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Abramson Cancer CenterNCI CANCERLIT® Search: Non-polyposis Colon Cancer, Hereditary - March 2002
National Cancer Institute®
Last Modified: March 1, 2002
Table of Contents
1
UI - 11793469
AU - Yuan ZQ; Gottlieb B; Beitel LK; Wong N; Gordon PH; Wang Q; Puisieux A;
TI -
Foulkes WD; Trifiro M
Polymorphisms and HNPCC: PMS2-MLH1 protein interactions diminished by
single nucleotide polymorphisms.
SO - Hum Mutat 2002 Feb;19(2):108-13
AD - Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish
General Hospital, Montreal, Quebec, Canada.
Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most
common autosomal dominant inherited diseases. Mutations in the human
mismatch repair (MMR) proteins MLH1, MSH2, MSH6, PMS1, and PMS2 have
been found to co-segregate with HNPCC. The MLH1 and MSH2 proteins have
been demonstrated to interact with PMS1, PMS2, and MSH6 proteins. A
previous study reported that missense mutations in specific regions of
MLH1 can lead to defects in protein-protein interactions with PMS2. Here
we report that three missense alterations previously identified as
single nucleotide polymorphisms (SNPs) in PMS2 (P511K, T597S, and M622I)
cause defective protein-protein interactions with MLH1, even though the
alterations are not in the previously reported interaction domain. These
results suggest that an additional domain in PMS2 affects MLH1-PMS2
interaction. This study also demonstrates that SNPs can result in gene
alterations that indeed have a functional effect on protein phenotype.
Thus, these three SNPs may ultimately represent variants with an
increased risk factor for tumorgenesis in HNPCC. This study is one of
the first to use a functional assay to appraise the role of SNPs and
suggests that traditional definitions of polymorphisms and mutations are
in need of reconsideration. Copyright 2002 Wiley-Liss, Inc.
2
UI - 11830542
AU - Charbonnier F; Olschwang S; Wang Q; Boisson C; Martin C; Buisine MP;
TI -
Puisieux A; Frebourg T
MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic
and promoter rearrangements in hereditary nonpolyposis colorectal
cancer.
SO - Cancer Res 2002 Feb 1;62(3):848-53
AD - Laboratoire de Genetique Moleculaire, CHU de Rouen et Institut National
de la Sante et de la Recherche Medicale EMI 9906, Faculte de Medecine et
de Pharmacie, IFRMP, 22 Boulevard de Gambetta, 76183 Rouen, France.
To estimate the relative frequency of mismatch repair genes,
rearrangements in hereditary nonpolyposis colorectal cancer (HNPCC)
families without detectable mutations in MSH2 or MLH1, we have analyzed
by multiplex PCR of short fluorescent fragments MSH2, MLH1, and MSH6 in
61 families, either fulfilling Amsterdam criteria or including cases of
multiple primary cancers belonging to the HNPCC spectrum. We detected 13
different genomic rearrangements of MSH2 in 14 families (23%), whereas
we found no rearrangement of MLH1 and MSH6. Analysis of 31 other
families, partially meeting Amsterdam criteria, revealed no additional
rearrangement of MSH2. All of the MSH2 rearrangements, except one,
corresponded to genomic deletions involving one or several exons. In 8
of 13 families with a MSH2 genomic deletion, the MSH2 promoter was also
deleted, and the 5' breakpoint was located either within or upstream the
MSH2 gene. This study demonstrates the heterogeneity of MSH2 exonic and
promoter rearrangements and shows that, in HNPCC families without
detectable MSH2 or MLH1 point mutation, one must consider the presence
of MSH2 genomic rearrangements before the involvement of other mismatch
repair genes. The simplicity and rapidity of their detection, using
fluorescent multiplex PCR, led us to recommend to begin the molecular
analysis in HNPCC by screening for MSH2 rearrangements.
3
UI - 11748856
AU - Godino J; de La Hoya M; Diaz-Rubio E; Benito M; Caldes T
TI -
Eight novel germline MLH1 and MSH2 mutations in hereditary non-polyposis
colorectal cancer families from Spain.
SO - Hum Mutat 2001 Dec;18(6):549
AD - Laboratory of Molecular Oncology, San Carlos University Hospital, 28040
Madrid, Spain.
Germline mutations in the MLH1 and MSH2 genes, account for the majority
of HNPCC families. We have screened such families from Spain by using
DGGE analysis and subsequent direct sequencing techniques. In eight
families we identified six novel MLH1 and two novel MSH2 mutations
comprising one frame shift mutation (c.1420 del C), two missense
mutations (L622H and R687W), two splice site mutations (c.1990-1 G>A and
c.453+2 T>C and one nonsense mutation (K329X) in the MLH1 gene as well
as two frame shift mutations (c.1979-1980 del AT and c.1704-1705 del AG)
in the MSH2 gene. Our analysis contributes to the further
characterization of the mutational spectrum of MLH1 and MSH2 genes in
HNPCC families. Copyright 2001 Wiley-Liss, Inc.
4
UI - 11852992
AU - Muller A; Fishel R
TI -
Mismatch repair and the hereditary non-polyposis colorectal cancer
syndrome (HNPCC).
SO - Cancer Invest 2002;20(1):102-9
AD - Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas
Jefferson University, Philadelphia, PA 19107-5541, USA.
The hereditary non-polyposis colorectal cancer (HNPCC)-syndrome is the
most common form of hereditary colorectal cancers, and accounts for 2-7%
of the total colorectal cancer burden. Since there are no single
clinical features specific for HNPCC, diagnosis is based on family
history (Amsterdam or Bethesda criteria) and is confirmed by the
detection of a mutation in one of the responsible mismatch repair (MMR)
genes. Two types of HNPCC-families can be distinguished. Type I HNPCC
tumors are exclusively located in the colon, whereas in Type II HNPCC
patients, extracolonic tumors are present in the stomach, endometrium,
ovary, and urinary tract. The identification of the human homologues of
yeast mismatch repair genes hMSH2, hMSH3, hMSH6, hMLH1, hMLH3, hPMS1
(scMLH2), and hPMS2 (scPMS1) offered the prospect of genetic screening
leading to an extensive search for mutations in HNPCC-families. The
majority of the alterations have been found in hMSH2 (40%) and hMLH1
(40%) genes. Mutations in the other MMR genes appear rare, absent,
and/or associated with atypical families (1-5%). As a result of the
mismatch repair deficiency, replication misincorporation errors
accumulate, resulting in a mutator phenotype. Diagnosis of
HNPCC-associated replication errors is most easily determined by the
examination of a panel of the National Cancer Institute
(NCI)-recommended simple repeated sequences (microsatellites), combined
with immunohistochemical analysis. Although the exact molecular
mechanism of the tumor development in these patients remains poorly
understood, the identification of tumors that harbor a microsatellite
instability has clinical and prognostic implications.
5
UI - 11797394
AU - Shimada M
TI -
[Application of genetic diagnosis for colorectal cancer]
SO - Rinsho Byori 2001 Dec;49(12):1237-41
AD - Genetic Diagnosis Center, Takara Shuzo Co. Ltd., Kusatsu 525-0055.
Recently, PCR techniques have been introduced for genetic diagnosis of
colorectal cancer. The clinical significance of the genetic diagnosis of
cancers includes preclinical diagnosis of hereditary cancers and viral
tumors, prediction of malignancy and chemosensitivity focusing on
expression profiling of related genes, and detection of micrometastasis
in lymph node or bone marrow as well as of circulating tumor cells in
peripheral blood targeting tumor-specific mRNA expression such as
cytokeratin 19, 20 and CEA. In this report, molecular biological
techniques for genetic diagnosis of colorectal cancer are discussed.
6
UI - 11825119
AU - Trojan J; Raedle J; Herrmann G; Brieger A; Zeuzem S
TI -
Detection of microsatellite instability from archival,
hematoxylin-eosin-stained colorectal cancer specimen.
SO - Arch Pathol Lab Med 2002 Feb;126(2):202-4
AD - Second Department of Internal Medicine, Johann Wolfgang
Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
Microsatellite instability (MSI) is characteristic of hereditary
nonpolyposis colorectal cancer (HNPCC). Owing to early onset of
colorectal cancer before the age of 50 years and/or familial clustering
of HNPCC-related malignancies, the diagnosis of HNPCC was suspected in 2
patients. Because no paraffin-embedded tumor tissue was available, we
used archival 5-microm, hematoxylin-eosin-stained tumor specimen slides
for direct MSI analysis. Tissue was microdissected and cells were lysed
using 1% Triton. Fluorescence polymerase chain reaction amplification of
a panel of 7 microsatellite markers, including all markers of the
current international reference panel (BAT-25, BAT-26, D2S123, D5S346,
and D17S250), demonstrated MSI in one patient and excluded MSI in the
other. In conclusion, this study demonstrates the feasibility of MSI
analysis by direct fluorescence polymerase chain reaction amplification
using hematoxylin-eosin-stained tissue specimens without the need for
prior DNA extraction.
7
UI - 11043825
AU - Fridrichova I; Ilencikova D; Friedl W; Hlavcak P; Skorvaga M; Krizan P;
TI -
Palaj J; Pirsel M; Farkasova E; Bartosova Z
Approaches to identification of HNPCC suspected patients in Slovak
population.
SO - Neoplasma 2000;47(4):219-26
AD - Cancer Research Institute, Slovak Academy of Sciences, Bratislava.
exonfri@savba.sk
Patients with hereditary non-polyposis colorectal cancer (HNPCC) have a
DNA mismatch repair defect (MMR) in their tumor tissue that results in
instability of microsatellite DNA sequences (MSI). Thus, MSI analysis
may effectively indicate this form of cancer that should be then proved
by analysis of germline mutations in MMR genes. The aim of this study
was to identify HNPCC suspected patients in the Slovak population by
investigating microsatellite instability in colorectal tumor tissues.
MSI was studied at 5-11 loci in matched tumor and normal DNA using
radioactively labeled PCR products separated on sequencing gels. High
microsatellite instability (MSI-H) was present only in patients younger
than 50 years, in 100% of patients having two affected relatives by
colorectal cancer and in 67% of patients with only one affected
relative. In both groups of patients colorectal cancer was present in
two successive generations. No MSI-H was found in the group of patients
older than 50 years, even if they had positive family history for
colorectal cancer. Among all markers used, the BAT26 mononucleotide
repeat (100%), DI0S197 and D13S175 (62.5%) dinucleotide repeats were the
most frequently altered in the tumor tissues. Retrospective analysis
revealed that some of the patients having MSI-H tumors have had
clinicopathological characteristics frequently reported to HNPCC. The
family members of those patients with MSI-H are enrolled in preventive
health care program until mutational analyses will enable to select
carriers from non-carriers of mutated MMR genes.
8
UI - 11844809
AU - de La Chapelle A
TI -
Microsatellite instability phenotype of tumors: genotyping or
immunohistochemistry? The jury is still out.
SO - J Clin Oncol 2002 Feb 15;20(4):897-9
9
UI - 11824249
AU - Moslein G; Albrecht J; Ohmann C; Schackert HK
TI -
[Preventive therapy of HNPCC--a study concept]
SO - Kongressbd Dtsch Ges Chir Kongr 2001;118():213-7
AD - Chirurgische Klinik A, Heinrich-Heine-Universitat, Moorenstrasse 5,
40225 Dusseldorf.
Due to different pattern of penetrance and heterogeneity, the role of
prophylactic surgery must be individually defined for every hereditary
cancer predisposition. For HNPCC (hereditary nonpolyposis colorectal
cancer) subtotal colectomy at the time of colorectal cancer diagnosis is
being recommended by the Cancer Genetics Studies Consortium Recent
Guidelines from the DGVS (Deutsche Gesellschaft fur Verdauungs- und
Stoffwechselkrankheiten) state that to date no general recommendation
favouring this approach can be made. The open question is: how effective
is segmental resection and endoscopic surveillance in given time
intervals compared with the reduction of risk by performing extended
(prophylactic) surgery. Also the issue of dealing with rectal cancer as
the first primary in HNPCC patients must be addressed. In order to
answer these questions and after the lessons learned from BRCA mutation
carriers and prophylactic mastectomies, quality of life measurement is
mandatory for this study.
10
UI - 11824361
AU - Herfarth C
TI -
[Surgery and molecular biology: new insight or stray path?]
SO - Kongressbd Dtsch Ges Chir Kongr 2001;118():769-85
Surgery has the optimal possibility for theoretical-clinical transfer of
molecular biological knowledge. On the basis of the existing research
emphasis on clinical molecular biology at the Department of Surgery,
University of Heidelberg, this is shown by the example of colorectal
cancer: Establishment of a large clinical register for hereditary
colorect cancer, use of molecular biological methods to improve
phenotype/genotype correlations, definition of risk groups, decision on
surgical therapeutical concepts for hereditary cancers and
considerations on the creation of problem-orientated centers for
hereditary cancer. A further example for the application of molecular
methods is the detection of minimal residual disease or tumor cells in
the different compartments (blood, lymph nodes, bone marrow and
peritoneum) in order to achieve a better risk evaluation exceeding the
standard pathohistological stage definition. The goal is an
individualized or more focused therapy for each patient. Transfer of
research from the basic sciences into the clinical setting, integrated
into the daily clinical work, is possible in a so-called tandem model.
11
UI - 11824368
AU - Pistorius S; Schackert HK; Saeger HD
TI -
[Can molecular genetic knowledge from studies of hereditary carcinoma be
applied to sporadic colorectal carcinoma?]
SO - Kongressbd Dtsch Ges Chir Kongr 2001;118():820-4
AD - Klinik und Poliklinik fur Viszeral-, Thorax- und Gefasschirurgie,
Universitatsklinikum Carl Gustav Carus, TU Dresden, Fetscherstrasse 74,
01307 Dresden.
Colorectal carcinomas without a family history are considered to be
"sporadic" carcinomas, however, also have a genetic basis. Within the
hereditary forms there are 15-50% of patients without a family history
being carriers of de novo germline mutations. In addition,
non-pathogenic polymorphisms in these tumorsyndrome-genes as well as in
genes involved in the carcinogen metabolism (GST, NAT, CYP, MTHFR) are
associated with an increased or decreased colorectal cancer risk.
Identification of these genetic risk factors will enable individually
tailored surveillance and recommendations for prophylaxis as well as
individually tailored treatment.
12
UI - 11839702
AU - Bishop DT
TI -
Proximal and progressive: adenomas in HNPCC.
SO - Gut 2002 Mar;50(3):291-2
AD - ICRF Genetic Epidemiology Division, ICRF Clinical Centre in Leeds,
Cancer Genetics Building, St James's University Hospital, Beckett
Street, Leeds LS9 7TF, UK. t.bishop@icrf.icnet.uk
13
UI - 11839723
AU - Cravo M; Afonso AJ; Lage P; Albuquerque C; Maia L; Lacerda C; Fidalgo P;
TI -
Chaves P; Cruz C; Nobre-Leitao C
Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1
mismatch repair genes: implications for genetic testing.
SO - Gut 2002 Mar;50(3):405-12
AD - Servico de Gastrenterologia and Centro de Investigacao de Patobiologia
Molecular, Instituto Portugues de Oncologia Francisco Gentil, 1093
Lisboa Codex, Portugal. mcravo.cplancha@mail.telepac.pt
BACKGROUND: In hereditary non-polyposis colorectal cancer, over 90% of
the identified mutations are in two genes, hMSH2 and hMLH1. A large
proportion of the mutations detected in these genes are of the missense
type which may be either deleterious mutations or harmless
polymorphisms. AIM: To investigate whether nine missense and one splice
site mutation of hMLH1 and hMSH2, in 10 kindreds with a familial history
of colorectal cancer or young age of onset, could be interpreted as
pathogenic. METHODS: Clinical and genetic characteristics were
collected: (i) evolutionary conservation of the codon involved; (ii)
type of amino acid change; (iii) occurrence of mutation in healthy
controls; (iv) cosegregation of mutation with disease phenotype; (v)
functional consequences of gene variant; and (vi) microssatellite
instability and immunoexpression of hMSH2 and hMLH1 analysis. RESULTS:
Seven different missense and one splice site mutation were identified.
Only 1/8 was found in the control group, 2/7 occurred in conserved
residues, and 5/7 resulted in non-conservative changes. Functional
studies were available for only 2/8 mutations. Segregation of the
missense variant with disease phenotype was observed in three kindreds.
CONCLUSION: In the majority of families included, there was no
definitive evidence that the missense or splice site alterations were
causally associated with an increased risk of developing colorectal
cancer. Until further evidence is available, these mutational events
should be regarded and interpreted carefully and genetic diagnosis
should not be offered to these kindreds.
14
UI - 11857745
AU - Wang Y; Friedl W; Sengteller M; Jungck M; Filges I; Propping P; Mangold
TI -
E
A modified multiplex PCR assay for detection of large deletions in MSH2
and MLH1.
SO - Hum Mutat 2002 Mar;19(3):279-86
AD - Institute of Human Genetics, University of Bonn, Bonn, Germany.
A method for detection of large genomic deletions in the MSH2 and MLH1
genes based on multiplex PCR and quantitative evaluation of PCR products
is presented. All 35 exons of MSH2 and MLH1 were screened simultaneously
in seven PCR reactions, each of them including primers for both genes.
The method is reliable for uncovering large genomic deletions in
patients suspected of HNPCC. With this method, six novel deletions were
identified, two in MSH2: EX1_10del and EX1_16del (representing deletion
of the entire MSH2 gene); and four in MLH1: EX1_10del in two unrelated
patients, EX3_5del, and EX4del. The deletions were detected in 18
unrelated patients in whom no germline mutation had been identified by
SSCP and DHPLC. These results indicate that our modified multiplex PCR
assay is suited for the detection of large deletions both in the MSH2
and MLH1 gene and therefore represents an additional valuable tool for
mutation screening in HNPCC families. Copyright 2002 Wiley-Liss, Inc.
15
UI - 11870666
AU - Ikenaga M; Tomita N; Sekimoto M; Ohue M; Yamamoto H; Miyake Y; Mishima
TI -
H; Nishisho I; Kikkawa N; Monden M
Use of microsatellite analysis in young patients with colorectal cancer
to identify those with hereditary nonpolyposis colorectal cancer.
SO - J Surg Oncol 2002 Mar;79(3):157-65
AD - Department of Surgery and Clinical Oncology, Graduate School of
Medicine, Osaka University, Osaka, Japan.
BACKGROUND AND OBJECTIVES: The frequency of microsatellite instability
(MSI) in young patients with colorectal cancer was evaluated, including
reexamination of the medical and family history of each patient, and
interviews with the patients to determine any possible new occurrence of
hereditary nonpolyposis colorectal cancer (HNPCC) in the patients
themselves or their family members. METHODS: Fifty-three young patients
(younger than 40 years of age) with colorectal cancer were selected and
investigated. DNA was extracted from paraffin sections and
microsatellite analysis was performed. RESULTS: The frequency of MSI
among the young patients with colorectal cancer was 50.9%, which was
significantly higher than the rate of 12-21% noted in older patients
with colorectal cancer (P < 0.001). For the 24 young patients with
colorectal cancer who did not have MSI, only one case of HNPCC kindred
and two cases with a family history of cancer were identified. In
contrast, among the 20 young patients with colorectal cancer who had
MSI, five cases of HNPCC kindred, two cases with metachronous patients
with colorectal cancer, and three cases with a family history of cancer
were identified. CONCLUSION: Our results suggest that a defect in the
DNA mismatch repair system may play some role in carcinogenesis in young
patients with colorectal cancer. Microsatellite analysis and subsequent
interviews regarding medical and family history are useful tools for
efficiently identifying possible cases of HNPCC among young patients
with colorectal cancer. Copyright 2002 Wiley--Liss, Inc.
16
UI - 11861375
AU - Muller A; Edmonston TB; Corao DA; Rose DG; Palazzo JP; Becker H; Fry RD;
TI -
Rueschoff J; Fishel R
Exclusion of breast cancer as an integral tumor of hereditary
nonpolyposis colorectal cancer.
SO - Cancer Res 2002 Feb 15;62(4):1014-9
AD - Genetics and Molecular Biology Program, Department of Microbiology and
Immunology, Kimmel Cancer Center, Philadelphia, PA 19107-5541, USA.
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal
dominant genetic predisposition syndrome that accounts for 2-7% of all
colorectal cancers. Diagnosis of HNPCC is based on family history
(defined by Amsterdam or Bethesda Criteria), which often includes a
history of multiple synchronous or metachronous cancers. The majority of
HNPCC results from germ-line mutations in the DNA mismatch repair (MMR)
genes hMSH2 and hMLH1 with rare alterations in hMSH6 and hPMS2 in
atypical families. Both HNPCC and sporadic MMR-deficient tumors
invariably display high microsatellite instability (MSI-H). Two types of
HNPCC families can be distinguished: type I (Lynch I) with tumors
exclusively located in the colon; and type II (Lynch II) with tumors
found in the endometrium, stomach, ovary, and upper urinary tract in
addition to the colon. A proposed association of breast cancer with type
II HNPCC is controversial. To address this important clinical question,
we examined MSI in a series of 27 female patients who presented with
synchronous or metachronous breast plus colorectal cancer. Although
MSI-H was found in 5 of 27 (18.5%) of the colon cancers, in all cases
the matched breast cancer was microsatellite stable. We also examined
the breast tumors from three women who were carriers of MMR gene
mutations from HNPCC families. None of these three breast tumors
displayed MSI nor was the expression of MMR proteins altered in these
tumors. We conclude that breast cancer largely arises sporadically in
HNPCC patients and is rarely associated with the HNPCC syndrome.
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