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Abramson Cancer CenterNCI CANCERLIT® Search: Non-polyposis Colon Cancer, Hereditary - April 2002
National Cancer Institute®
Last Modified: April 1, 2002
Table of Contents
1
UI - 11484291
AU - Yar'mov N; Gachev N
TI -
[Colorectal carcinoma and molecular genetics]
SO - Khirurgiia (Sofiia) 2000;56(2):50-2
In the last few years, problems relating to genetic determination of
colorectal carcinoma are comprehensively discussed by a number of
authors. The new elaborations concerning the familial polypoid and
carcinoid syndromes discovered, as well as molecular researches along
this line answer a great number of questions posed in connection with
substantiating the old idea about many-staged cancerigenesis. As much as
94 per cent of colorectal carcinoma cases are assigned to the sporadic
cancer diagnosis category. Familial polyposis accounts for 1 per cent of
all neoplasms of the colon, while the remainder 5 per cent make part of
diverse familial carcinoid syndromes. Most of the data on genetic
etiology of colorectal carcinoma so far elucidated are presented in a
summed up fashion.
2
UI - 11852407
AU - Terdiman J; Gum Jr J; Conrad P; Miller G; Weinberg V; Crawley S; Levin
TI -
T; Reeves C; Schmitt A; Hepburn M; Sleisenger M; Kim Y
[Search for microsatellite instability in colorectal cancer: an
effective way to detect HNPCC?]
SO - Gastroenterol Clin Biol 2001 Oct;25(10):929-31
AD - Federation Transversale de Cancerologie, CHU de Toulouse et Institut,
Claudius-Regaud, Tououse, France.
3
UI - 11899542
AU - Krutilkova V; Havlovicova M; Goetz P
TI -
[Specialized genetic counseling in pediatric and adult oncology
patients]
SO - Cas Lek Cesk 2002;141(1):23-7
AD - Ustav biologie a lekarske genetiky 2. LF UK a FNM, Praha.
vera.krutilkova@lfmotol.cuni.cz
Five to ten percent of oncological diseases exhibit monogenic mode of
inheritance. They occur as a consequence of the germline mutations of
tumor suppressor genes and of the genes engaged in reparative processes.
Most common monogenically determined oncological diseases are: AD form
of breast and ovarian cancer, hereditary nonpolyposis colorectal cancer
(HNPCC, Lynch sy.) and familiar adenomatous polyposis (FAP). The aim of
the genetic investigation is to evaluate whether the index family deals
with the hereditary form of tumor predisposition, than, if possible, to
perform DNA analysis in the family and to propose preventive screening
program (methods) for the probands in risk.
4
UI - 11870161
AU - Scartozzi M; Bianchi F; Rosati S; Galizia E; Antolini A; Loretelli C;
TI -
Piga A; Bearzi I; Cellerino R; Porfiri E
Mutations of hMLH1 and hMSH2 in patients with suspected hereditary
nonpolyposis colorectal cancer: correlation with microsatellite
instability and abnormalities of mismatch repair protein expression.
SO - J Clin Oncol 2002 Mar 1;20(5):1203-8
AD - Department of Clinica di Oncologia Medica, University of Ancona, Ancona,
Italy.
PURPOSE: The relationship between germ-line mutations of hMSH2 and
hMLH1, microsatellite instability (MSI), and loss of DNA mismatch repair
(MMR) gene expression were studied to formulate an effective selection
protocol for patients with suspected hereditary nonpolyposis colorectal
cancer who should be offered genetic testing. PATIENTS AND METHODS:
Patients eligible for germ-line analysis of hMLH1 and hMSH2 were
selected. Tumor specimens were obtained to assess MSI and loss of MMR
gene expression. RESULTS: Among 37 patients who participated in the
study, two hMSH2 and two hMLH1 missense mutations (11%) were detected,
none of which was found in a panel of 60 healthy volunteers. High MSI
was found in five tumors (19%) and low MSI in 10 tumors (39%); 12 tumors
(46%) were microsatellite stable. Four tumors demonstrated loss of
hMLH1, and three tumors demonstrated loss of hMSH2 protein expression.
CONCLUSION: No relationship was found between MMR gene mutations and
MSI; low or no MSI was found in the four patients with germ-line
mutations, and none of the five patients with high MSI demonstrated
abnormalities of MMR genes. On the contrary, loss of hMLH1 or hMSH2
expression was found in the tumors from three of the four patients
demonstrating germ-line mutations. These data suggest that germ-line
mutations of the MMR gene can occur in people with MSI-negative tumors.
Sensitive clinical criteria and the study of MMR gene expression may be
useful to identify this subset of patients.
5
UI - 11920532
AU - Dove-Edwin I; Boks D; Goff S; Kenter GG; Carpenter R; Vasen HF; Thomas
TI -
HJ
The outcome of endometrial carcinoma surveillance by ultrasound scan in
women at risk of hereditary nonpolyposis colorectal carcinoma and
familial colorectal carcinoma.
SO - Cancer 2002 Mar 15;94(6):1708-12
AD - Imperial Cancer Research Fund Family Cancer Clinic, St Mark's Hospital,
London, UK.
BACKGROUND: Endometrial carcinoma is the most common extracolonic
malignancy associated with hereditary nonpolyposis colorectal carcinoma
syndrome (HNPCC). The risk of endometrial carcinoma in HNPCC mutation
carriers is approximately ten times that of the general population, and
endometrial ultrasound surveillance to detect early cancer in
asymptomatic individuals is recommended by the International
Collaborative Group on HNPCC. There is little, if any, published data
addressing the effectiveness of surveillance in HNPCC and familial
colorectal carcinoma. METHODS: The outcomes of endometrial carcinoma
surveillance scans were collected from the St Mark's Hospital Imperial
Cancer Research Fund Family Cancer Clinic in the UK and the Netherlands
Foundation for the Detection of Hereditary Tumors. Two hundred ninety
two women from HNPCC (171) or HNPCC-like (98) families between the ages
of 25-65 years were offered pelvic ultrasound surveillance scans for a
period of up to 13 years. RESULTS: Results were available from 269
women. The study period included a total of 825.7 years of risk. Two
cases of endometrial carcinoma were reported. Neither case was detected
by surveillance scanning. Both cases presented at an early stage with
symptoms and were subsequently cured. CONCLUSIONS: Endometrial carcinoma
surveillance in hereditary colorectal carcinoma may not offer obvious
clinical benefits. Copyright 2002 American Cancer Society.
6
UI - 11778159
AU - Wullen B; Muhlhofer A; Zoller WG
TI -
[Controlled 15-year trial on screening for colorectal cancer in families
with hereditary nonpolyposis colorectal cancer]
SO - Z Gastroenterol 2001 Nov;39(11):981-4
AD - Zentrum fur Innere Medizin, Klinik fur Allgemeine Innere Medizin,
Stuttgart.
7
UI - 11920458
AU - Furukawa T; Konishi F; Shitoh K; Kojima M; Nagai H; Tsukamoto T
TI -
Evaluation of screening strategy for detecting hereditary nonpolyposis
colorectal carcinoma.
SO - Cancer 2002 Feb 15;94(4):911-20
AD - Department of Surgery, Jichi Medical School, Kawachi-gun, Tochigi,
Japan. furukawa@jichi.ac.jp
BACKGROUND: The Amsterdam criteria are used worldwide for the clinical
diagnosis of hereditary nonpolyposis colorectal carcinoma (HNPCC). In
Japan, clinical criteria (JCC) have been proposed to identify as many
HNPCC cases as possible, but the suitability of the JCC remains
uncertain. In this article, the authors evaluate retrospectively whether
the JCC are adequate to diagnose HNPCC compared with the Bethesda
guidelines (BG) and also investigated useful screening methods for
HNPCC. METHODS: The authors studied 452 colorectal carcinoma cases, of
which 69 cases fulfilled the JCC (A, 12; B, 57) and 106 fulfilled the
BG. Microsatellite instability (MSI) was examined for 452 cases. TGF
beta RII, immunohistochemical staining, and germline mutations of hMLH1
and hMSH2 were analyzed in high-frequency MSI cases. RESULTS:
High-frequency MSI was found in 21.7% (98 of 452). Germline mutations
were detected in eight cases (hMLH1, three, hMSH2; five). Six cases
fulfilled the JCC (A, four; B, two), and six fulfilled the BG. The
germline mutation rate was significantly higher in the JCCA than in
non-JCCA cases (33.3% vs. 0.91%; P < 0.001) and in cases with an age at
onset younger than 50 years than older than 50 years (9.3% vs. 0.27%, P
< 0.001). All germline mutation carriers had the TGF beta RII mutation.
Immunohistochemically, a decreased nuclear staining was found in 57.3%
(47 of 82) for hMLH1 and in 18.3% (15 of 82) for hMSH2. The frequency of
predicted germline mutations was higher in cases with decreased hMSH2
than hMLH1 (33.3% vs. 6.4%; P = 0.016). CONCLUSIONS: The JCCA are
suitable for selecting cases to analyze for gene mutations, but the JCCB
are not useful for the clinical setting. The authors suggest that an age
at onset younger than 50 years is also important for screening.
Analyzing TGF beta RII mutations and immunohistochemical staining of
hMLH1 or hMSH2 for cases with MSI phenotype are useful for selecting
cases who should be tested for germline mutations. Copyright 2002
American Cancer Society. DOI 10.1002/cncr.10332
8
UI - 11579115
AU - Percesepe A; Borghi F; Menigatti M; Losi L; Foroni M; Di Gregorio C;
TI -
Rossi G; Pedroni M; Sala E; Vaccina F; Roncucci L; Benatti P; Viel A;
Genuardi M; Marra G; Kristo P; Peltomaki P; Ponz de Leon M
Molecular screening for hereditary nonpolyposis colorectal cancer: a
prospective, population-based study.
SO - J Clin Oncol 2001 Oct 1;19(19):3944-50
AD - Department of Internal Medicine, University of Modena, Modena, Italy.
percesepe.antonio@unimo.it
PURPOSE: Germline mutations in mismatch repair genes predispose to
hereditary nonpolyposis colorectal cancer (HNPCC). To address effective
screening programs, the true incidence of the disease must be known.
Previous clinical investigations reported estimates ranging between 0.5%
and 13% of all the colorectal cancer (CRC) cases, whereas biomolecular
studies in Finland found an incidence of 2% to 2.7% of mutation carriers
for the disease. The aim of the present report is to establish the
frequency of the disease in a high-incidence area for colon cancer.
PATIENTS AND METHODS: Through the data of the local CRC registry, we
prospectively collected all cases of CRC from January 1, 1996, through
December 31, 1997 (N = 391). Three hundred thirty-six CRC cases (85.9%
of the incident cases) were screened for microsatellite instability
(MSI) with six to 12 mono- and dinucleotide markers. MSI cases were
subjected to MSH2 and MLH1 germline mutation analysis and
immunohistochemistry; the methylation of the promoter region was studied
for MLH1. RESULTS: Twenty-eight cases (8.3% of the total) showed MSI.
MSI cases differed significantly from microsatellite-stable (MSS) cases
for their proximal location (P <.01), high mucinous component (P <.01),
and poor differentiation (P =.002). Of MSI cases studied (n = 12), only
one with a family history compatible with HNPCC had a germline mutation
(in MSH2). Five other patients with a family history of HNPCC (two with
MSI and three with MSS tumors) did not show germline mutations.
CONCLUSION: We conclude that the incidence of molecularly confirmed
HNPCC (one [0.3%] of 336) in a high-incidence area for CRC is lower than
in previous biomolecular and clinical estimates.
9
UI - 11896123
AU - Andermann A; Thiffault I; Wong N; Gordon P; MacNamara E; Chong G;
TI -
Foulkes W
Multimodal molecular screening is required to improve the sensitivity of
MLH1 and MSH2 mutation analysis.
SO - J Clin Oncol 2002 Mar 15;20(6):1705-7
10
UI - 11920650
AU - Caldes T; Godino J; de la Hoya M; Garcia Carbonero I; Perez Segura P;
TI -
Eng C; Benito M; Diaz-Rubio E
Prevalence of germline mutations of MLH1 and MSH2 in hereditary
nonpolyposis colorectal cancer families from Spain.
SO - Int J Cancer 2002 Apr 10;98(5):774-9
AD - Laboratory of Molecular Oncology, San Carlos University Hospital,
Madrid, Spain. tcaldes@hcsc.es
HNPCC is an autosomal dominantly inherited cancer-susceptibility
syndrome that confers an increased risk for colorectal cancer and
endometrial cancer at a young age. It also entails an increased risk of
a variety of other tumors, such as ovarian, gastric, uroepithelial and
biliary tract cancers. The underlying pathogenic mutation lies in 1 of
the 5 known DNA MMR genes (MSH2, MLH1, PMS1, PMS2 and MSH6). We screened
a total of 140 individuals from 56 Spanish families with suspected HNPCC
for mutations in the DNA mismatch repair genes MLH1 and MSH2, using DGGE
and direct DNA sequencing. Families were selected on the basis of a
history of HNPCC-related tumors or the occurrence of other associated
tumors in members besides the index case affected with colorectal
cancer. We detected 14 definite pathogenic germline mutations, 9 in MLH1
and 5 in MSH2 in 13 unrelated families selected by the Amsterdam
criteria and Bethesda guidelines (1 family carries 2 mutations) and 3
missense mutations in 3 unrelated families selected by the Amsterdam
criteria. Among the 17 germline mutations noted in the Spanish cohort,
10 are novel, 7 in MLH1 and 3 in MSH2, perhaps demonstrating different
mutational spectra in the Spanish population, where no founder mutation
has been identified. Based on our results, we suggest that in the
Spanish population not only HNPCC families fulfilling the Amsterdam
criteria but also those following Bethesda guidelines should undergo
genetic testing for MSH2 and MLH1 mutations. Copyright 2002 Wiley-Liss,
Inc.
11
UI - 8072530
AU - Nicolaides NC; Papadopoulos N; Liu B; Wei YF; Carter KC; Ruben SM; Rosen
TI -
CA; Haseltine WA; Fleischmann RD; Fraser CM; et al
Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.
SO - Nature 1994 Sep 1;371(6492):75-80
AD - Johns Hopkins Oncology Center, Baltimore, Maryland 21231.
Hereditary nonpolyposis colorectal cancer (HNPCC) is one of man's
commonest hereditary diseases. Several studies have implicated a defect
in DNA mismatch repair in the pathogenesis of this disease. In
particular, hMSH2 and hMLH1 homologues of the bacterial DNA mismatch
repair genes mutS and mutL, respectively, were shown to be mutated in a
subset of HNPCC cases. Here we report the nucleotide sequence,
chromosome localization and mutational analysis of hPMS1 and hPMS2, two
additional homologues of the prokaryotic mutL gene. Both hPMS1 and hPMS2
were found to be mutated in the germline of HNPCC patients. This doubles
the number of genes implicated in HNPCC and may help explain the
relatively high incidence of this disease.
12
UI - 7616541
AU - Froggatt NJ; Koch J; Davies R; Evans DG; Clamp A; Quarrell OW;
TI -
Weissenbach J; Hodgson SV; Ponder BA; Barton DE; et al
Genetic linkage analysis in hereditary non-polyposis colon cancer
syndrome.
SO - J Med Genet 1995 May;32(5):352-7
AD - Cambridge University Department of Pathology, Addenbrooke's Hospital,
Cambridge, UK.
Hereditary Non-polyposis Colon Cancer Syndrome (HNPCC) is the most
common cause of familial colorectal cancer. Molecular genetic studies of
HNPCC have shown evidence of locus heterogeneity, and mutations in four
genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of the
mismatch enzyme repair system may cause HNPCC. To determine the extent
and nature of locus heterogeneity in HNPCC, we performed genetic linkage
studies in 14 HNPCC families from eastern and north-western England.
Linkage to hMLH1 was excluded in six families, each of which were likely
to be linked to hMSH2 (lod score > 1.0 in each family and total lod
score for all six families = 7.64). Linkage to hMSH2 was excluded in
three families, each of which were likely to be linked to hMLH1 (lod
score > 1.0 in each family and total lod score at hMLH1 for all three
families = 3.93). In the remaining five families linkage to hMSH2 or
hMLH1 could not be excluded. These results confirm locus heterogeneity
in HNPCC and suggest that, in the population studied, most large
families with HNPCC will have mutations in hMSH2 or hMLH1. We did not
detect any correlation between clinical phenotype and the genetic
linkage results, but a Muir-Torre syndrome family excluded from linkage
to hMLH1 was likely to be linked to hMSH2 and showed microsatellite
instability in a tumour from an affected relative.
13
UI - 8586419
AU - Nicolaides NC; Carter KC; Shell BK; Papadopoulos N; Vogelstein B;
TI -
Kinzler KW
Genomic organization of the human PMS2 gene family.
SO - Genomics 1995 Nov 20;30(2):195-206
AD - Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
The hPMS2 gene (HGMW-approved symbol PMS2) encodes a mutL homolog that
causes hereditary non-polyposis colon cancer (HNPCC) when inherited in
mutant form. We have here characterized the genomic structure of the
hPMS2 gene to facilitate its analysis in HNPCC kindreds. The hPMS2
genomic locus was found to encompass 16 kb and consist of 15 exons.
During its analysis, we identified a family of hPMS2-related genes
located on chromosome 7 at bands 7p12-p13, 7q11, and 7q22. Exons 1
through 5 of these homologs shared a high degree of identity with hPMS2.
We present the sequence of seven novel genes that represent the hPMSR
(hPMS2-related) gene family. The similarity and number of these genes
made specific amplification of hPMS2 problematic, but knowledge of them
aided the successful design of oligonucleotides for this purpose.
14
UI - 8666379
AU - Nicolaides NC; Kinzler KW; Vogelstein B
TI -
Analysis of the 5' region of PMS2 reveals heterogeneous transcripts and
a novel overlapping gene.
SO - Genomics 1995 Sep 20;29(2):329-34
AD - Howard Hughes Medical Institute, Baltimore, Maryland 21231, USA.
The PMS2 gene encodes a protein that is involved in DNA mismatch repair
and is mutated in a subset of patients with hereditary nonpolyposis
colon cancer (HNPCC). The previously published PMS2 cDNA sequence lacks
an upstream in-frame stop codon preceding the presumptive initiating
methionine. To evaluate the 5' terminus of the PMS2 coding region
further, we isolated additional cDNA clones, RT-PCR products, and the
corresponding 5' genomic segment of the PMS2 locus. The PMS2 gene
transcripts were found to have heterogeneous but colinear 5' termini,
one of which contained an in-frame termination codon preceding the
initiating methionine. In addition, a novel gene encoding a 34.5-kDa
polypeptide was found to initiate transcriptionally within PMS2 from the
opposite strand.
15
UI - 8614807
AU - Mellon I; Rajpal DK; Koi M; Boland CR; Champe GN
TI -
Transcription-coupled repair deficiency and mutations in human mismatch
repair genes.
SO - Science 1996 Apr 26;272(5261):557-60
AD - Department of Pathology, Program in Toxicology, Markey Cancer Center,
University of Kentucky, Lexington, KY 40536, USA.
Deficiencies in mismatch repair have been linked to a common cancer
predisposition syndrome in humans, hereditary nonpolyposis colorectal
cancer (HNPCC), and a subset of sporadic cancers. Here, several mismatch
repair-deficient tumor cell lines and HNPCC-derived lymphoblastoid cell
lines were found to be deficient in an additional DNA repair process
termed transcription-coupled repair (TCR). The TCR defect was corrected
in a mutant cell line whose mismatch repair deficiency had been
corrected by chromosome transfer. Thus, the connection between excision
repair and mismatch repair previously described in Escherichia coli
extends to humans. These results imply that deficiencies in TCR and
exposure to carcinogens present in the environment may contribute to the
etiology of tumors associated with genetic defects in mismatch repair.
16
UI - 9000555
AU - Meyers M; Theodosiou M; Acharya S; Odegaard E; Wilson T; Lewis JE; Davis
TI -
TW; Wilson-Van Patten C; Fishel R; Boothman DA
Cell cycle regulation of the human DNA mismatch repair genes hMSH2,
hMLH1, and hPMS2.
SO - Cancer Res 1997 Jan 15;57(2):206-8
AD - Department of Human Oncology, University of Wisconsin, Madison 53792,
USA.
Hereditary nonpolyposis colorectal cancer is a cancer susceptibility
syndrome that has been found to be caused by mutations in any of several
genes involved in DNA mismatch repair, including hMSH2, hMLH1, or hPMS2.
Recent reports have suggested that hMSH2 and hMLH1 have a role in the
regulation of the cell cycle. To determine if these genes are cell cycle
regulated, we examined their mRNA and protein levels throughout the cell
cycle in IMR-90 normal human lung fibroblasts. We demonstrate that the
levels of hMSH2 mRNA and protein do not change appreciably throughout
the cell cycle. Although hMLH1 mRNA levels remained constant, there was
a modest (approximately 50%) increase in its protein levels during late
G1 and S phase. The levels of hPMS2 mRNA fluctuated (decreasing 50% in
G1 and increasing 50% in S phase), whereas hPMS2 protein levels
increased 50% in late G1 and S phase. Our data indicate that, at least
in normal cells, the machinery responsible for the detection and repair
of mismatched DNA bases is present throughout the cell cycle.
17
UI - 9062331
AU - Burke W; Petersen G; Lynch P; Botkin J; Daly M; Garber J; Kahn MJ;
TI -
McTiernan A; Offit K; Thomson E; Varricchio C
Recommendations for follow-up care of individuals with an inherited
predisposition to cancer. I. Hereditary nonpolyposis colon cancer.
Cancer Genetics Studies Consortium.
SO - JAMA 1997 Mar 19;277(11):915-9
AD - Department of Medicine, University of Washington, Seattle 98105-6920,
USA.
OBJECTIVE: To provide recommendations for cancer surveillance and risk
reduction for individuals carrying mutations associated with hereditary
nonpolyposis colon cancer (HNPCC). PARTICIPANTS: A task force with
expertise in medical genetics, oncology, primary care, gastroenterology,
and epidemiology convened by the Cancer Genetics Studies Consortium
(CGSC), organized by the National Human Genome Research Institute
(previously the National Center for Human Genome Research). EVIDENCE:
Studies evaluating cancer risk, surveillance, and risk reduction in
individuals genetically susceptible to colon cancer were identified
using MEDLINE and bibliographies of articles thus identified. Indexing
terms used were "genetics" in combination with "colon cancer," and
"screening" in combination with "cancer family" and "HNPCC." For studies
evaluating specific interventions, quality of evidence was assessed
using criteria of the US Preventive Services Task Force. CONSENSUS
PROCESS: The task force developed recommendations through discussions
over a 14-month period. CONCLUSIONS: Efficacy of cancer surveillance or
other measures to reduce risk in individuals who carry
cancer-predisposing mutations is unknown. Based on observational
studies, colonoscopy every 1 to 3 years starting at age 25 years is
recommended for individuals known to have HNPCC-associated mutations.
Endometrial cancer screening is also recommended, based on expert
opinion concerning presumptive benefit. No recommendation is made for or
against prophylactic surgery (ie, colectomy, hysterectomy); these
surgeries are an option for mutation carriers, but evidence of benefit
is lacking. It is recommended that individuals considering genetic
testing be counseled regarding the unknown efficacy of measures to
reduce risk and that care for individuals with cancer-predisposing
mutations be provided whenever possible within the context of research
protocols designed to evaluate clinical outcomes.
18
UI - 9060003
AU - Lothe RA
TI -
Microsatellite instability in human solid tumors.
SO - Mol Med Today 1997 Feb;3(2):61-8
AD - Department of Genetics, Institute for Cancer Research, Norwegian Radium
Hospital, Montebello, Oslo, Norway. rlothe@ulrik.uio.no
A genome-wide instability has been found in almost all analyzed
malignant tumors from patients with hereditary non-polyposis colorectal
cancer (HNPCC), and in a subgroup of sporadic (non-inherited) cancers of
the same type. This mutator phenotype was initially seen as novel
alleles at microsatellite loci (a family of repetitive DNA sequences)
and was shown to be caused by mutations in the highly conserved mismatch
repair genes. Mutations have been found in each of four of these human
genes: hMSH2, hMLH1, hPMS1 and hPMS2, in the germline of HNPCC patients
and in their tumors, as well as in sporadic tumors. These recent
discoveries provide new molecular diagnostic tools for the detection of
patients at high risk of developing carcinomas of the large bowel and
other HNPCC-related tumors. Ongoing international research is
progressively solving many of the unanswered questions at the genotypic
and phenotypic levels of this newly identified mechanism in
carcinogenesis.
19
UI - 9111864
AU - Peltomaki P; de la Chapelle A
TI -
Mutations predisposing to hereditary nonpolyposis colorectal cancer.
SO - Adv Cancer Res 1997;71():93-119
AD - Department of Medical Genetics, Haartman Institute, University of
Helsinki, Finland.
Since 1993 four genes have been identified that, when mutated, confer
predisposition to a form of hereditary colon cancer (hereditary
nonpolyposis colorectal cancer [HNPCC]). These genes belong to the
Mut-related family of DNA mismatch repair genes whose protein products
are responsible for the recognition and correction of errors that arise
during DNA replication. Mutational inactivation of both copies of a DNA
mismatch repair gene results in a profound repair defect demonstrable by
biochemical assays, and in vivo this defect is presumed to lead to
progressive accumulation of secondary mutations throughout the genome,
some of which affect important growth-regulatory genes and, hence, give
rise to cancer. To date, more than 70 different germline mutations have
been detected in DNA mismatch repair genes and shown to be associated
with HNPCC. Current evidence suggests that two genes, MSH2 and MLH1,
account for roughly equal proportions of HNPCC kindreds, together being
responsible for a majority of these families, but striking interethnic
differences occur. Most mutations lead to truncated protein products.
Mutation screening is quite demanding in HNPCC since, with a few
exceptions, the predisposing mutations typically vary from kindred to
kindred and individual mutations are scattered throughout the genes.
Knowledge of the predisposing mutations allows genotype-phenotype
correlations and forms the basis for further studies clarifying the
pathogenesis of this disorder. In at-risk individuals, it allows
predictive testing for cancer susceptibility and, consequently,
appropriate clinical management of mutation carriers and noncarriers.
20
UI - 9259192
AU - Papadopoulos N; Lindblom A
TI -
Molecular basis of HNPCC: mutations of MMR genes.
SO - Hum Mutat 1997;10(2):89-99
AD - Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Hereditary nonpolyposis colorectal cancer (HNPCC) is inherited as a
dominant disorder caused by germline defects in one of at least four
mismatch repair (MMR) genes. Two of these genes, hMSH2 and hMLH1,
account for the vast majority of the germline mutations in HNPCC
kindreds, whereas hPMS1 and hPMS2 are mutated in only few families. MMR
genes also are susceptible to somatic mutations in sporadic tumors. The
mutational spectrum of the MMR genes shows no predominant type of
mutation. Furthermore, the mutations are spread throughout the length of
the genes, with no significant hot spots. Identification of MMR genes as
the cause of HNPCC made presymptomatic diagnosis a reality. However, the
presence of multiple genes and the heterogeneity of mutations present
challenges to the development of diagnostic tests for this disease.
21
UI - 9322509
AU - Peltomaki P; Vasen HF
TI -
Mutations predisposing to hereditary nonpolyposis colorectal cancer:
database and results of a collaborative study. The International
Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer.
SO - Gastroenterology 1997 Oct;113(4):1146-58
AD - Department of Medical Genetics, Haartman Institute, Helsinki, Finland.
Paivi.Peltomaki@helsinki.fi
BACKGROUND & AIMS: Germline mutations in four DNA mismatch repair genes
are known to cause susceptibility to hereditary nonpolyposis colorectal
cancer (HNPCC). The rapidly increasing information about these mutations
needs to be collected and appropriately stored to facilitate further
studies on the biological and clinical significance of the findings.
METHODS: The International Collaborative Group on HNPCC has established
a database of DNA mismatch repair gene mutations and polymorphisms. In
this report, 126 predisposing mutations were analyzed. RESULTS: A
majority of the mutations affected either the Mut L homologue (MLH) 1 (n
= 75) or the Mut S homologue (MSH) 2 (n = 48) and were quite evenly
distributed, with some clustering in MSH2 exon 12 and MLH1 exon 16. Most
MSH2 mutations consisted of frameshift (60%) or nonsense changes (23%),
whereas MLH1 was mainly affected by frameshift (40%) or missense
alterations (31%). Although most mutations were unique, a few common
recurring mutations were identified. Of the families studied (n = 202),
82% met the Amsterdam criteria and 15% did not; the general mutation
profile was similar in both groups. CONCLUSIONS: The construction of
mutation profiles will facilitate the development of diagnostic
strategies in HNPCC.
22
UI - 9365839
AU - Moliaka YK; Cella M; Chudina AP; Kolesnikova TN; Terracciano L; Cathomas
TI -
G; Bochkov NP; Buerstedde JM
Mechanisms underlying mismatch repair deficiencies in normal cells.
SO - Genes Chromosomes Cancer 1997 Nov;20(3):305-9
AD - Department of Medical Genetics, Sechenov Moscow Medical Academy, Moscow,
Russia.
Hereditary nonpolyposis colon cancer (HNPCC) is an autosomal dominantly
inherited cancer predisposition which is linked to heterozygous
mutations in mismatch repair genes. HNPCC tumour cells, in which the
remaining wild-type copy of the mismatch repair gene is inactivated,
display instability of microsatellite markers reflecting a defect in
mismatch repair. Recently, patients carrying either one of two distinct
germline mutations in the MLH1 and PMS2 genes were reported to
accumulate somatic mutations of microsatellites in untransformed cells.
One of the mechanisms that might account for this phenomenon was a
dominant negative effect of the mutant allele. To evaluate this
possibility, we examined a different family carrying one of the
mutations (deletion of codon 618K in the MLH1 gene) which has been
suspected to induce genetic instability in untransformed cells. No
mutations in dinucleotide repeat markers were observed in a large number
of lymphoblast clones derived from a carrier. Evidence for the deletion
of the wild-type allele in two different tumours suggested that the
inactivation of both gene copies was required for tumour initiation.
These results indicate that the MLH1 618K deletion mutation alone does
not necessarily cause marked mismatch repair deficiency in the presence
of a wild-type allele.
23
UI - 9419392
AU - Lynch HT; Lemon SJ; Karr B; Franklin B; Lynch JF; Watson P; Tinley S;
TI -
Lerman C; Carter C
Etiology, natural history, management and molecular genetics of
hereditary nonpolyposis colorectal cancer (Lynch syndromes): genetic
counseling implications.
SO - Cancer Epidemiol Biomarkers Prev 1997 Dec;6(12):987-91
AD - Department of Preventive Medicine, Creighton University School of
Medicine, Omaha, Nebraska 68178, USA.
We estimate that 5-10% of virtually all forms of cancer are due to a
primary hereditary etiology. However, a hereditary cancer diagnosis is
often missed because the family history of cancer is given short shrift
in medical practice. Hereditary nonpolyposis colorectal cancer (HNPCC)
certainly fits this estimate, although some studies suggest that a
minimum of 2% with a range as high as 10% of the total colorectal cancer
burden is due to HNPCC. Mutations in one of the four mismatch repair
genes, i.e., hMSH2, hMLH1, hPMS1, and hPMS2, account for about 70% of
HNPCC kindreds. Other germ-line mutations are likely to be identified to
account for the remainder of HNPCC patients. By far the most common
HNPCC mutations involve hMSH2 and hMLH1, with hPMS1 and hPMS2 accounting
for only about 3% of such families. Prior to these molecular genetic
discoveries, the genetic counselor could only provide the patient with
an estimate of a 50% likelihood of manifesting HNPCC based on the
counselee having one or more first-degree relatives manifesting syndrome
cancers in their direct genetic lineage. Because DNA testing has become
available in families with known mutations, we have provided pretest
group education in the form of a family information service with
intensive education about the natural history, genetic risk,
surveillance, and options for management of HNPCC, as well as discussion
of the potential for fear, anxiety, apprehension, and insurance or
employer discrimination that might impact on this DNA testing. Following
informed consent, these relatives were then counseled on a one-to-one
basis. Using DNA-based genetic counseling involving hMSH2 or hMLH1, we
have provided this service to four extended HNPCC kindreds. Details of
this genetic counseling experience on these four kindreds will be
discussed.
24
UI - 9445183
AU - Senba S; Konishi F; Okamoto T; Kashiwagi H; Kanazawa K; Miyaki M;
TI -
Konishi M; Tsukamoto T
Clinicopathologic and genetic features of nonfamilial colorectal
carcinomas with DNA replication errors.
SO - Cancer 1998 Jan 15;82(2):279-85
AD - Department of Surgery, Jichi Medical School, Tochigi, Japan.
BACKGROUND. DNA replication errors (RERs) are closely associated with
hereditary nonpolyposis colorectal carcinoma (HNPCC). Recently,
alterations in DNA mismatch repair genes, including hMSH2, hMLH1, and
hPMS2, have been implicated in the pathogenesis of HNPCC. Several
studies have demonstrated RER in 13-17% of nonfamilial colorectal
carcinomas. It is unclear, however, as to whether or not these RER
positive nonfamilial colorectal carcinomas are incomplete forms of HNPCC
or are caused by incidental alterations of DNA mismatch repair genes.
Consequently, the authors studied the characteristics of RER positive
nonfamilial colorectal carcinomas, placing particular emphasis on hMSH2
and hMLH1 gene mutations. METHODS. Fresh or frozen samples of 103
nonfamilial colorectal carcinomas were examined for RERs using the
polymerase chain reaction (PCR) and specific microsatellite primers. The
authors also identified mutations of the hMSH2 and hMLH1 genes in RER
positive samples by a PCR single strand conformational polymorphism
analysis followed by direct nucleotide sequencing. RESULTS. The
incidence of RER was 15.7% (17/103) in nonfamilial colorectal
carcinomas, and only 1 case, which was found in the ascending colon,
showed a somatic mutation at exon 12 in the hMSH2 gene. Neither germline
nor somatic mutations of the hMSH2 or hMLH1 genes could be found in any
of the remaining RER positive tumors. RER positive nonfamilial
carcinomas tended to be located more frequently in the right colon.
There was no increased prevalence in young patients, and the
clinicopathologic characteristics of HNPCC were absent in the patients
with RER positive nonfamilial colorectal carcinoma. CONCLUSIONS. Based
on these findings, the carcinogenesis of RER positive nonfamilial
colorectal carcinoma is considered different from that of HNPCC.
25
UI - 9683794
AU - Viel A; Novella E; Genuardi M; Capozzi E; Fornasarig M; Pedroni M;
TI -
Santarosa M; De Leon MP; Della Puppa L; Anti M; Boiocchi M
Lack of PMS2 gene-truncating mutations in patients with hereditary
colorectal cancer.
SO - Int J Oncol 1998 Sep;13(3):565-9
AD - Division of Experimental Oncology 1, Centro di Riferimento Oncologico,
33081 Aviano (PN), Italy.
Hereditary non-polyposis colorectal cancer (HNPCC) is a genetically
heterogeneous disease for which PMS2 gene, a member of the human PMS
gene family, is believed to have a marginal role. To better define the
contribution of PMS2 to hereditary colorectal cancer, we investigated
this gene in 22 unrelated Italian patients that, despite a positive
family history and/or early onset and development of tumors with
microsatellite instability (MSI), did not carry constitutional mutations
of MLH1 and MSH2 genes. No mutations with clear-cut pathogenetic
significance were detected in the coding regions of PMS2 gene, but only
8 polymorphisms (7 common and 1 rare, 3 silent and 5 missense) and 3
unique molecular variants (2 missense substitutions and one 3-nucleotide
deletion) were seen. Lack of PMS2 truncating mutations in our study does
not disagree with its supposed marginal involvement in hereditary
colorectal cancer, but at the same time points out the need to
investigate the phenotypic molecular and clinical characteristics more
specifically associated with PMS2 mutations.
26
UI - 10480359
AU - Wang Q; Lasset C; Desseigne F; Saurin JC; Maugard C; Navarro C; Ruano E;
TI -
Descos L; Trillet-Lenoir V; Bosset JF; Puisieux A
Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and
hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.
SO - Hum Genet 1999 Jul-Aug;105(1-2):79-85
AD - Departement d'Oncologie Fondamentale et Appliquee, INSERM Unite 453,
Centre Leon Berard, Lyon, France.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome
characterized by familial predisposition to colorectal carcinoma and
extracolonic cancers of the gastrointestinal, urological, and female
reproductive tracts. This dominant disorder is caused by germline
defects in one of at least five DNA mismatch repair (MMR) genes: hMLH1,
hMSH2, hPMS1, hPMS2, and hMSH6 (GTBP). Germline mutations of hMSH2 and
hMLH1 are also frequently identified in families not fulfilling all the
Amsterdam criteria, thereby demonstrating that the involvement of these
genes is not confined to typical HNPCC. To evaluate the respective
involvement of the various MMR genes in typical and incomplete HNPCC
syndromes, we have performed an analysis of the hMLH1, hMSH2, hPMS1,
hPMS2, and hMSH6 genes in a large series of French kindreds (n=75) with
colorectal tumors and/or aggregation of extracolonic cancers belonging
to the HNPCC spectrum. Mutational analysis has been performed in all
families, without preselection for the tumor phenotype. We have detected
26 pathogenic germline mutations of the hMLH1 and hMSH2 genes and
several novel variants of the hPMS1, hPMS2, and hMSH6 genes. Our data
confirm that, regardless of the type of families and the tumor
phenotype, hPMS1, hPMS2, and hMSH6 germline mutations are rare in
familial aggregation of colorectal cancers. Furthermore, they suggest
that the presence of multiple primary malignancies in a single
individual and the observation of extracolonic tumors in relatives of a
colorectal cancer patient should be included among the guidelines for
referring patients for genetic testing.
27
UI - 10470121
AU - Johannsdottir JT; Bergthorsson JT; Gretarsdottir S; Kristjansson AK;
TI -
Ragnarsson G; Jonasson JG; Egilsson V; Ingvarsson S
Replication error in colorectal carcinoma: association with loss of
heterozygosity at mismatch repair loci and clinicopathological
variables.
SO - Anticancer Res 1999 May-Jun;19(3A):1821-6
AD - Department of Pathology, National University Hospital, Reykjavik,
Iceland.
Instability of microsatellite DNA or replication error (RER) is
characteristic of tumours caused by mismatch repair (MMR) deficiency.
Germline mutations in MMR genes are associated with Hereditary
non-polyposis colorectal carcinoma (HNPCC) and somatic mutations in
these genes are also found in a substantial fraction of colorectal
cancers (CRC). In this study we concurrently screened colorectal tumours
for the RER phenotype and loss of heterozygosity (LOH) at MMR gene loci.
The RER phenotype was evident in 47/197 (24%) tumours. RER was more
commonly detected in young patients (< 50 years) and in tumours located
in the proximal colon. RER was positively associated with LOH at the
hMSH2/hMSH6 loci on chromosome 2p, where LOH was observed in 46% of the
RER+ tumours. LOH at hMLH1 and hPMS1 loci was more frequent in the
younger patients (< 50 years). RER was not associated with
clinicopathological parameters, such as Duke's stage and tumour
differentiation (grade). The RER phenotype was associated with better
overall survival, but there was a trend towards significance when
multivariate analysis was used. This indicates that loss of MMR genes
generate a less aggressive phenotype, and raises the question about RER
being a useful indicator of prognosis for CRC patients.
28
UI - 10822375
AU - Ma AH; Xia L; Littman SJ; Swinler S; Lader G; Polinkovsky A; Olechnowicz
TI -
J; Kasturi L; Lutterbaugh J; Modrich P; Veigl ML; Markowitz SD; Sedwick
WD
Somatic mutation of hPMS2 as a possible cause of sporadic human colon
cancer with microsatellite instability.
SO - Oncogene 2000 Apr 27;19(18):2249-56
AD - Ireland Cancer Center, Case Western Reserve University and University
Hospitals of Cleveland, OH 44106, USA.
Inactivation of DNA-mismatch repair underlies the genesis of
microsatellite unstable (MSI) colon cancers. hPMS2 is one of several
genes encoding components of the DNA-mismatch repair complex, and
germline hPMS2 mutations have been found in a few kindreds with
hereditary nonpolyposis colorectal carcinoma (HNPCC), in whom hereditary
MSI colon cancers develop. However, mice bearing null hPMS2 genes do not
develop colon cancers and hPMS2 mutations in sporadic human colon
cancers have not been described. Here we report that in Vaco481 colon
cancer the hPMS2 gene is inactivated by somatic mutations of both hPMS2
alleles. The cell line derived from this tumor is functionally deficient
in DNA mismatch repair. This deficiency can be biochemically
complemented by addition of a purified hMLH1-hPMS2 (hMutLalpha) complex.
The hPMS2 deficient Vaco481 cancer cell line demonstrates microsatellite
instability, an elevated HPRT gene mutation rate, and resistance to the
cytotoxicity of the alkylator MNNG. We conclude that somatic
inactivation of hPMS2 can play a role in development of sporadic MSI
colon cancer expressing the full range of cancer phenotypes associated
with inactivation of the mismatch repair system.
29
UI - 11358834
AU - Chen Y; Wang J; Fraig MM; Metcalf J; Turner WR; Bissada NK; Watson DK;
TI -
Schweinfest CW
Defects of DNA mismatch repair in human prostate cancer.
SO - Cancer Res 2001 May 15;61(10):4112-21
AD - Laboratory of Cancer Genomics, Hollings Cancer Center, Medical
University of South Carolina, Charleston, SC 29425, USA.
Loss of mismatch repair (MMR) function leads to the accumulation of
errors that normally occur during DNA replication, resulting in genetic
instability. Germ-line mutations of MMR genes in the patients with
hereditary nonpolyposis colorectal cancer lead to inactivation of MMR
protein functions, and the defects of MMR are well correlated to the
high rate of microsatellite instability in their tumors. Previous
studies (T. Uchida, et al. Oncogene, 10: 1019-1022, 1995; S. Egawa, et
al. Cancer RES:, 55: 2418-2421, 1995; J. M. Cunningham, et al. Cancer
RES:, 56: 4475-4482, 1996; X. Gao, et al. Oncogene, 9: 2999-3003, 1994;
H. Rohrbach, et al. Prostate, 40: 20-27, 1999) have shown that genetic
instability (chromosomal and microsatellite instability) is detectable
in human prostate cancer. To elucidate the role of MMR genes in the
tumorigenesis of prostate cancer, we evaluated the expression of these
genes in human cancer cell lines and in tumor specimens. Using Western
blot analysis, we detected loss among MSH2, MLH1, PMS2, and PMS1
proteins in DU145, LNCaP, p69SV40T, M2182, and M12 cells. In addition,
genomic instability in the prostate cell lines including DU145, PC3,
LNCaP, p67SV40T, M2182, and M12 was detected by a microsatellite
mutation assay. Significantly, immunohistochemical analysis of prostatic
tissue revealed the reduction or absence of MMR protein expression in
the epithelium of prostate tumor foci compared with normal adjacent
prostate tissue. In contrast to hereditary nonpolyposis colorectal
cancer, characterized by defects predominantly in MLH1 and MSH2, the
samples we examined showed more tumor foci with loss of PMS1 and PMS2.
PMS1, which is only expressed in the basal cells in normal glands, is
conspicuously absent in most prostate cancer. From these results, we
conclude that there are defects of MMR genes in human prostate cancer.
30
UI - 11371367
AU - Soussi T
TI -
[44 .PMS2 (post meiotic segregation increased, S. cerevisiae 2]
SO - Bull Cancer 2001 Apr;88(4):341-2
31
UI - 11429708
AU - Jager AC; Rasmussen M; Bisgaard HC; Singh KK; Nielsen FC; Rasmussen LJ
TI -
HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence
assembly of hMutLalpha and hMLH1-hEXO1 complexes.
SO - Oncogene 2001 Jun 14;20(27):3590-5
AD - Department of Clinical Biochemistry, Rigshospitalet, DK-2100 Copenhagen,
Denmark.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a common inherited
form of neoplasia caused by germline mutations in DNA mismatch repair
(MMR) genes. MMR proteins have been reported to associate with several
proteins, including the human exonuclease 1 (hEXO1). We report here
novel HNPCC-hMLH1 mutant proteins (T117M, Q426X and 1813insA) in Danish
HNPCC patients. We demonstrate that these mutant HNPCC-hMLH1 proteins
are unable to form complexes with hEXO1 and hPMS2 in vivo. The results
indicate that mutations found in HNPCC gene carriers disrupt hMLH1-hEXO1
complex formation and hMutLalpha heterodimer assembly essential for MMR
activity.
32
UI - 11546830
AU - Liu T; Chen J; Salahshor S; Kuismanen S; Holmberg E; Gronberg H;
TI -
Peltomaki P; Lindblom A
Screening families with endometrial and colorectal cancers for germline
mutations.
SO - J Med Genet 2001 Sep;38(9):E29
33
UI - 11574484
AU - Guarne A; Junop MS; Yang W
TI -
Structure and function of the N-terminal 40 kDa fragment of human PMS2:
a monomeric GHL ATPase.
SO
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