National Cancer Institute®
Last Modified: May 1, 2002
UI - 11112663
AU - Scott RJ; McPhillips M; Meldrum CJ; Fitzgerald PE; Adams K; Spigelman
TI - AD; du Sart D; Tucker K; Kirk J Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds.
SO - Am J Hum Genet 2001 Jan;68(1):118-127
AD - Discipline of Medical Genetics, Hunter Area Pathology Service, John Hunter Hospital, New Lambton, New South Wales, Australia. firstname.lastname@example.org
Hereditary nonpolyposis colorectal cancer (HNPCC) describes the condition of a disparate group of families that have in common a predisposition to colorectal cancer in the absence of a premalignant phenotype. The genetic basis of this disease has been linked to mutations in genes associated with DNA mismatch repair. A large proportion of families harbor changes in one of two genes, hMSH2 and hMLH1. Approximately 35% of families in which the diagnosis is based on the Amsterdam criteria do not appear to harbor mutations in DNA-mismatch-repair genes. In this report we present data from a large series of families with HNPCC and indicate that there are subtle differences between families that harbor germline changes in hMSH2 and families that harbor hMLH1 mutations. Furthermore, there are differences between the mutation-positive group (hMSH2 and hMLH1 combined) of families and the mutation-negative group of families. The major findings identified in this study focus primarily on the extracolonic disease profile observed between the mutation-positive families and the mutation-negative families. Breast cancer was not significantly overrepresented in the hMSH2 mutation-positive group but was overrepresented in the hMLH1 mutation-positive group and in the mutation-negative group. Prostate cancer was not overrepresented in the mutation-positive groups but was overrepresented in the mutation-negative group. In age at diagnosis of colorectal cancer, there was no difference between the hMSH2 mutation-positive group and the hMLH1 mutation-positive group, but there was a significant difference between these two groups and the mutation-negative group.
UI - 11745471
AU - Hemminki K; Li X
TI - Familial colorectal adenocarcinoma from the Swedish Family-Cancer Database.
SO - Int J Cancer 2001 Dec 1;94(5):743-8
AD - Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden. email@example.com
Familial risks for colorectal (CRC) adenocarcinoma were characterized from the Swedish Family-Cancer Database covering 9.6 million individuals, whose family relationships and cancers were obtained from registered sources, not sensitive to reporting or ascertainment bias. Cancer cases were retrieved from the Swedish Cancer Registry from years 1958-96. Standardized incidence ratios (SIRs) were calculated based on gender-, age-, period- and tumor type specific rates. A total of 4,794 and 67,925 CRCs were recorded in offspring and parents, respectively. For colon and rectal adenocarcinoma, the SIRs in offspring were 2.28 and 1.68 by parental CRC adenocarcinoma, giving attributable proportions of 6.45 and 3.31%, respectively. The SIR of CRC was over 10 when both offspring and parents were diagnosed at a young age. The risk for parental CRC adenocarcinoma was over 100 when 2 or more children were affected. The risk in siblings was also very high when a parent was affected. The familial cancer sites that associated with CRC were those typical of hereditary nonpolyposis colorectal cancer (HNPCC). This is the largest study published on familial CRC and the only one reporting specifically on adenocarcinoma. The data suggest that HNPCC is the largest single disease entity among CRCs, probably accounting for less than 50% of familial CRC. Other familial components appear heterogeneous, characterized by incomplete penetrance, recessive mode of inheritance and few associated tumor sites. Copyright 2001 Wiley-Liss, Inc.
UI - 11916155
AU - van Stolk RU
TI - Familial and inherited colorectal cancer: endoscopic screening and surveillance.
SO - Gastrointest Endosc Clin N Am 2002 Jan;12(1):111-33
AD - Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA.
Familial risk of colorectal cancer is very common. The high-risk inherited syndromes are well described and much is known about the genetics and the effectiveness of registration, endoscopic surveillance, and appropriate intervention in these patients. The inherited syndromes, however, are extremely rare. There is a large group of patients in our population who can benefit from risk stratification based on the number of their relatives with colon cancer or adenomas and the age at which those relatives developed neoplasm. The GI endoscopist has a vital role in recommending and providing colonoscopic screening for this large group of patients.
UI - 11996796
AU - Planck M; Halvarsson B; Palsson E; Hallen M; Ekelund M; Palsson B;
TI - Baldetorp B; Nilbert M Cytogenetic aberrations and heterogeneity of mutations in repeat-containing genes in a colon carcinoma from a patient with hereditary nonpolyposis colorectal cancer.
SO - Cancer Genet Cytogenet 2002 Apr 1;134(1):46-54
AD - Department of Oncology, University Hospital, 221 85 Lund, Sweden. firstname.lastname@example.org
The majority of tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) exhibit a mutator phenotype characterized by widespread microsatellite instability (MSI) and somatic mutations in repeated sequences in several cancer-associated genes. An inverse relationship between MSI and chromosomal instability (CIN) has been demonstrated and HNPCC-associated tumors are generally characterized by diploid or near-diploid cells with few or no chromosomal rearrangements. We have studied MSI, somatic mutations in repeat-containing genes, DNA-ploidy, and cytogenetic aberrations in a colon carcinoma from a patient with a germline MLH1 mutation. Mutations in coding repeats were assessed in 10 macroscopically separate areas of the primary tumor and in two lymph nodes. Some of the genes studied (E2F4, MSH3, MSH6, TCF4, and TGFBRII) showed a consistent lack of mutations, whereas others (BAX, Caspase-5 and IGFIIR) displayed alterations in some tumor regions but not in others. The tumor had DNA-index 1.1-1.2 and a stable, aberrant karyotype with extra copies of chromosomes 7 and 12 and the structural aberrations i(1q), der(20)t(8;20), and der(22)t(1;22). The finding of CIN, MSI, and somatic mutations in coding repeats in this tumor suggests that these phenomena may act together in HNPCC tumorigenesis. Furthermore, the observed intratumoral heterogeneity of mutations in coding repeats implies these changes occur late in tumorigenesis and, thus, probably play a role in tumor progression rather than initiation.
UI - 11977532
AU - Katai M; Sakurai A; Fukushima Y
TI - [Genetic testing and counseling for familial tumor syndromes]
SO - Gan To Kagaku Ryoho 2002 Apr;29(4):502-7
AD - Division of Molecular and Clinical Genetics, Shinshu University Hospital.
Recent developments in molecular biology have increased our understanding of the genetics of familial tumor syndromes. Isolation of the responsible genes has made it possible to identify gene carriers before they manifest clinical symptoms, which enables early detection of disease and at times prophylactic surgery. Indications for genetic testing of susceptible family members, however, should be carefully considered. Genetic counseling must be provided to clients before genetic tests. Patients should be provided with the latest knowledge on the disease and appropriately informed of the benefits and possible problems associated with genetic test, as such information is essential for clients to decide whether they will undergo such tests. Genetic medicine is not sufficiently available at present in Japan. Establishment of genetic services that deal with genetic counseling, family support and ethical, social and legal issues is strongly desired.
UI - 11977537
AU - Takenoshita S; Takita K
TI - [Hereditary non-polyposis colorectal cancer (HNPCC)]
SO - Gan To Kagaku Ryoho 2002 Apr;29(4):539-44
AD - Department of Surgery II, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan.
Hereditary non-polyposis colorectal cancer (HNPCC) is a type of hereditary colorectal cancer with autosomal dominant traits. Its causal genes are mismatch repair genes such as the hMSH2 and hMLH1 genes. Owing to its frequency, juvenile onset, and the outbreaks of multiple colorectal cancers and cancers occurring over multiple organs, it is recognized as a very important disease for the purpose of understanding not only colorectal cancers, but also other digestive cancers, and furthering pathological inquiry into the state of cancers in general.
UI - 11950865
AU - Albuquerque C; Cravo M; Cruz C; Lage P; Chaves P; Fidalgo P; Suspiro A;
TI - Nobre Leitao C Genetic characterisation of patients with multiple colonic polyps.
SO - J Med Genet 2002 Apr;39(4):297-302
UI - 12011148
AU - Hutter P; Wijnen J; Rey-Berthod C; Thiffault I; Verkuijlen P; Farber D;
TI - Hamel N; Bapat B; Thibodeau SN; Burn J; Wu J; MacNamara E; Heinimann K; Chong G; Foulkes WD An MLH1 haplotype is over-represented on chromosomes carrying an HNPCC predisposing mutation in MLH1.
SO - J Med Genet 2002 May;39(5):323-7
AD - Unit of Genetics, Institut Central des Hopitaux Valaisans, Sion, Switzerland. email@example.com
BACKGROUND: The mismatch repair gene, MLH1, appears to occur as two main haplotypes at least in white populations. These are referred to as A and G types with reference to the A/G polymorphism at IVS14-19. On the basis of preliminary experimental data, we hypothesised that deviations from the expected frequency of these two haplotypes could exist in carriers of disease associated MLH1 germline mutations. METHODS: We assembled a series (n=119) of germline MLH1 mutation carriers in whom phase between the haplotype and the mutation had been conclusively established. Controls, without cancer, were obtained from each contributing centre. Cases and controls were genotyped for the polymorphism in IVS14. RESULTS: Overall, 66 of 119 MLH1 mutations occurred on a G haplotype (55.5%), compared with 315 G haplotypes on 804 control chromosomes (39.2%, p=0.001). The odds ratio (OR) of a mutation occurring on a G rather than an A haplotype was 1.93 (95% CI 1.29 to 2.91). When we compared the haplotype frequencies in mutation bearing chromosomes carried by people of different nationalities with those seen in pooled controls, all groups showed a ratio of A/G haplotypes that was skewed towards G, except the Dutch group. On further analysis of the type of each mutation, it was notable that, compared with control frequencies, deletion and substitution mutations were preferentially represented on the G haplotype (p=0.003 and 0.005, respectively). CONCLUSION: We have found that disease associated mutations in MLH1 appear to occur more often on one of only two known ancient haplotypes. The underlying reason for this observation is obscure, but it is tempting to suggest a possible role of either distant regulatory sequences or of chromatin structure influencing access to DNA sequence. Alternatively, differential behaviour of otherwise similar haplotypes should be considered as prime areas for further study.
UI - 12011152
AU - Carayol J; Khlat M; Maccario J; Bonaiti-Pellie C
TI - Hereditary non-polyposis colorectal cancer: current risks of colorectal cancer largely overestimated.
SO - J Med Genet 2002 May;39(5):335-9
UI - 11967905
AU - Koshiji M; Yonekura Y; Saito T; Yoshioka K
TI - Microsatellite analysis of fecal DNA for colorectal cancer detection.
SO - J Surg Oncol 2002 May;80(1):34-40
AD - The Second Department of Surgery, Kansai Medical University, Osaka, Japan. firstname.lastname@example.org
BACKGROUND AND OBJECTIVES: The advent of noninvasive methods of testing for colorectal cancer that have a high level of specificity and sensitivity is eagerly awaited. METHODS: Thirty patients with sporadic colorectal cancer and 11 patients with hereditary nonpolyposis colon cancer (HNPCC) enrolled in this study. We analyzed the loss of heterozygosity (LOH) in matched genomic DNA extracted from blood and surgical specimens (tumor and tumor-free colonic mucosa), and the corresponding oral rinse and stool specimens using seven microsatellite loci (APC, p53, DCC, hMLH1, D9S162, D9S171, and IFNA). To reduce the normal colonocyte DNA contamination of the stool samples, we compared three different methods for fecal genomic DNA extraction. As normal controls, we analyzed the LOH using the oral rinse and stool samples from 15 individuals without cancer. RESULTS: The LOH determined from the oral rinse and the stool samples matched those determined from the blood and the neoplastic tissue. All patients with HNPCC had microsatellite alterations at hMLH-1 in tumor DNA and corresponding fecal DNA. There were significant differences in the frequency of p53-LOH and D9S171-LOH between the group with sporadic disease and those with HNSCC (P = 0.0031 and 0.0294, respectively). Two cases with D9S162-LOH were detected in individuals without cancer. For the patients with sporadic disease, using p53 and adenomatous polyposis coli (APC), the sensitivity of the fecal DNA analysis was 96.7% (95% CI, 83-100) with a specificity of 100%. CONCLUSION: We demonstrate that LOH analysis using oral rinse and stool samples may be a suitable screening tool for colorectal cancer. Copyright 2002 Wiley-Liss, Inc.
UI - 12004844
AU - Fornasarig M; Viel A; Bidoli E; Campagnutta E; Minisini AM; Cannizzaro
TI - R; Della Puppa L; Boiocchi M Amsterdam criteria II and endometrial cancer index cases for an accurate selection of HNPCC families.
SO - Tumori 2002 Jan-Feb;88(1):18-20
AD - Department of Gastroenterology, Centro di Riferimento Oncologico, Aviano, Italy. email@example.com
Endometrial carcinoma (EC) is the second most common tumor in hereditary nonpolyposis colorectal cancer (HNPCC), with an incidence rate of 60% by the age of 70 in mutation carriers. The International Collaborative Group on HNPCC revised the Amsterdam criteria and proposed a new, wider definition including extracolonic cancers. The aim of our study was to evaluate the accuracy of a new definition called Amsterdam criteria II. We updated, reclassified and compared the pedigrees of 29 women, already reported as being affected by EC and having a colorectal cancer familial background, according to the two clinical diagnostic criteria for HNPCC (Amsterdam criteria I, ACI, and Amsterdam criteria II, ACII) after two periods of observation (1990-1995 and 1995-2000). According to ACII the frequency of HNPCC in the population under study increased from 0.9% to 3.7% in the period 1990-1995 and from 3.2% to 3.7% in the period 1995-2000. ACII allowed early detection of HNPCC families and thus made it possible to provide them with a suitable surveillance program and genetic testing.
UI - 11782355
AU - Shin KH; Shin JH; Kim JH; Park JG
TI - Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene.
SO - Cancer Res 2002 Jan 1;62(1):38-42
AD - Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.
The human DNA mismatch repair genes hMSH2 and hMLH1 are responsible for the development of hereditary nonpolyposis colorectal cancer (HNPCC). Although genetic alteration of the coding region of hMSH2 and hMLH1 has been well investigated in HNPCC patients, the regulatory regions of these genes have been poorly investigated, though recent studies have defined and characterized the core promoter regions of hMSH2 and hMLH1. Therefore, to investigate the presence of germ-line mutations, we screened the core promoter regions of hMSH2 and hMLH1 from 157 nonmalignant control individuals, 40 cases of HNPCC, 56 suspected HNPCC cases, and 45 sporadic early onset colorectal cancer patients. Three novel germ-line mutations of the hMSH2 promoter were identified in two suspected HNPCC cases and one sporadic early onset colorectal cancer patient but not in the 157 nonmalignant controls, namely, an A insertion at position -80, a G-to-A transition at position -190, and a G-to-C transversion at position -225. Tumors from patients containing the promoter mutations displayed microsatellite instability. The A insertion at -80 is within a sequence homologous to the consensus sequence for E1AF and very close to the major transcription start point. Luciferase assay demonstrated that the -80A insertion and the -190A allele decreased the transcriptional efficiency by 82 and 77%, respectively, and the -225C allele increased the transcriptional efficiency by 466%. The -80A insertion allele was detected only in affected members within the family and showed novel transcription factor binding ability. Furthermore, the loss of single nucleotide polymorphism allelic expression was identified in blood of the patient containing the -80A insertion. Our results indicate that mutations in the promoter region of hMSH2 have a limited role in development of suspected HNPCC and sporadic early onset colorectal cancer.
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