National Cancer Institute®
Last Modified: October 1, 2002
UI - 12269688
AU - Baxter NP; Duffy SR; Sheridan E
TI - Endometrial abnormalities in three sisters from a family with hereditary non-polyposis colorectal cancer syndrome.
SO - BJOG 2002 Sep;109(9):1076-8
AD - University Department of Obstetrics and Gynaecology, St James's University Hospital, Leeds, UK.
UI - 12353948
AU - Calvert PM; Frucht H
TI - The genetics of colorectal cancer.
SO - Ann Intern Med 2002 Oct 1;137(7):603-12
AD - Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Colon cancer is a common disease that can be sporadic, familial, or inherited. Recent advances have contributed to the understanding of the molecular basis of these various patterns of colon cancer. Germline genetic mutations are the basis of inherited colon cancer syndromes; an accumulation of somatic mutations in a cell is the basis of sporadic colon cancer; and, in Ashkenazi Jewish persons, a mutation that was previously thought to be a polymorphism may cause familial colon cancer. Mutations of three different classes of genes have been described in colon cancer etiology: oncogenes, suppressor genes, and mismatch repair genes. Knowledge of many of the specific mutations responsible for colon carcinogenesis allows an understanding of the phenotypic manifestations observed and forms the basis of genetic testing for inherited disease. Although genetic testing is possible and available, it is only an adjunct to the clinical management of persons at risk for colon cancer and patients with colon cancer. As a result of advances in the understanding of the molecular causes of colon cancer and the availability of colon cancer screening methods such as colonoscopy, it should be possible to prevent the vast majority of colon cancer in our society. Practicing clinicians should recognize the patterns of clinical colon cancer, understand its causes, and be able to use genetic testing and endoscopic screening for prevention.
UI - 12019211
AU - Kariola R; Raevaara TE; Lonnqvist KE; Nystrom-Lahti M
TI - Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome.
SO - Hum Mol Genet 2002 May 15;11(11):1303-10
AD - Department of Biosciences, Division of Genetics, University of Helsinki, FIN-00014 Helsinki, Finland.
To date, five mismatch-repair (MMR) genes, MLH1, MSH2, MSH6, MSH3 and PMS2, are known to be involved in human MMR function. Two of those, MLH1 and MSH2, are further the most common susceptibility genes for hereditary non-polyposis colorectal cancer (HNPCC), while MSH3 and PMS2 are seldom (PMS2) or not at all (MSH3 ) reported to be involved in HNPCC. Despite the increasing number of MSH6 germline mutations, their pathogenicity remains questionable, because the mutations are mainly linked to putative HNPCC families lacking the typical clinical and molecular characteristics of the syndrome, such as early age at onset and high microsatellite instability (MSI). High MSI is a consequence of MMR defect, and the pathogenicity of germline mutations in HNPCC is thus linked to malfunction of MMR. To address the question of whether and how MSH6 mutations cause susceptibility to HNPCC, we studied heterodimerization of four MSH6 variants with MSH2, and the functionality of these MutSalpha complexes in an in vitro MMR assay. All mutations occurred in putative HNPCC patients. Irrespective of the type or the site of the amino acid substitutions, all the variants repaired G.T mismatches to A.T as wild-type MSH6 protein. However, the MSH6 protein carrying a mutation in the MSH2/MSH6 interaction region was poorly expressed, suggesting problems in its stability. Our results are clinically relevant, since they demonstrate that under the stable in vitro conditions, when the amounts of the proteins are adequate for repair, the tested MSH6 mutations do not affect repair function. Consequently, while the typical HNPCC syndrome is associated with problems in repair reaction, the pathogenicity of mutations in putative HNPCC families may be linked to other biochemical events.
UI - 12362848
AU - Nilbert M; Gronberg H; Lindblom A
TI - [Essential to discover hereditary colorectal and endometrial cancer. Mutations in "HNPCC individuals" can cause several different tumors]
SO - Lakartidningen 2002 Aug 22;99(34):3296-300
AD - Onkologiska kliniken, Universitetssjukhuset i Lund. Mef.Nilbert@onk.lu.se
Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is one of our most common hereditary cancer syndromes and confers an increased risk for several tumor types, with the greatest lifetime risks being for colorectal cancer and endometrial cancer. Hereditary mutations in one of several mismatch-repair (MMR) genes cause the syndrome, and 39 such mutations, involving the genes MLH1, MSH2 and MSH6, have been been characterized in Sweden. Screening programs for HNPCC have been shown to be cost-effective and to prevent cancer. Identification of HNPCC individuals thus allows prevention of additional tumors in the patient as well as in the family.
UI - 12352241
AU - Green J; O'Driscoll M; Barnes A; Maher ER; Bridge P; Shields K; Parfrey
TI - PS Impact of gender and parent of origin on the phenotypic expression of hereditary nonpolyposis colorectal cancer in a large Newfoundland kindred with a common MSH2 mutation.
SO - Dis Colon Rectum 2002 Sep;45(9):1223-32
AD - Medical Genetics Program, Memorial University, St. John's, Newfoundland, Canada.
PURPOSE: This study was designed to provide precise estimates of death and cancer risks, by gender and parent of origin, in hereditary nonpolyposis colorectal cancer independent of mutation, geographic variation, and ascertainment bias. METHODS: A group of 12 families with a founder MSH2 mutation (nucleotide 943+3, A --> T) causing hereditary nonpolyposis colorectal cancer was identified in Newfoundland. Genetic testing was offered to those at 50 percent risk of inheriting the mutation. Medical records were reviewed to identify cancer types, age at onset of cancer, and age at death. Ascertainment bias was limited by analyzing only sibships with good ascertainment of genetic status (> or =50 percent of sibships had known genetic status). RESULTS: Of 302 family members with hereditary nonpolyposis colorectal cancer or at 50 percent risk, 151 (50 percent) were considered to be mutation carriers, 96 (32 percent) were mutation negative, and 55 (18 percent) were of unknown mutation status. By age 50 years, 72 percent of males and 72 percent of females who were hereditary nonpolyposis colorectal cancer mutation carriers had developed cancer. The age-related risks of colorectal cancer or of death of cancer were significantly higher in males than in females (relative risk = 2.8, P = 0.0001 and relative risk = 2.1, P = 0.01, respectively). The mutation was transmitted by the mother more frequently than the father. Females who inherited the mutation from their father had an increased risk of developing colorectal cancer (relative risk = 2.5, P = 0.05) and of dying of cancer (relative risk = 2.7, P = 0.04) compared with females who inherited the mutation from their mother. CONCLUSIONS: Investigation of large kindreds from the same geographic area who share the same MSH2 mutation and in whom family members have been identified with little ascertainment bias suggests that the risks for colorectal cancer and death of cancer are higher for male mutation carriers than for females and that females who inherit the mutation from their father are at higher risk of colorectal cancer than females who inherit the mutation from their mother.
UI - 10656143
AU - Janin N
TI - [Explanation of enigmas of the Lynch syndrome thanks to a new carcinogenesis model characterized by an unorthodox initiation process]
SO - C R Acad Sci III 1999 Dec;322(12):1017-31
AD - Unite d'oncologie medicale, Hopital Laennec, Paris, France.
The genotype-phenotype relationship of Lynch syndrome displays many enigmatic features which cannot be explained satisfactorily by the prevailing concepts of carcinogenesis and genetic predisposition to cancer. We propose here a new model of carcinogenesis divided into two and only two evolutive phases: a) a preliminary phase starting with the counter-selective loss of mismatch repair function, in which most clones with the RER mutator phenotype are eliminated through apoptosis or an accelerated ageing process; b) an explosive phase that is initiated only if mutations blocking apoptosis and senescence, rapidly acquired during the short life span of the non-transformed RER+ clones, eventually rescue one mismatch repair-deficient cell that gives rise to the malignant clone. Carcinogenesis is proposed here to progress irreversibly and very rapidly once initiated. We shall show how this model provides a meaningful etiologic and pathogenic interpretation of all the curious features of Lynch syndrome.
UI - 11969232
AU - Tejpar S; Van Cutsem E
TI - Molecular and genetic defects in colorectal tumorigenesis.
SO - Best Pract Res Clin Gastroenterol 2002 Apr;16(2):171-85
AD - Center for Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium.
Colorectal cancers, whether sporadic or hereditary, are caused by a defined set of molecular events. There are at least two different pathogenetic pathways for colorectal cancer: the chromosomal instability pathway and the microsatellite instability pathway; the two major inherited syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), are examples of these two mechanisms. These different pathways, however, converge on common pathological entities that have crucial functions in the regulation of normal crypt homeostasis. Preventive strategies aimed at reversing these changes, or therapeutic interventions targeting cell populations with these alterations, should be most efficacious. Genetic testing for inherited syndromes is now available and allows appropriate management of these disorders. Further insight into colorectal tumorigenesis pathways can lead to the development of useful prognostic indicators and target preventive and therapeutic strategies in the management of colorectal cancer. Copyright 2002 Elsevier Science Ltd.
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