Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial adenomatous polyposis (FAP), an autosomal dominant inherited disease, confers a high risk of colon cancer. For presymptomatic diagnosis of FAP, we performed linkage studies in three unrelated Israeli families with FAP, using seven polymorphic systems around or at the APC locus on chromosome 5q. These systems are constituted of three DNA probes, recognizing four restriction fragment length polymorphism: C11p11, YN5.48 and pi227; three cytosine-adenine repeat markers: D5S318, D5S346 and MBC; and one intragenic polymorphism: APC-SspI. A meiotic recombination event was detected, apparently between the FAP gene and probe pi227. Based on the different analysis systems, we determined the haplotype at the APC locus in 11 at-risk individuals of the three families, six of whom were found to carry the disease-linked allele. Additionally, we identified a new FAP patient, in whom sigmoidoscopy showed the presence of adenomatous polyps throughout the colon.
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PMID:The use of DNA markers in the pre-clinical diagnosis of familial adenomatous polyposis. 920 21

Barrett's esophagus carries a 30- to 100-fold increased risk of adenocarcinoma, which is thought to develop via a metaplasia-dysplasia-carcinoma progression. A common genetic abnormality detected in Barrett's adenocarcinoma is loss of heterozygosity (LOH) at the sites of known or putative tumor suppressor genes, of which there are at least 9 associated with esophageal adenocarcinoma. The aim of this study was to identify at which histological stage of carcinogenesis LOH at these sites occur. Microdissection of multiple paraffin-embedded tissue blocks from 17 esophagogastrectomy specimens of adenocarcinoma arising in Barrett's esophagus yielded areas of metaplasia, low-, intermediate- and high-grade dysplasia, and carcinoma. LOH analysis of microdissected tissues was performed using a double polymerase chain reaction technique with 11 microsatellite primers shown previously to have LOH in at least 30% of esophageal adenocarcinomas. Identical LOH was detected in premalignant and malignant tissues in 4 of 17 patients, and was located at 5q21-q22 (D5S346 primer), 17p11.1-p12 (TCF2 primer), 17p13.1 (TP53 primer), 18q21.1 (detected in colon cancer tumor suppressor gene [DCC] primer), and 18q23-qter (D18S70 primer). These results suggest that LOH at the sites of the DCC, adenomatous polyposis coli (APC), and TP53 tumor suppressor genes occur before the development of adenocarcinoma in Barrett's esophagus, and so merit further study as potential biomarkers of neoplastic progression in patients with Barrett's esophagus undergoing endoscopic and histological surveillance.
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PMID:LOH at the sites of the DCC, APC, and TP53 tumor suppressor genes occurs in Barrett's metaplasia and dysplasia adjacent to adenocarcinoma of the esophagus. 1066 31

Microsatellite instability (MSI), characterized by contraction or expansion in microsatellite length or short tandem repeats compared with germline lengths, is found in 85% to 90% of colon cancer arising in hereditary nonpolyposis colorectal cancer families. These cancers commonly have characteristic histologic appearances, including medullary features with intense lymphoid infiltrates. In pancreatic cancer, a rare medullary histologic subtype more often demonstrates MSI than the more common adenocarcinoma subtype. We hypothesized that the medullary histologic pattern might correlate with MSI in additional tumor types and analyzed 8 cases of typical and atypical medullary carcinoma of the breast. Tumor and normal DNA was extracted from paraffinized tissue blocks of tumor and histologically uninvolved axillary lymph nodes, respectively. We analyzed the tumors for instability in 5 primary (BAT25, BAT26, D17S250, D5S346, D2S123) and 3 alternative (BAT40, D18S55, D18S58) microsatellites recommended at the National Cancer Institute--sponsored conference for diagnosis of MSI in colorectal cancer. All 8 tumors were microsatellite stable at the 8 loci, suggesting that MSI is not commonly associated with medullary or atypical medullary breast carcinoma, in contrast with the reported association with medullary tumors of the colon and pancreas.
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PMID:Microsatellite instability is infrequent in medullary breast cancer. 1139 77

African Americans (AAs) have a 1.5 times higher risk of colorectal carcinoma (CRC) than Caucasians. Gene silencing through CpG island hypermethylation has been associated with the genesis or progression of microsatellite instability (MSI) largely due to 1 target for hypermethylation being the DNA mismatch repair gene hMLH1; there is anecdotal evidence of an increased incidence of MSI among AAs. P16 and hMLH1 can be inactivated by hypermethylation of their respective promoter regions, abrogating the ability to regulate cell proliferation and repair processes. We studied such methylation, as well as hMHS2 expression in colorectal cancers from AA patients to determine if MSI is associated with epigenetic silencing. Experiments were conducted on matched normal and colon cancer tissues from AA patients (n = 51). A total of 5 microsatellite markers (D2S123, D5S346, D17S250, BAT25 and BAT26) were used to evaluate MSI status. P16 and hMLH1 promoter methylation status was determined following bisulfite modification of DNA and using methylation specific PCR, while immunohistochemistry (IHC) was used to examine expression of hMLH1 and hMSH2. A total of 22 (43%) cancers demonstrated microsatellite instability-high (MSI-H), while 27 were microsatellite stable (MSS) and 2 were microsatellite instability-low (MSH-L). Most of the MSI-H tumors were proximal, well differentiated and highly mucinous. Most patients in the MSI-H group were females (68%). The p16 promoter was methylated in 19 of 47 (40%) tumors. A total of 7 of these CRCs demonstrated MSI-H (33%). The hMLH1 promoter was methylated in 29 of 34 (85%) tumors, of which 13 CRCs demonstrated MSI-H (87%). hMLH1 and hMSH2 staining was observed in 66% and 38% of MSI-H tumors, respectively. Overall, the prevalence of MSI-H colorectal tumor was 2-3-fold higher, while the defect in the percentage expression of mismatch repair (MMR) genes (hMLH1 and hMSH2) was similar in AA patients compared to the U.S. Caucasian population. Similar numbers of AA MSS tumors with p16 and hMLH1 methylation likely indicate hemimethylation of genes that might reflect environmental or genetic influences that might be more common in the AA population.
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PMID:Clinicopathological features and microsatellite instability (MSI) in colorectal cancers from African Americans. 1585 72

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a critical role in folate metabolism. Studies on the association between MTHFR polymorphisms and length changes in short tandem repeat DNA sequences [microsatellite instability (MSI)] are inconsistent. Using data from colon cancer cases (n=503) enrolled as part of an existing population-based case-control study, we investigated the association between MTHFR 677 and MTHFR 1298 polymorphisms and MSI. We also examined whether the association was modified by folate intake. Participants were case subjects enrolled as part of the North Carolina Colon Cancer Study. Consenting cases provided information about lifestyle and diet during in-home interviews as well as blood specimens and permission to obtain tumor blocks. DNA from normal and tumor tissue sections was used to determine microsatellite status (MSI). Tumors were classified as MSI if two or more microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250) had changes in the number of DNA sequence repeats compared with matched nontumor tissue. Tumors with one positive marker (MSI-low) or no positive markers (microsatellite stable) were grouped together as non-MSI tumors (microsatellite stable). MTHFR 677 and MTHFR 1298 genotypes were determined by real-time PCR using the 5' exonuclease (Taqman) assay. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (95% CI). MSI was more common in proximal tumors (OR, 3.8; 95% CI, 1.7-8.4) and in current smokers (OR, 4.0; 95% CI, 1.6-9.7). Compared with MTHFR 677 CC referent, MTHFR 677 CT/TT genotype was inversely associated with MSI among White cases (OR, 0.36; 95% CI, 0.16-0.81) but not significant among African Americans. Although not statistically significant, a similar inverse association was observed between MTHFR 677 CT/TT genotype and MSI among the entire case subjects (OR, 0.54; 95% CI, 0.26-1.10). Among those with adequate folate intake (>400 microg total folate), we found strong inverse associations between combined MTHFR genotypes and MSI (677 CC+1298 AC/CC, OR, 0.09; 95% CI, 0.01-0.59; 677 CT/TT+1298 AA, OR, 0.13; 95% CI, 0.02-0.85) compared with the combined wild-type genotypes (677 CC+1298 AA). This protective effect was not evident among those with low folate (<400 microg total folate) intake. Our results suggest that MTHFR variant genotypes are associated with reduced risk of MSI tumors under conditions of adequate folate intake, although the data are imprecise due to small numbers. These results indicate that the relationship between MTHFR genotypes and MSI is influenced by folate status.
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PMID:5,10-methylenetetrahydrofolate reductase 677 and 1298 polymorphisms, folate intake, and microsatellite instability in colon cancer. 1610 55

Nearly 10% of patients with colorectal cancer (CRC) develop a metachronous cancer after curative resection of their primary malignancy, however identifying these patients is problematic. Although microsatellite instability (MSI) is associated with the development of multiple CRC, this is predominantly seen in those with hereditary non-polyposis colon cancer (HNPCC). This study has examined the value of MSI analysis in identifying patients at risk of developing metachronous cancer from the general population. MSI analysis was performed at the Bat25, Bat26, Bat40, D2S123, D5S346 and D17S250 loci using polymerase chain reaction and single-stranded conformational polymorphism on DNA extracted from 62 specimens taken from 49 patients with metachronous CRC, and from 71 primary single CRCs. MSI status was classified into MSI-H, MSI-L and MSS. MSI-H was more prevalent in metachronous cancers, 34/62 compared to 8/71 single cancers (P < 0.0001). The incidence of MSI-H from proximal colon cancers in index metachronous group, 4/22 was similar to single cancer group, 7/71 (P = 0.28), however MSI-H was more commonly identified in index metachronous cancers located distal to the splenic flexure 9/22 than single cancers 1/71 (P < 0.0001). Patients presenting with MSI-H colorectal cancers distal to the splenic flexure are more likely to develop a metachronous cancer and will benefit from surveillance.
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PMID:Is MSI-H of value in predicting the development of metachronous colorectal cancer? 1642 80

Familial adenomatous polyposis is a severe autosomal dominant cancer predisposition syndrome. It is characterized by the development of hundreds to thousands of polyps in the gastrointestinal tract, primarily in the colon, at a mean age of 16 years. Without a colectomy, colon cancer is inevitable. FAP is caused by mutations in the adenomatous polyposis coli (APC) gene. A couple was referred to Monash IVF following a request to undertake preimplantation genetic diagnosis for FAP. The female proband had an AGTT deletion mutation in exon 15 of the APC gene. Analysis of the APC-linked marker D5S346 showed that the parental alleles were fully informative. A multiplex polymerase chain reaction (PCR) test was developed involving direct mutation detection and the co-analysis of D5S346 to identify allele drop out and avoid a misdiagnosis. The delAGTT mutation and D5S346 alleles were diagnosed by fluorescent PCR and allele sizing. Following standard hormone stimulation and IVF procedures, 14 oocytes were collected, 11 inseminated and nine embryos were biopsied on day 3. Of the nine embryos that were analysed, five embryos were affected and four were unaffected. Two unaffected embryos were transferred on day 4 resulting in a triplet pregnancy and the birth of three healthy babies.
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PMID:Preimplantation genetic diagnosis of familial adenomatous polyposis. 1716 85