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)

Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency). This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.
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PMID:Contribution of large genomic rearrangements in Italian Lynch syndrome patients: characterization of a novel alu-mediated deletion. 2348 96

Detection of mutations in families with a hereditary predisposition to colon cancer gives an opportunity to precisely define the high-risk group. 36 patients operated on for colon cancer, with familiar prevalence of this malignancy, were investigated using the DNA microarrays method with the potential detection of 170 mutations in MLH1, MSH2, MSH6, CHEK2, and NOD2 genes. In microarrays analysis of DNA in 9 patients (25% of the investigated group), 6 different mutations were found. The effectiveness of genetic screening using the microarray method is comparable to the effectiveness of other, much more expensive and time-consuming methods.
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PMID:Development of a new, simple and cost-effective diagnostic tool for genetic screening of hereditary colorectal cancer--the DNA microarray assay. 2374 19

Colorectal cancer is a rare disease in the pediatric age group and, when present, suggests an underlying genetic predisposition. The most common hereditary colon cancer susceptibility condition, Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant condition caused by a germline mutation in 1 of 4 DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, or PMS2. The mutation-prone phenotype of this disorder is associated with gastrointestinal, endometrial, and other cancers and is now being identified in both symptomatic adolescents with malignancy as well in asymptomatic mutation carriers who are at risk for a spectrum of gastrointestinal and other cancers later in life. We review the DNA MMR system, our present understanding of LS in the pediatric population, and discuss the newly identified biallelic form of the disease known as constitutional mismatch repair deficiency syndrome. Both family history and tumor characteristics can help to identify patients who should undergo genetic testing for these cancer predisposition syndromes. Patients who carry either single allele (LS) or double allele (constitutional mismatch repair deficiency syndrome) mutations in the MMR genes benefit from cancer surveillance programs that target both the digestive and extraintestinal cancer risk of these diseases. Because spontaneous mutation in any one of the MMR genes is extremely rare, genetic counseling and testing are suggested for all at-risk family members.
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PMID:Lynch syndrome: a pediatric perspective. 2405 81

Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner. Finally, MYH-associated polyposis is caused by mutations in the MUTYH gene and is inherited in an autosomal recessive manner but may or may not be associated with polyps. There are variants of both familial adenomatous polyposis (Gardner syndrome--with extracolonic features--and Turcot syndrome, which features medulloblastoma) and Lynch syndrome (Muir-Torre syndrome features sebaceous skin carcinomas, and Turcot syndrome features glioblastomas). Although a clinical diagnosis of familial adenomatous polyposis can be made using colonoscopy, genetic testing is needed to inform at-risk relatives. Because of the overlapping phenotypes between attenuated familial adenomatous polyposis, MYH-associated polyposis, and Lynch syndrome, genetic testing is needed to distinguish among these conditions. This distinction is important, especially for women with Lynch syndrome, who are at increased risk for gynecological cancers. Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing. To assist clinical laboratories in developing and validating testing for this group of inherited colorectal cancers, the American College of Medical Genetics and Genomics has developed the following technical standards and guidelines. An algorithm for testing is also proposed.
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PMID:ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). 2431 Mar 8

We have recently experienced an endometrial cancer 12 years after the diagnosis of colon cancer with Lynch syndrome. A 49-year-old Korean woman had a family history of colon cancer. Her mother had colon cancer at 56-year-old, and her brother had colon cancer at 48 years old. The patient received surgery for endometrial cancer at the same hospital 12 years after being treated for colon cancer. Immunohistochemistry showed that her endometrial tissue stained negative for MSH2. A microsatellite instability test was performed and showed the presence of instability high microsatellite instability. An hMLH2 gene mutation was detected at codon 629 codon of exon 12, in which a glutamine was replaced with an arginine (1886A>G [p.Gln629Arg]). To our knowledge, this is the first case of metachronous cancer in a Lynch syndrome family in Korea with a gap of more than ten years between cancer diagnoses.
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PMID:One case of endometrial cancer occurrence: Over 10 years after colon cancer in Lynch family. 2439 21

Differentiating sporadic microsatellite-unstable colorectal carcinoma due to MLH1 promoter hypermethylation from Lynch syndrome (LS)-associated tumors due to mutations in mismatch-repair proteins is time consuming, cost intensive, and requires advanced laboratory testing. A mutation in BRAF has been shown to be highly specific for sporadic tumors; however, a significant proportion of sporadic microsatellite-unstable tumors lack BRAF mutations. MLH1 promoter methylation analysis is subsequently used to differentiate LS and sporadic tumors, but both tests require specialized laboratories and are costly. Through previous gene expression profiling of serrated polyps, we identified annexin A10 as a protein highly expressed in sessile serrated adenomas/polyps. As these polyps give rise to the majority of sporadic microsatellite-unstable tumors, we evaluated the ability of annexin A10 expression to discriminate between LS and sporadic tumors. A marked increase in annexin A10 mRNA was observed in sporadic microsatellite-unstable tumors compared with LS tumors (378-fold increase, P<0.001). Using immunohistochemistry, annexin A10 was expressed in 23/53 (43%) BRAF-mutated and 9/22 (41%) BRAF wild-type sporadic tumors. In contrast, only 3/56 (5%) LS tumors were positive for annexin A10 (P<0.0001). One patient had a deleterious MSH2 mutation, and another had a variant of uncertain significance in MSH6. These 2 tumors could be easily distinguished from sporadic tumors using mismatch-repair protein immunohistochemistry. Only 1/28 (4%) LS tumors with loss of MLH1 was positive for annexin A10. This patient did not have a deleterious MLH1 mutation but rather germline promoter hypermethylation of MLH1. On the basis of these results, immunohistochemistry for annexin A10 may be a useful marker to distinguish sporadic from LS-associated microsatellite-unstable colon cancer.
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PMID:Immunohistochemistry for annexin A10 can distinguish sporadic from Lynch syndrome-associated microsatellite-unstable colorectal carcinoma. 2511 14

Inheritable colorectal cancers (CRC) accounted for about 20% of the CRC cases, such as hereditary nonpolyposis colorectal cancer (HNPCC), Gardner syndrome and familial adenomatous polyposis (FAP). A four-generation Han Chinese family was found affected with polyposis in colons. Inferred from the pedigree structure, the disease in this family showed an autosomal dominant inheritance model. To locate the causal mutations in this family, genomic DNAs were extracted and the next generation sequencing for 5 genes relating to colon cancer performed by Ion Torrent Personal Genome Machine with a 314 chip. The reads were aligned with human reference genome hg19 to call variants in the 5 genes. After analysis, 14 variants were detected in the sequenced sample and 13 been collected in dbSNP database and assigned with a rs identification number. In these variants, 9 were synonymous, 4 missense and 1 non-sense. In them, 2 rare variants (c.694C>T in APC and c.1690A>G in MSH2) might be the putative causal mutations for familial adenomatous polyposis (FAP) since the rarity of the mutated allele in normal controls. c.694C>T was detected in only affected members and generated a premature stop codon in APC. It should be a de novo germline mutation making APC containing this stop codon as targets for nonsense-mediated mRNA decay (NMD). c.1690A>G in MSH2 was not only detected in affected members, but also in normal ones in the family. Functional prediction revealed that the amino acid affected by this variant had no effect on the function of MSH2. Here, we report a de novo germline mutation of APC as the causal variant in a Chinese family with inheritable colon cancer by the next generation sequencing.
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PMID:A de novo germline mutation of APC for inheritable colon cancer in a Chinese family using multigene next generation sequencing. 2473 42

Adenocarcinoma of the colon in 10-20% is associated with microsatellite instability, which can occur both in sporadic cancers and in hereditary nonpolyposis colon cancer. Our analysis of 195 cases of adenocarcinoma of the colon showed that microsatellite instability (MSI-H) was found only in 1.5% of patients. Subsequent choice of patients with suspected hereditary Lynch syndrome led to the identification of additional 17 patients with microsatellite instability. They passed an analysis of genes of repair system of unpaired nucleotides of DNA. The study showed that immunohistochemical staining of MSH2, MSH6, MLH1, PMS2 could effectively conduct a preliminary screening of the Lynch syndrome but was unable to divide cases of sporadic and hereditary MSI-H colon cancer.
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PMID:[Immunohistochemical examination of MSH2, PMS2, MLH1, MSH6 compared with the analysis of microsatellite instability in colon adenocarcinoma]. 2491 61

Lynch syndrome (LS), the most common familial colon cancer, is associated with mismatch repair (MMR) malfunction. As mutation carriers inherit one normal and one defected MMR gene allele, cancer risk can be considered as limited amount of normal MMR gene product. How reductions in different MMR gene expressions affect MMR capability is, however, not known. The in vitro MMR assay is a method for the pathogenicity assessment of MMR gene variants causing functional or expressional defects and thus also suitable to evaluate the effects of reduced expression of normal mRNA. Here, the assay was applied to quantify repair efficiencies of human cells retaining varying expression levels (25%/50%/75%) of the main LS susceptibility genes MLH1, MSH2, or MSH6. Compared with the shRNA knockdown control, already a 50% reduction in mRNA levels could be detected as decreased MMR function although without statistical significance in MLH1. In MSH2 and MLH1, total loss of MMR was achieved with 25% expression, whereas in MSH6 and MSH2, the repair capability decreased significantly already with 75% expression. Our results provide a preliminary indication of relative expressions required for wild-type function and suggest that the in vitro MMR assay could be used to recognize expression levels indicative of LS.
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PMID:Assessing how reduced expression levels of the mismatch repair genes MLH1, MSH2, and MSH6 affect repair efficiency. 2492 10

A 5-year survival of patients with Stage III colon cancer with prophylactic panhysterectomy in anamnesis was 83.3%, significantly higher than that of patients with Stage III colon cancer without panhysterectomy (69.3%) and than in colon cancer patients with metachronous ovarian metastases (42%). In families of patients with primary multiple malignant tumors (PMMT) of colon, endometrium and/or ovaries as well as in cases of accumulation in the same family of solitary tumors of the above locations it is necessary to carry out genetic testing to identify mutations in genes MSH2, MLH1, MSH6. Carriers of mutations in genes of mismatch repair MSH2, MLH1, MSH6 should be assumed to the high-risk group for the development of malignancies both PMMT of colon and organs of the female reproductive system and solitary tumors of the above locations. All women suffering from colon cancer, especially in the presence of mutations in genes of mismatch repair, in pre- and menopause should be undergone simultaneous prophylactic surgery: panhysterectomy. The question about the greater omentum should be decided situationally.
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PMID:[Simultaneous prophylactic surgery for colon cancer in women. Viewpoint of the gynecologist]. 2503 82


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