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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical cancer genetics is becoming an integral part of the care of cancer patients. This review describes the clinical aspects, genetics, and clinical genetic management of most of the major hereditary cancer susceptibility syndromes. Multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and familial adenomatous polyposis are examples of syndromes for which genetic testing to identify at-risk family members is considered the standard of care. Genetic testing for these syndromes is sensitive and affordable, and it will change medical management. Cancer genetic counseling and testing is probably beneficial in other syndromes, such as the hereditary breast cancer syndromes, hereditary nonpolyposis colorectal cancer syndrome, Peutz-Jeghers syndrome, and juvenile polyposis. There are also hereditary cancer syndromes for which testing is not yet available and/or is unlikely to change medical management, including Li-Fraumeni syndrome and hereditary malignant melanoma. Thorough medical care requires the identification of families likely to have a hereditary cancer susceptibility syndrome for referral to cancer genetics professionals.
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PMID:Genetic testing for cancer predisposition. 1116 Jul 85

Glutathione S-transferases (GSTs) are a superfamily of detoxification enzymes that may play an important role in human carcinogenesis. While the genetic polymorphisms GSTM1 and GSTT1 have drawn particular interest in relation to cancer susceptibility, previous studies of colorectal cancer are inconsistent regarding their role. We examined the relation between GSTM1 and GSTT1 genotypes combined and colorectal adenomas, and the interaction with cigarette smoking among 205 cases of colorectal adenomas and 220 controls with normal total colonoscopy in Japanese men. Neither GSTM1 nor GSTT1 was related to colorectal adenomas, nor were the null genotypes of GSTM1 and GSTT1 combined. The lack of an association with GSTM1 and GSTT1 genotypes combined persisted even when the analysis was done separately for proximal and distal colorectal adenomas. A three- to fivefold significant increase in the odds of colorectal adenomas was observed among men with a high exposure to cigarette smoking across the genotype groups, and a statistically significant increasing trend was noted within each genotype group. The present findings do not support the role for GSTM1 and GSTT1 genotypes in the development of colorectal adenomas.
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PMID:Glutathione S-transferase polymorphisms and risk of colorectal adenomas. 1116 55

1-5% of all patients presenting with colorectal cancer, have an underlying genetic predisposition with an autosomal dominant of pattern of inheritance. Recently the underlying molecular genetic pathway of this syndrome known as HNPCC (hereditary nonpolyposis colorectal cancer) has been characterized: the predisposition is due to a pathogenic mutation in one of the DNA mismatch-repair genes. Colorectal cancers are the leading characterisitic of the syndrom and are frequently encountered at a young age of onset. However, endometrial cancer, stomach cancer, small bowel cancer, urinary tract cancer and skin cancer among others are also inherent to the syndrome. Based on the identification of the underlying molecular genetic pathway, predictive testing has become an option. Once the family-specific underlying pathogenic mutation in one of the DNA mismatch-repair genes has been identified in a proband, at-risk family members may be offered DNA testing with an unequivocal answer to if or if not they have inherited the increased cancer susceptibility. Multiple facets of family DNA testing require a multidisciplinary approach integrating clinicians, geneticists, psychologists, molecular biologist and pathologists. Mutations are identified in a rate of 50-60% of families complying with the Amsterdam criteria for HNPCC. The incidence of recta cancer in HNPCC has as yet not clearly been defined, due to a lack of unequivocal data. In a retrospective analysis (submitted) rectal cancers were encountered in 30% of the HNPCC patients. Half of the patients affected developed metachronous colon cancers. It is essential to address the issue of prophylactic surgery in HNPCC patients presenting with colorectal cancer: Prospective data is required in order to decide which of the options is more beneficial for the HNPCC patient presenting with his first colorectal primary: subtotal colectomy and ileorectal anastomosis versus restorative proctocolectomy. It is evident that apart from the more clinical data quality of life data must be evaluated in this study.
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PMID:[Hereditary nonpolyposis colorectal carcinoma (HNPCC): surgical aspects]. 1132 7

Colorectal cancer has been described in terms of genetic instability selectively affecting either microsatellite sequences (MIN) or chromosome number and structure (CIN). A subgroup with apparently stable, near-diploid chromosomes and stable microsatellites (MACS) also exists. These distinctions are important, partly because of their value in highlighting different pathways of carcinogenesis, and partly because of their direct relevance to prognosis. Study of early-onset cancer has often proved a fruitful resource for the identification of the nature and function of cancer susceptibility genes. In a study of colorectal cancer with stable microsatellite DNA, we describe 22 early-onset tumours (mean age=33), compared with 16 late-onset tumours (mean age=68). Both groups contained carcinomas with the MACS phenotype, characterized by near diploid DNA content, as defined by flow cytometry, and minimal chromosome arm deletion or amplification (six or less events per genome), determined by comparative genomic hybridization (CGH). Minimal chromosome imbalance correlated strongly with diploid DNA content (P<0.001). The proportion of MACS cancers was significantly greater in early-onset as compared to late-onset tumours (64 vs 13%, P=0.005). Of the chromosome arm imbalances commonly observed in late-onset tumours, only 18q- was observed more than twice amongst the 14 early-onset MACS tumours. Seventy-nine per cent of these MACS tumours were located in the distal colon, and 69% were at advanced clinico-pathological stages (with lymph node or distant metastasis). A positive family history of colorectal or other cancers was elicited in seven patients in the MACS early-onset group, and one additional patient in this group had a metachronous ovarian cancer. The results suggest that MACS cancer may have a genetic basis different from either MIN or CIN, and further studies of these cancers may lead to discovery of new mechanisms of colorectal carcinogenesis and cancer susceptibility.
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PMID:Early-onset colorectal cancer with stable microsatellite DNA and near-diploid chromosomes. 1152 Nov 98

The inactivation of the DNA mismah repair (MMR) system, which is associated with the predisposition to the hereditary non-polyposis colorectal cancer (HNPCC), has also been documented in nearly 20% of the sporadic colorectal cancers. These tumors are characterized by a high frequency of microsatellite instability (MSI(+) phenotype), resulting from the accumulation of small insertions or deletions that frequently arise during replication of these short repeated sequences. A germline mutation of one of the two major MMR genes (hMSH2 or hMLH1) is found in half to two-thirds of the patients with HNPCC, whereas in sporadic cases hypermethylation of the hMLH1 promoter is the major cause of the MMR defect. Germline mutations in hMSH6 are rare and rather confer predisposition to late-onset familial colorectal cancer, and frequent extracolonic tumors. Yet, the genetic background of a number of HNPCC patients remains unexplained, indicating that other genes participate in MMR and play important roles in cancer susceptibility. The tumor-suppressor genes that are potential targets for the MSI-driven mutations because they contain hypermutable repeated sequences are likely to contribute to the etiology and tissue specificity of the MSI-associated carcinogenesis. Because the prognosis and the chemosensitivity of the MSI(+) colorectal tumors differ from those without instability, the determination of the MSI phenotype is expected to improve the clinical management of patients. This review gives an overview of various aspects of the biochemistry and genetics of the DNA mismah repair system, with particular emphasis in its role in colorectal carcinogenesis.
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PMID:DNA mismatch repair defects: role in colorectal carcinogenesis. 1190 Aug 75

The mammalian DNA mismatch-repair genes belong to a family of genes that comprise several homologs of the Escherichia coli mutS and mutL genes. The observation that mutations in the two human repair genes MSH2 and MLH1 are responsible for hereditary nonpolyposis colorectal cancer, as well as a significant number of sporadic colorectal cancers, raises several questions about the role of these proteins and their family members in the initiation and progression of colorectal cancer. To address these questions, mice with inactivating mutations in all the known mutS and mutL homologs have been generated. The development of these mouse lines has permitted the systematic analysis of the role of each gene in the repair process and has underscored their significance in mutation avoidance and cancer susceptibility. These analyses were critical for our understanding of the function of these genes at the organismal level and also revealed an essential role for some of the DNA mismatch-repair genes in mammalian meiosis.
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PMID:Mouse models for human DNA mismatch-repair gene defects. 1211 15

Mutations in the currently known mismatch repair genes cannot explain all cases of hereditary nonpolyposis colorectal cancer (HNPCC), and novel predisposing genes are actively sought. Recently, mutations in the DNA repair gene EXO1 have been implicated in HNPCC. One truncating and several missense changes were observed in familial colorectal cancer (CRC) cases but not in controls. We evaluated a series of European CRC patients and population controls to clarify whether EXO1 variants may indeed predispose to familial CRC. Several variants observed in patients were also observed in controls with similar frequencies, including the truncating variant proposed previously to be a disease-causing mutation. Thus, little evidence was obtained to support a major causative role of EXO1 in HNPCC, although we cannot exclude a role for EXO1 as a low penetrance cancer susceptibility or modifying gene.
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PMID:EXO1 variants occur commonly in normal population: evidence against a role in hereditary nonpolyposis colorectal cancer. 1251 92

Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome. Germline mutations in five different mismatch repair (MMR) genes, MSH2, MSH6, MLH1, MLH3, and PMS2 are linked to HNPCC. Here, we describe two colon cancer families in which the index patients carry missense mutations in both MSH2 and MSH6. The MSH2 mutation, I145M, is the same in both families, whereas the MSH6 mutations are different (R1095H and L1354Q). The families do not fulfil the international criteria for HNPCC, one family comprising two and the other family four colon cancer patients, all in one generation, resembling a recessive rather than dominant inheritance characteristic of HNPCC. The tumors of the index patients showed microsatellite instability. Functional analysis was performed to determine which one of the mutations could primarily underlie the cancer susceptibility in the families. MSH2 and MSH6 are known to form a heterodimeric complex (MutSalpha) responsible for mismatch recognition. The interaction of each mutated protein with its wild-type partner and with its mutated partner present in the colon cancer patient, and the MMR function of the mutated MutSalpha complexes were determined. Since none of the three mutations affected the MSH2-MSH6 interaction or the function of MutSalpha in an in-vitro MMR assay, our results suggest that alone the mutations do not cause MMR deficiency typical of HNPCC. However, our results do not exclude the possible compound pathogenicity of the two mutations.
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PMID:Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic? 1252 49

Aneuploidy is a characteristic of a subset of colorectal tumours. CHEK2 (also known as CHK2) is one of the cell cycle checkpoint genes coding for a family of proteins that sense damage in eukaryotic cells. Germline variation in CHEK2 has recently been shown to confer cancer susceptibility. Heterozygous mutations have been identified in patients with TP53-negative Li-Fraumeni syndrome. Furthermore, the CHEK2 1100delC variant carried by 1% of the population has been shown to act as a low penetrance allele for both breast and prostate cancers. To further our knowledge about the contribution of CHEK2 1100delC to cancer incidence we have analysed a series of 149 patients with multiple colorectal adenomas some of whom developed colorectal cancer. The CHEK2 1100delC allele was not over-represented in cases suggesting that this variant is not associated with an increased risk of colorectal disease.
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PMID:Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma. 1456 68

Hereditary Non-Polyposis Colorectal Cancer (HNPCC, Lynch syndrome) is an autosomal dominant condition of cancer susceptibility with high penetrance, characterised by early onset of colon tumours as well as a variety of extracolonic tumours including ovarian cancer and, in particular, cancer of the endometrium. Germline mutations in one of five DNA-mismatch repair (MMR) genes (hMLH1, hMSH2, hMSH6, PMS1, PMS2) are known to cause HNPCC. To date, mutations in two of these genes (hMSH2 and hMLH1) are found in the majority of mutation positive families. Recent literature suggests that especially hMSH2 mutations are associated with extracolonic tumours. We describe two women from an HNPCC family carrying an hMSH2 mutation (deletion of exon 6 of this gene) who developed ovarian cancer. In these patients (full cousins) the ovarian cancers were noted for their aggressive development and rapid recurrence after surgical debulking and during regular multichemotherapy including Cisplatin. This report strengthens recent in vitro studies suggesting an involvement of MMR-gene mutations in ovarian cancer cell biology with decreased susceptibility to Cisplatin therapy. The possible implications for the therapy of ovarian cancer, the screening and genetic counselling of family members are discussed.
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PMID:Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation? 1457 6


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