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)

A 65-year-old man presented with a history of multiple skin coloured papules on his face that were asymptomatic. He had an adenocarcinoma resected from his proximal colon 12 years prior to presentation as well as a family history of colon cancer on the maternal side. Diagnostic biopsies showed the lesions to be sebaceous adenomas and epitheliomas and the diagnosis of Muir-Torre syndrome was made. The sebaceous tumour tissue showed microsatellite instability and immunohistochemical staining indicated diminished expression in the DNA mismatch-repair protein complex MSH2/MSH6. Genetic analysis showed a germline mutation in the MSH2 gene confirming the diagnosis of Muir-Torre syndrome. The patient and his first-degree relatives have been referred for genetic counselling and screening. We review the diagnostic criteria in this syndrome and review the recommended screening guidelines.
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PMID:Muir-Torre syndrome: Diagnostic and screening guidelines. 1703 69

We report the rare but serious association between sebaceous carcinoma of eyelid and Muir-Torre syndrome in two cases, a 79-year-old woman and 54-year-old man. The presenting sign was a yellow-pink nodule with telangiectatic vessels on the left lower eyelid in one patient and a yellowish-red, pedunculated lesion with intrinsic vascularization on the right superior tarsal conjunctiva in the other. A history of multiple primary colon cancers was present in both patients, associated transitional cell carcinoma of bladder and renal cancer in one patient and prostate cancer in the other. Both patients underwent excisional biopsy and cryotherapy of the eyelid tumors. Histopathology revealed sebaceous carcinoma of eyelid and conjunctiva. Immunohistochemical staining for MSH2 DNA mismatch repair gene performed in one patient showed lack of expression. Muir-Torre syndrome was diagnosed on the basis of sebaceous carcinoma, associated with multiple visceral malignancies in both patients. We conclude that patients with sebaceous carcinoma should have evaluation for visceral malignancies, mainly colon cancer.
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PMID:Eyelid sebaceous carcinoma associated with Muir-Torre syndrome in two cases. 1723 5

Colorectal cancer (CRC) forms through a series of histologic steps that are accompanied by mutations and epigenetic alterations, which is called the polyp-cancer sequence. The role of epigenetic alterations, such as aberrant DNA methylation, in the polyp-cancer sequence in sporadic CRC and particularly in hereditary colon cancer is not well understood. Consequently, we assessed the methylation status of CDKN2A/p16, MGMT, MLH1 and p14(ARF) in adenomas arising in the Lynch syndrome, a familial colon cancer syndrome caused by MLH1 and MSH2 mutations, to determine if DNA methylation is a "second hit" mechanism in CRC and to characterize the role of DNA methylation in the polyp phase of the Lynch syndrome. We found MLH1 and p14(ARF) are methylated in 53 and 60% of the Lynch syndrome adenomas and in 4 and 20% of sporadic adenomas, whereas CDKN2A/p16 and MGMT are methylated in 6 and 14% of the Lynch syndrome adenomas versus 50 and 64% of sporadic adenomas. Therefore, the frequency and pattern of gene methylation varies between the Lynch syndrome and sporadic colon adenomas, implying differences in the molecular pathogenesis of the tumors. MLH1 methylation in the Lynch syndrome adenomas suggests gene methylation might have a role in the initiation of these neoplasms.
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PMID:Evidence for the role of aberrant DNA methylation in the pathogenesis of Lynch syndrome adenomas. 1727 92

Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly MLH1, MSH2, and MSH6, underlie Hereditary non-polyposis colorectal cancer (HNPCC) and are mostly family-specific, with few reported founder mutations in MSH2 (Ashkenazim) MLH1 (Finnish). No mutations in colon cancer susceptibility genes have ever been reported in Druze individuals, a Moslem related faith encompassing approximately 1,000,000 individuals worldwide. A novel MSH2 mutation is described in a Druze HNPCC family: a multigenerational family with 10 members in 4 generations affected with colorectal cancer (mean age of diagnosis 46.5 years), two with gastric cancer and one--endometrial cancer. Mutational analysis of the MSH2 gene using denaturing gradient gel electrophoresis (DGGE) and direct sequencing revealed the c.702delA mutation in codon 234 of exon 4 of the MSH2 gene leading to a premature early stop in codon 245, p.Thr234fsX245. Analysis of mutation-carrying or presumed carriers individuals' offspring, revealed 11/42 asymptomatic mutation carriers, age range 17-50 years. The mutation was not present in two additional Druze HNPCC families and 20 Druze sporadic colon cancer patients. This is the first mutation ever reported in a colon cancer susceptibility gene in a Druze family and it appears not to be a founder mutation in Druze individuals with HNPCC.
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PMID:A novel MSH2 germline mutation in a Druze HNPCC family. 1766 Nov 83

In this case report of Muir-Torre syndrome (MTS), we describe a 47-year-old man with a personal and family history of colon cancer and a personal history of keratoacanthoma who presented with a sebaceous carcinoma and, subsequently, had a cystic sebaceous tumor. Immunohistochemical examination of the patient's colonic tumor, located proximal to the splenic flexure, revealed absence of MutL homolog (MLH)-1 protein. MTS is a rare genodermatosis defined clinically by the occurrence of a sebaceous neoplasm and an internal malignancy in the absence of other predisposing factors. Most patients present with sebaceous adenomas, but cystic sebaceous neoplasms have been reported as specific markers of MTS. Gastrointestinal and genitourinary cancers are the most common internal malignancies, with colorectal cancers often occurring at or proximal to the splenic flexure, contrary to most sporadic colorectal cancers. MTS is most frequently found as a variant of the autosomal dominant disorder hereditary non-polyposis colorectal cancer (HNPCC), with tumors demonstrating microsatellite instability and germline mutations in the DNA mismatch repair genes MutS homolog (MSH)-2 and MLH1. However, the distribution of gene mutations of patients with MTS is slightly different from that seen in all HNPCC families, and some cases of MTS arise spontaneously. Physicians should consider MTS in patients presenting with a sebaceous neoplasm, and immunohistochemical examination of tumors for MSH2 and MLH1 protein can be used as a screening test to identify patients with MTS. While the sebaceous and internal neoplasms of MTS are thought to follow a more indolent course than sporadic malignancies, patients with this disorder should be treated with standard therapies and carefully followed. Evidence indicates that for individuals with or at risk of MTS or HNPCC, colonoscopy every 1-2 years beginning at age 20-25 or 10 years younger than the youngest age at diagnosis in the family can be strongly recommended. Additionally, most experts believe that an annual history and physical examination, including a complete skin examination and urinalysis, as well as periodic endometrial sampling and/or transvaginal ultrasound for women, are worthwhile screening tests for these high-risk patients.
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PMID:Muir-Torre syndrome. 1790 35

Mismatch repair deficiency in tumors can result from germ line mutations in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2), or from sporadic promoter hypermethylation of MLH1. The role of unclassified variants (UVs) in MMR genes is subject to debate. To establish the extend of chromosomal instability and copy neutral loss of heterozygosity (cnLOH), we analyzed 41 archival microsatellite unstable carcinomas, mainly colon cancer, from 23 patients with pathogenic MMR mutations, from eight patients with UVs in one of the MMR genes and 10 cases with MLH1 promoter hypermethylation. We assessed genome wide copy number abnormalities and cnLOH using SNP arrays. SNP arrays overcome the problems of detecting LOH due to instability of polymorphic microsatellite markers. All carcinomas showed relatively few chromosomal aberrations. Also cnLOH was infrequent and in Lynch syndrome carcinomas usually confined to the locus harbouring pathogenic mutations in MLH1, MSH2 or PMS2 In the carcinomas from the MMR-UV carriers such cnLOH was less common and in the carcinomas with MLH1 promoter hypermethylation no cnLOH at MLH1 occurred. MSI-H carcinomas of most MMR-UV carriers present on average with more aberrations compared to the carcinomas from pathogenic MMR mutation carriers, suggesting that another possible pathogenic MMR mutation had not been missed. The approach we describe here shows to be an excellent way to study genome-wide cnLOH in archival mismatch repair deficient tumors.
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PMID:Genome-wide copy neutral LOH is infrequent in familial and sporadic microsatellite unstable carcinomas. 1841 27

Low folate intake is associated with colon cancer. We combined a proteomics and biochemical approach to identify proteins and pathways affected by folate deficiency in human colonocytes. Folate differentially altered activity and expression of proteins involved in proliferation [e.g., PCNA], DNA repair [e.g., XRCC5, MSH2], apoptosis [e.g., BAG family chaperone protein, DIABLO and porin], cytoskeletal organization [e.g., actin, ezrin, elfin], and expression of proteins implicated in malignant transformation [COMT, Nit2].
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PMID:The response of human colonocytes to folate deficiency in vitro: functional and proteomic analyses. 1859 13

Patients with Muir-Torre syndrome, an autosomal-dominant familial tumor condition caused by germline mutation of the DNA mismatch repair genes, MSH2 or MLH1, present with tumors of the sebaceous gland and visceral malignancies characterized by microsatellite instability. Here we show development of glioblastoma multiforme in a patient with Muir-Torre syndrome. Immunohistochemical analysis of the brain tumor and colon cancer revealed loss of the DNA mismatch repair gene detected by the genetic test, suggesting a pathogenic link.
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PMID:Identifying Muir-Torre syndrome in a patient with glioblastoma multiforme. 1902 98

Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation.
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PMID:Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. 1910 24

The prevalence and development of microsatellite instability (MSI) and underlying mismatch repair (MMR) deficiency in the carcinogenesis of adenocarcinomas of the papilla of Vater and their precursor lesions are not well established. We analyzed 120 ampullary adenomas (31 pure adenomas and 89 carcinoma-associated adenomas) and 170 pure adenocarcinomas for MSI, immunohistochemical expression of MMR proteins and specific histopathologic features. The most common histologic subtype was intestinal (46.5%), followed by pancreatobiliary (23.5%), poorly differentiated adenocarcinomas (12.9%), intestinal-mucinous (8.2%), and invasive papillary carcinomas (5.3%). Eight of 89 adenomas (9%) and 15/144 carcinomas (10%) showed high microsatellite instability (MSI-H), 10/89 adenomas (11%) and 5/144 carcinomas (4%) showed low microsatellite instability (MSI-L), and 71/89 adenomas (80%) and 124/144 carcinomas (86%) were microsatellite stable (MSS). MSI analysis from carcinomas contiguous with an adenomatous component (n=54) exhibited concordant results in 6/8 (75%) MSI-H and 42/46 (91.3%) MSS tumors. Of 14 carcinomas with MSI-H, 7 showed loss of MLH1 and 5/6 (83%) MLH1 promoter methylation, and 2 carcinomas showed simultaneous loss of MSH2 and MSH6. Two carcinomas and 3 adenomas with MSI-H revealed exclusive loss of MSH6. MSI-H cancers were significantly associated with intestinal mucinous subtype (P<0.001), high tumor grade (P=0.003), expansive growth pattern (P=0.044), and marked lymphoid host response (P=0.004). Patients with MSI-H carcinoma had a significantly longer overall survival (P=0.0082) than those with MSI-L or MSS tumors. Our findings indicate that the MSI-phenotype is an early event, which develops at the stage of adenoma and is reliably detectable in the precursor lesion. The MMR deficient molecular pathway of carcinogenesis is associated with a histopathologic phenotype in ampullary cancer, similar to the one that has been well described in colon cancer.
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PMID:Histopathologic features and microsatellite instability of cancers of the papilla of vater and their precursor lesions. 1925 34


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