoplastic process. This study evaluated their immunoprofiles in 3 groups: biopsies showing normal mucosa (n = 108), biopsies showing IM (n = 99), and gastric cancer resections (n = 117). In the last group, carcinoma and noninvolved mucosa were studied. All groups included material from both proximal and distal locations. The results of this study showed that there were no differences between proximal and distal locations with regard to APC, beta-catenin, or E-cadherin expression. In both locations, high normal expression rates for all 3 molecules were present in biopsies showing normal gastric mucosa or IM and noninvolved mucosa from gastric cancer resections. In carcinomas, there was a significant decrease in both APC and E-cadherin expression, whereas beta-catenin showed abnormal cytoplasmic and nuclear staining. Diffuse-type cancers showed significantly lower E-cadherin expression than intestinal types. Noninvolved mucosa from cancer resections showed normal APC, beta-catenin, and E-cadherin expression regardless of adjacent tumor type and whether the mucosa was morphologically normal or showed IM. In conclusion, proximal and distal gastric carcinomas show no differences in expression of APC, beta-catenin, or E-cadherin; thus, the observed abnormalities do not seem to contribute to the observed epidemiologic differences between these tumors. Because loss of APC, decreased E-cadherin, or abnormal beta-catenin expression did not occur in IM, even when associated with carcinoma these immunostains are unlikely to be of value in the assessment of malignant potential in IM.

Adult↗