Cases reported "Colorectal Neoplasms"

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1/16. genetic testing and counseling for hereditary forms of colorectal cancer.

    The discovery of genes responsible for inherited forms of colorectal cancer have the potential to improve cancer risk assessment and counseling. Germline mutations (nonsense, frameshift) of APC are associated with familial adenomatous polyposis, an autosomal dominant syndrome, clinically characterized by young onset, hundreds of adenomatous polyps in the colon, and increased risk for extracolonic tumors. Mutations in APC are also associated with forms of attenuated familial adenomatous polyposis. Germline mutations in five mismatch repair related genes (hMSH2, hMLH1, hMSH6, hPMS1, and hPMS2) cause hereditary nonpolyposis colorectal cancer and are associated with increased risk of somatic genetic alterations and high DNA microsatellite instability. Hereditary nonpolyposis colorectal cancer is characterized by young onset colorectal cancer, proximal colon location, and increased risk of extracolonic cancers. A missense mutation in APC (I1307K) is associated with some familial colorectal cancer in Ashkenazic jews. For persons at risk for hereditary forms of colorectal cancer, testing algorithms and gene test interpretations depend on identification of the pedigree germline gene mutation. Careful evaluation of the kindred for characteristic aggregation of tumor types among affected individuals and the availability of affected persons for testing are important issues in implementing genetic testing and follow-up management. case reports illustrate the importance of genetic counseling as a component of cancer genetic risk assessment. The genetic counseling process includes exploration of patient risk perception, sources of anxiety related to cancer risk, patient education (specific cancer-related issues, prevention/intervention options), discussion of possible gene test options, test limitations, and consequences of various gene test outcomes.
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ranking = 1
keywords = microsatellite instability, microsatellite, instability
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2/16. Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.

    Turcot's syndrome is a genetic disease characterized by the concurrence of primary brain tumors and colon cancers and/or multiple colorectal adenomas. We report a Turcot family with no parental consanguinity, in which two affected sisters, with no history of tumors in their parents, died of a brain tumor and of a colorectal tumor, respectively, at a very early age. The proband had a severe microsatellite instability (MIN) phenotype in both tumor and normal colon mucosa, and mutations in the TGFbeta-RII and APC genes in the colorectal tumor. We identified two germline mutations within the PMS2 gene: a G deletion (1221delG) in exon 11 and a four-base-pair deletion (2361delCTTC) in exon 14, both of which were inherited from the patient's unaffected parents. These results represent the first evidence that two germline frameshift mutations in PMS2, an MMR gene which is only rarely involved in HNPCC, are not pathogenic per se, but become so when occurring together in a compound heterozygote. The compound heterozygosity for two mutations in the PMS2 gene has implications for the role of protein PMS2 in the mismatch repair mechanism, as well as for the presymptomatic molecular diagnosis of at-risk family members. Furthermore, our data support and enlarge the notion that high DNA instability in normal tissues might trigger the development of cancer in this syndrome.
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ranking = 1.0014688973335
keywords = microsatellite instability, microsatellite, instability
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3/16. microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for muir-torre syndrome.

    Sebaceous gland carcinomas (SGCs) are rare malignant skin tumors occurring sporadically or as a phenotypic feature of the muir-torre syndrome (MTS). A subset of patients with MTS have a variant of the hereditary nonpolyposis colorectal cancer syndrome caused by mutations in mismatch repair (MMR) genes, which lead to microsatellite instability (MSI). We evaluated the value of MSI and loss of expression of the MMR genes, hMLH-1 and hMSH-2, as a marker to identify and distinguish MTS from sporadic SGC. Using a nationwide pathology report database system, we identified patients with the MTS phenotype. SGCs from 10 MTS patients and the colorectal carcinomas from 3 additional MTS patients were collected. In addition, SGCs from eight patients without a history of visceral neoplasm were collected. MSI was detected in 9 of 13 MTS-associated tumors (69%) versus 0 of 8 sporadic SGCs (P = 0.002). Except for the age of onset of colorectal carcinoma [58 years in the MSI-positive group versus 69.8 years in the MSI-negative group (P = 0.17)], no differences were seen between the MSI-negative and the MSI-positive MTS patients. Loss of expression of hMLH-1 (n = 4) or hMSH-2 (n = 4) was found in MSI-positive patients only. MSI and loss of expression of MMR genes can be used as markers for MTS in patients with SGC. Consequently, MSI and loss of MMR gene expression in a patient presenting with SGC as the initial malignancy have important consequences for the patient and family. There are at least two variants of MTS with different molecular genetic mechanisms because 31% of the patients with the MTS phenotype had no MSI.
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ranking = 1.0058755893339
keywords = microsatellite instability, microsatellite, instability
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4/16. Colorectal carcinomas arising in the hyperplastic polyposis syndrome progress through the chromosomal instability pathway.

    The hyperplastic polyposis syndrome is characterized by the presence within the colon of multiple large hyperplastic polyps. We describe a case of hyperplastic polyposis syndrome associated with two synchronous carcinomas, one of which arises within a pre-existing hyperplastic lesion. comparative genomic hybridization was used to determine genetic changes in both carcinomas and several associated hyperplastic lesions. Microsatellite analysis at five loci was performed on carcinomas and representative hyperplastic polyps, and p53 status was analyzed by immunohistochemistry. Both carcinomas showed multiple genetic aberrations, including high level gains of 8q and 13q, and loss of 5q. These changes were not seen in the hyperplastic polyps. microsatellite instability was not seen in the carcinomas, four separate hyperplastic polyps, the hyperplastic polyp with mild adenomatous change associated with the carcinoma, or a separate serrated adenoma. allelic imbalance in the cancers at D5S346 and D17S938 suggested allelic loss of both p53 and APC, as well as at the loci D13S263, D13S174, D13S159, and D18S49. An early invasive carcinoma in one hyperplastic polyp stained for p53 protein, but the associated hyperplastic polyp was negative. In this case, neoplastic progression followed the typical genetic pathway of common colorectal carcinoma and occurred synchronously with mutation of p53.
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ranking = 0.0073444866673247
keywords = instability
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5/16. Adrenocortical adenocarcinoma in an MSH2 carrier: coincidence or causal relation?

    A woman is described who developed an ovarian adenocarcinoma, 3 metachronous colorectal adenocarcinomas, and a primary adrenocortical adenocarcinoma. Genetic investigation of the mismatch repair genes MLH1 and MSH2 showed a germline mutation in MSH2. Colorectal and ovarian carcinoma belong to the tumor spectrum of hereditary nonpolyposis colorectal cancer (HNPCC). Adrenocortical adenocarcinoma, however, has never been described as 1 of the HNPCC-associated tumors. To investigate whether the adrenocortical adenocarcinoma in this patient was caused by the MSH2 germline mutation, determination of microsatellite instability (MSI) and immunohistochemical analysis were performed on 1 of the colorectal tumors and the adrenocortical adenocarcinoma. MSI and general loss of MSH2 protein expression could be seen in the colorectal tumor but not in the adrenocortical adenocarcinoma. Therefore, it is highly unlikely that the adrenocortical adenocarcinoma found in this patient was due to her genetic predisposition for HNPCC. HUM PATHOL 31:1522-1527.
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ranking = 1
keywords = microsatellite instability, microsatellite, instability
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6/16. Germline characterization of early-aged onset of hereditary non-polyposis colorectal cancer.

    OBJECTIVES: Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by the early onset of colorectal cancer (approximately 40 years). adolescent colorectal cancer is unusual in HNPCC families. We speculated that some dna mismatch repair germline mutations might be associated with early onset of disease. STUDY DESIGN: Genomic DNA was extracted from members of a kindred with virulent HNPCC fitting the Amsterdam Criteria for HNPCC and sequenced for 2 dna mismatch repair genes, hMSH2 and hMLH1. A sigmoid adenocarcinoma from the 14-year-old proband was analyzed for highfrequency microsatellite instability and immunostained for dna mismatch repair gene expression. RESULTS: A germline mutation was identified at nucleotide 676 (codon 226) of the hMLH1 gene. The C to T transition created a nonsense mutation, truncating the hMLH1 protein. This mutation also alters the splice donor sequence, because nucleotide 676 is 2 base pairs from the 3' end of the exon 8. The proband's tumor demonstrated high-frequency microsatellite instability and displayed loss of hMLH1 expression, indicating bi-allelic inactivation of hMLH1. CONCLUSIONS: A complex mutation of hMLH1 at codon 226 is associated with adolescent onset of colorectal cancer in an HNPCC family. Genetic screening of other suspected HNPCC families with unusually young members with cancer might reveal certain genotypes with particularly virulent forms of this disease.
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ranking = 2
keywords = microsatellite instability, microsatellite, instability
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7/16. Overexpression of an mRNA-binding protein in human colorectal cancer.

    A Coding Region instability Determinant-Binding Protein (CRD-BP) binds in vitro to c-myc mRNA and appears to stabilize the mRNA. The CRD-BP gene is amplified in one-third of human breast cancer cases, and the CRD-BP appears to be an oncofetal protein. To analyse CRD-BP expression in human cancer tissue, paired extracts of cancer and normal colon specimens from 21 patients were analysed by immunoblotting and/or reverse transcriptase-polymerase chain reaction. Seventeen cancer specimens out of 21 (81%) were positive for CRD-BP expression by one or both assays. With one exception, normal colon specimens were negative for CRD-BP expression; specimens of inflammatory bowel and a villous adenoma also had no detectable CRD-BP. The lack of CRD-BP expression in normal colon did not result from indiscriminate protein or rna degradation. c-myc mRNA levels appeared to be elevated in tumor specimens. We conclude that the CRD-BP is scarce or absent from normal colon but is overexpressed in colorectal cancer. The CRD-BP might be a novel human tumor marker.
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ranking = 0.0014688973334649
keywords = instability
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8/16. Minisatellite instability is found in colorectal tumours with mismatch repair deficiency.

    microsatellite instability (MSI) in colorectal tumours is demonstrated by PCR amplification of several different microsatellite loci. Minisatellites, which are repeats of longer sequences also found throughout the genome, may also be affected by tumorigenesis. Certain minisatellite alleles contain 2 types of similar repeat unit that are randomly interspersed. The interspersion pattern can be analysed by mapping variant repeat units along an amplified allele, minisatellite variant repeat unit mapping PCR (MVR-PCR). We have applied microsatellite analysis with 10 markers and MVR-PCR for locus D7S21 to 33 cases of colorectal neoplasia, 27 sporadic and 6 from patients suspected of having hereditary non-polyposis colorectal cancer (HNPCC). Of the 27 sporadic cases, 3 were MSI-high on microsatellite analysis and one MSI-low. Instability with MVR-PCR was observed, but only in the MSI-high cases. Four of the HNPCC patients had mismatch repair (MMR) gene mutations in either hMLH1 or hMSH2. All 4 had DNA instability by MVR-PCR, but only two of these had MSI (one high, one low). The other 2 of the 6 patients with suspected HNPCC were negative to mutation analysis. One had features strongly suggestive of HNPCC and was unstable by both microsatellite analysis (MSI-high) and by MVR-PCR. The other tumour, from an Amsterdam criteria positive kindred, did not demonstrate instability by any technique. Thus MVR-PCR detects DNA instability in MSI-high sporadic tumours and in those associated with HNPCC where MSI is observed. Further, in some MMR mutation positive cases MSI was not seen but instability was observed by MVR-PCR. MVR-PCR may be a valuable adjunct to the detection of MMR deficiency in colorectal tumours and it may allow new insights into the nature of DNA instability in this condition.
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ranking = 0.22029758445578
keywords = microsatellite, instability
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9/16. Challenge in the differentiation between attenuated familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer: case report with review of the literature.

    The clinical differentiation between hereditary nonpolyposis colorectal cancer (HNPCC) and attenuated familial adenomatous polyposis (AFAP) is very difficult. The 62-yr-old proband presented with duodenal adenocarcinoma. His history of subtotal colectomy for colon cancer, the rarity of duodenal adenocarcinoma in the general population, and his family history of colon cancer made us suspect that he might have FAP. We investigated this family by obtaining medical records and performing gene analysis. The proband had only 10 adenomatous colon polyps when he underwent subtotal colectomy for the cancer, so classic FAP was excluded. His family history included rectal cancer in his brother at 69 yr of age, colon cancer in his mother at 75 yr, and colon cancer in one maternal cousin at 42 yr. Three months after we started to study this family, the proband's 32-yr-old son presented with rectal cancer. His family fulfilled the Amsterdam criteria for HNPCC, but AFAP could not be excluded. Upon gene testing, the proband was negative for APC gene germline mutation, which made AFAP highly unlikely. Moreover, high microsatellite instability (MSI) was detected in his adenomas and cancer tissues. The fulfillment of Amsterdam criteria, the exclusion of FAP and AFAP, and the high MSI established the diagnosis of HNPCC in this family. We also summarize the differences between FAP, AFAP, and HNPCC; extend the graphic description of the MSI mechanism; and propose a diagnostic strategy for HNPCC.
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ranking = 1
keywords = microsatellite instability, microsatellite, instability
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10/16. The characterization of somatic APC mutations in colonic adenomas and carcinomas in Ashkenazi jews with the APC I1307K variant using linkage disequilibrium.

    Mutations of the adenomatous polyposis coli (APC) gene play a critical role in the development of colorectal neoplasms. A novel mechanism involves a germline variant, at codon 1307 of the APC gene. The mutation is thought to create an unstable segment of DNA, which facilitates the development of somatic mutations. I1307K has been shown to be ancestral in Middle Eastern populations. The aim of the present study was to confirm this observation for a Western population and to utilize this information in the characterization of the somatic changes in colorectal neoplasia in carriers of I1307K. DNA from 182 US Ashkenazim was screened for the I1307K variant, which was found in 22 (12.1%), and the ancestral nature of this variant was confirmed in this population by showing that all of those with the I1307K variant carried a specific allele at the D5S346 locus, while the majority shared a D5S1385 allele. Subsequently, 79 neoplasms were analysed from 15 I1307K carriers for loss of heterozygosity (LOH) at the D5S346 locus. LOH was detected in 18 neoplasms (23%). Of these 18, four neoplasms showed loss of the I1307K-associated allele, while 14 neoplasms had retained the I1307K-associated allele and, by implication, the I1307K variant. PCR products were also cloned into a plasmid vector to isolate individual APC alleles. For those neoplasms with LOH, 13 of the 18 neoplasms (72%) had a somatic mutation, of which 12 involved the I307K-bearing chromosome. This study is consistent with two previous studies in showing that additional somatic mutations close to codon 1307 are almost always on the I1307K-bearing chromosome, but either allele may demonstrate LOH. Further evidence for the interpretation of the action of I1307K as producing DNA instability is provided by analysing multiple neoplasms from the same person and by showing that these neoplasms have differing patterns of LOH and associated somatic mutations.
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ranking = 0.0014688973334649
keywords = instability
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