Table of Contents
1
UI - 11732490
AU - Aktan-Collan K; Haukkala A; Mecklin JP; Uutela A; Kaariainen H
TI -
Comprehension of cancer risk one and 12 months after predictive genetic
testing for hereditary non-polyposis colorectal cancer.
SO - J Med Genet 2001 Nov;38(11):787-92
2
UI - 11521793
AU - Olopade OI; Pichert G
TI -
Cancer genetics in oncology practice.
SO - Ann Oncol 2001 Jul;12(7):895-908
AD - University of Chicago Pritzker School of Medicine, Illinois, USA.
folopade@medicine.bsd.uchicago.edu
Cancer is a genetic disease caused by the progressive accumulation of
mutations in critical genes that control cell growth and
differentiation. Completion of the Human Genome Project promises to
revolutionize the practice of Medicine, especially Oncology care. The
tremendous gains in the knowledge of the structure and function of human
genes will surely impact the diagnosis, prognosis and treatment of
cancer. Moreover, it will lead to more effective cancer control through
the use of genetics to quantify individual cancer risks. This article
reviews the current status of genetic testing and counseling for cancer
risk assessment and will suggest a framework for integrating such
counseling into oncology practice.
3
UI - 11726306
AU - Muller-Koch Y; Kopp R; Lohse P; Baretton G; Stoetzer A; Aust D; Daum J;
TI -
Kerker B; Gross M; Dietmeier W; Holinski-Feder E
Sixteen rare sequence variants of the hMLH1 and hMSH2 genes found in a
cohort of 254 suspected HNPCC (hereditary non-polyposis colorectal
cancer) patients: mutations or polymorphisms?
SO - Eur J Med Res 2001 Nov 20;6(11):473-82
AD - Department of Medical Genetics, University of Munich, Goethestr. 29,
D-80336 Munich, Germany.
5-8% of all colorectal cancer cases are assumed to be due to germline
mutations in DNA mismatch repair genes. Mutation analysis of these genes
in affected families enables one to identify subjects with an inborn
susceptibility to colorectal tumorogenesis and to offer presymptomatic
testing to family members at risk, provided that the mutation detected
is a truncating one or a missense mutation that has either been judged
as disease causing in other families or segregates with the disease and
results in a microsatellite instability of the corresponding tumor.
Segregation analysis within the family or microsatellite analysis of the
tumor is, however, not always possible. In these cases, assessment of
the relevance of the sequence variation identified is very difficult. On
the other hand, discrimination between inactivating mutations and
innocuous sequence polymorphisms is of extreme importance for clinical
and genetic counseling of affected families. Here we report 16 rare
sequence variants of the hMLH1 and hMSH2 genes including 11 different
missense variations found in a cohort of 254 suspected HNPCC patients.
We provide evidence, that missense variations in hMLH1 do not
necessarily result in microsatellite instability of the corresponding
tumor DNA. These patients would have been missed had one followed the
recommendations of using only microsatellite analysis for the selection
of patients at high risk of hereditary non-polyposis colorectal cancer
for mutation analysis.
4
UI - 11781295
AU - Trojan J; Zeuzem S; Randolph A; Hemmerle C; Brieger A; Raedle J; Plotz
TI -
G; Jiricny J; Marra G
Functional analysis of hMLH1 variants and HNPCC-related mutations using
a human expression system.
SO - Gastroenterology 2002 Jan;122(1):211-9
AD - Second Department of Medicine, Johann Wolfgang Goethe-University,
Frankfurt a. M., Germany. Trojan@em.uni-franfurt.de
BACKGROUND & AIMS: Germline mutations in the DNA mismatch repair (MMR)
genes hMLH1 and hMSH2 are associated with susceptibility to hereditary
nonpolyposis colorectal cancer (HNPCC). Because a significant proportion
of hMLH1 mutations are missense, the assessment of their pathogenic role
may be difficult. To date, functional analysis of missense mutations has
been performed primarily in Saccharomyces cerevisiae. The aim of this
study was to examine the biochemical properties of hMLH1 protein
variants in a human expression system. METHODS: The HNPCC-related hMLH1
mutations T117M, V185G, R217C, G244D, R265C, V326A, and K618T, the
polymorphisms I219V and R265H, and a hMLH1 splicing variant lacking exon
9 and 10 (hMLH1 Delta 9/10) were cloned. On transfection of these
constructs into human 293T cells, which do not express hMLH1 because of
promoter hypermethylation, the hMLH1 protein variants were analyzed by
Western blotting and in a MMR assay. RESULTS: Transfection was
successful for all hMLH1 constructs. As anticipated, the mutations K618T
and T117M, which affect the highly conserved domains of hMLH1 that are
necessary for interaction with hPMS2 or for adenosine triphosphate (ATP)
binding, respectively, affected protein stability or its ability to
complement MMR-deficient 293T-cell extracts. The V185G, G244D, and Delta
9/10 variants were also unable to complement MMR in 293T cells, whereas
hMLH1 proteins carrying the I219V, R265H, R265C, R217C, and V326A
mutations were MMR competent. CONCLUSIONS: These data show that the
pathogenic role of hMLH1 missense mutations and splicing variants can be
assessed by analyzing the biochemical properties of their protein
products in a homologous expression system.
5
UI - 11754112
AU - Kruger S; Plaschke J; Pistorius S; Jeske B; Haas S; Kramer H;
TI -
Hinterseher I; Bier A; Kreuz FR; Theissig F; Saeger HD; Schackert HK
Seven novel MLH1 and MSH2 germline mutations in hereditary nonpolyposis
colorectal cancer.
SO - Hum Mutat 2002 Jan;19(1):82
AD - Department of Surgical Research, Universitatsklinikum Carl Gustav Carus,
University of Technology, Dresden, Germany.
Stefan.Krueger@mailbox.tu-dresden.de
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent
hereditary form of colorectal cancer and is caused by germline mutations
in mismatch repair (MMR) genes. The majority of mutations occur in MLH1
and MSH2. We report hereby seven novel germline mutations in these two
genes (five in MLH1 and two in MSH2). All mutations have been found in
families fulfilling criteria of the Bethesda guidelines and four of
which also fulfilled the Amsterdam criteria. We identified three
insertions or deletions of 1 bp leading to premature stop codons (MLH1:
c.341delC, c.1413-1414insA; MSH2: c.1119delG) and three nonsense
mutations (MLH1: c.67G>T [E23X], c.436C>T [Q146X]; MSH2: c.1857T>G
[Y619X]). The corresponding tumors showed a high level of microsatellite
instability (MSI-H) and a complete loss of expression of the affected
protein. In addition, a missense mutation in MLH1 was identified
(c.1984A>C [T662P]). The respective tumor also showed a high level of
microsatellite instability but a reduced, rather then lost, expression
of the MLH1-protein. This missense mutation was not found in 107 healthy
control individuals and in 54 HNPCC patients. Copyright 2001 Wiley-Liss,
Inc.
6
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.
7
UI - 11831075
AU - Kronborg O
TI -
[Colorectal cancer screening]
SO - Ugeskr Laeger 2002 Jan 7;164(2):153-5
AD - Kirurgisk afdeling A, Odense Universitetshospital, DK-5000 Odense C.
8
UI - 11788565
AU - Lindgren G; Liljegren A; Jaramillo E; Rubio C; Lindblom A
TI -
Adenoma prevalence and cancer risk in familial non-polyposis colorectal
cancer.
SO - Gut 2002 Feb;50(2):228-34
AD - Department of Clinical Genetics, Karolinska Hospital, S 171 76
Stockholm, Sweden.
BACKGROUND AND AIMS: Polypectomy in the colon has been shown to prevent
colorectal cancer in both the general population and in familial
colorectal cancer. Individuals with a family history of colorectal
cancer have an increased risk of the disease. Over a period of 10 years,
304 subjects at risk were included in ongoing surveillance with regular
colonoscopies. To compile the medical findings and experience generated
during this period, a retrospective cross sectional study was performed.
SUBJECTS: Subjects were classified into three family groups: families
with hereditary non-polyposis colorectal cancer (HNPCC); families with
hereditary colorectal cancer (HCC, non-Lynch syndrome); and a third
group of families with only empirical risk estimates based on a family
history of two close relatives (TCR) with colorectal cancer. METHODS:
The risk population was studied with regard to age at onset, prevalence,
number, cancer risk, size, dysplasia, and distribution of adenomas. A
comparison was made within the family groups and with a reference group
representing the general population. RESULTS: In total, 195 adenomas and
six cancers were detected among 85 individuals. The relative risk of
having an adenoma in the whole risk population compared with the general
population was 2.6. Subjects from TCR families had most adenomas and
HNPCC subjects had the least. A shift from proximal adenomas to distal
carcinomas in families with HCC and TCR suggested a higher cancer risk
in distal adenomas in these syndromes. HNPCC families showed a younger
age at onset and adenomas with a higher degree of dysplasia. In HNPCC,
there was a similar localisation of adenomas and carcinomas, suggesting
a high risk of cancer in all adenomas. CONCLUSIONS: There was clear
overrepresentation of adenomas in all three family types compared with
the reference population. In HNPCC, we found earlier onset of adenomas
and faster progression to cancer. Families with HCC, and even more so
TCR subjects, had a later onset and lower risk of cancer from proximal
adenomas. Based on these results, surveillance protocols in Sweden have
been revised.
9
UI - 11720433
AU - Coleman MG; Gough AC; Bunyan DJ; Braham D; Eccles DM; Primrose JN
TI -
Minisatellite instability is found in colorectal tumours with mismatch
repair deficiency.
SO - Br J Cancer 2001 Nov 16;85(10):1486-91
AD - University Department of Surgery, Southampton General Hospital, Tremona
Road, Southampton, SO16 6YD, UK.
Microsatellite instability (MSI) in colorectal tumours is demonstrated
by PCR amplification of several different microsatellite loci.
Minisatellites, which are repeats of longer sequences also found
throughout the genome, may also be affected by tumorigenesis. Certain
minisatellite alleles contain 2 types of similar repeat unit that are
randomly interspersed. The interspersion pattern can be analysed by
mapping variant repeat units along an amplified allele, minisatellite
variant repeat unit mapping PCR (MVR-PCR). We have applied
microsatellite analysis with 10 markers and MVR-PCR for locus D7S21 to
33 cases of colorectal neoplasia, 27 sporadic and 6 from patients
suspected of having hereditary non-polyposis colorectal cancer (HNPCC).
Of the 27 sporadic cases, 3 were MSI-high on microsatellite analysis and
one MSI-low. Instability with MVR-PCR was observed, but only in the
MSI-high cases. Four of the HNPCC patients had mismatch repair (MMR)
gene mutations in either hMLH1 or hMSH2. All 4 had DNA instability by
MVR-PCR, but only two of these had MSI (one high, one low). The other 2
of the 6 patients with suspected HNPCC were negative to mutation
analysis. One had features strongly suggestive of HNPCC and was unstable
by both microsatellite analysis (MSI-high) and by MVR-PCR. The other
tumour, from an Amsterdam criteria positive kindred, did not demonstrate
instability by any technique. Thus MVR-PCR detects DNA instability in
MSI-high sporadic tumours and in those associated with HNPCC where MSI
is observed. Further, in some MMR mutation positive cases MSI was not
seen but instability was observed by MVR-PCR. MVR-PCR may be a valuable
adjunct to the detection of MMR deficiency in colorectal tumours and it
may allow new insights into the nature of DNA instability in this
condition.
10
UI - 11705864
AU - Ikonen T; Matikainen M; Mononen N; Hyytinen ER; Helin HJ; Tommola S;
TI -
Tammela TL; Pukkala E; Schleutker J; Kallioniemi OP; Koivisto PA
Association of E-cadherin germ-line alterations with prostate cancer.
SO - Clin Cancer Res 2001 Nov;7(11):3465-71
AD - Laboratory of Cancer Genetics, Institute of Medical Technology,
University of Tampere, P.O. Box 607, FIN-33101 Tampere, Finland.
tarja.ikonen@uta.fi
In our recent cancer registry-based study, the incidence of gastric
carcinoma was increased up to 5-fold in male relatives of early-onset
prostate cancer (PCA) patients. This association may reflect the
influence of genetic factors predisposing individuals to both tumor
types. Germ-line mutations of the CDH1 gene at 16q have recently been
associated with familial gastric cancer. Furthermore, two genome-wide
linkage studies of PCA recently reported positivity at 16q. We therefore
identified families and individual patients with both gastric and PCA
and investigated whether the CDH1 gene mutations were involved in cancer
predisposition in these cases. Fifteen of the 180 Finnish hereditary PCA
families (8.3%) had one or more gastric cancer cases. No truncating or
splice site CDH1 mutations were identified by PCR single-strand
conformational polymorphism in these families or in eight individual
patients who had both prostate and gastric cancer. However, a novel
S270A missense mutation in exon 6 of the CDH1 gene was seen in a single
family with four prostate and two gastric cancers. A large-scale
population-based survey indicated a higher prevalence of S270A among
both familial PCA cases (3.3%; n = 120; P = 0.01) and unselected PCA
patients (1.5%; n = 472; P = 0.12) as compared with blood donors serving
as population controls (0.5%; n = 923). We conclude that individual rare
mutations and polymorphisms in the CDH1 gene, such as S270A, may
contribute to the onset of PCA and warrant further investigations in
other populations. However, the CDH1 gene does not appear to explain the
link between prostate and gastric cancer.
11
UI - 11805570
AU - Ruo L; Cellini C; La-Calle JP Jr; Murray M; Thaler HT; Quan SH; Guillem
TI -
JG
Limitations of family cancer history assessment at initial surgical
consultation.
SO - Dis Colon Rectum 2001 Jan;44(1):98-103; discussion 103-4
AD - Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York,
New York 10021, USA.
PURPOSE: Although important for the diagnosis of familial clustering of
colorectal cancer and hereditary nonpolyposis colorectal cancer, the
accuracy of familial cancer history assessment in the office setting has
been questioned. Furthermore, there are few publications describing the
optimal method for accurately capturing a family cancer history. The
purpose of this study was to determine how well family cancer history is
assessed in patients with early age-of-onset colorectal cancer at
initial surgical consultation compared with a telephone interview and
mailed questionnaire. METHODS: Medical records of patients 40 years old
or younger at the time of colorectal cancer surgery were reviewed for
documentation of family cancer history at initial surgical consultation.
In addition, family cancer history was solicited from surviving patients
or their next of kin by telephone and a mailed questionnaire. The kappa
coefficient was used to measure degree of correlation between family
cancer history obtained at initial surgical consultation and subsequent
telephone interview and questionnaire. RESULTS: One hundred twenty-five
patients were available for analysis. Family cancer history was
documented on the initial surgical consultation report in 78 percent of
cases. Although 31.2 percent were identified as having no family cancer
history at initial surgical consultation, this proportion decreased to
13.5 percent after telephone interviews and questionnaires. Family
history assessment at initial surgical consultation also failed to
identify 7 of 11 individuals meeting Amsterdam criteria for hereditary
nonpolyposis colorectal cancer and 10 of 16 individuals meeting modified
clinical criteria for hereditary nonpolyposis colorectal cancer.
CONCLUSIONS: Although family cancer history was commonly obtained during
the initial surgical consultation of patients with colorectal cancer,
there was a tendency to underestimate the extent of familial cancer. A
telephone interview and questionnaire conducted at a later date may
reveal a more comprehensive family cancer history. This is an important
observation, because individuals identified as high-risk for hereditary
nonpolyposis colorectal cancer or familial clustering of colorectal
cancer require special consideration with respect to screening,
surveillance, and surgical management.
12
UI - 11768563
AU - Berends MJ; Wu Y; Sijmons RH; Hofstra RM; van der Zee AG; Buys CH;
TI -
Kleibeuker JH
Clinical definition of hereditary non-polyposis colorectal cancer: a
search for the impossible?
SO - Scand J Gastroenterol Suppl 2001;(234):61-7
AD - Dept. of Gastroenterology, University Hospital, Groningen, The
Netherlands.
Hereditary non-polyposis colorectal cancer is an autosomal dominant
inherited disorder that predisposes its carriers to an almost 100%
lifetime risk of cancer, in particular colorectal and endometrial
cancer. Germline mutations, resulting in a deficient DNA mismatch repair
system, are responsible for the disease. Because of the lack of specific
phenotypical features, clinical diagnosis in an individual patient is
impossible and relies heavily on family history. Genetic diagnosis by
mismatch detection is now possible in a substantial proportion of
families. Thus there is a great need for reliable but simple criteria
that will help clinicians to recognize patients and families who can be
referred for genetic diagnostics. In this article the different criteria
that have been formulated and published in recent years are reviewed and
the results, in terms of the proportions of subjects satisfying the
criteria who were found to have a germline mutation, are discussed. In
most studies the criteria were evaluated in only a small number of
subjects. A population-based study is currently being carried out in the
north of The Netherlands that aims to include 400 patients fulfilling
one of a few simple criteria. Mutation analysis will be performed in all
patients. The results of this study will help in the formulation of
accurate and simple criteria for use in clinical practice.
13
UI - 11760904
AU - Pistorius SR; Nagel M; Kruger S; Plaschke J; Kruppa C; Wehrmann U;
TI -
Schackert HK; Saeger HD
Combined molecular and clinical approach for decision making for surgery
in HNPCC patients: a report on three cases in two families.
SO - Int J Colorectal Dis 2001 Nov;16(6):402-7
AD - Department of Visceral, Thoracic, and Vascular Surgery, Technical
University of Dresden, Germany. spisto2522@aol..com
Hereditary nonpolyposis colorectal cancer (HNPCC) is associated with
highly penetrant germline mutations in mismatch repair genes. Due to a
high lifetime risk in gene carriers for synchronous and for metachronous
colorectal cancer and endometrial cancer in women, prophylactic and
extended surgery are considered as options for gene carriers. A
54-year-old patient with a history of metachronous rectal cancer and a
family history fulfilling the Amsterdam criteria presented with
carcinoma of the cecum and highly dysplastic adenomas of the splenic
flexure and descending colon. As a result of these findings, medical
history and molecular diagnosis, the decision was made to perform
colectomy and prophylactic hysterectomy with oophorectomy; histological
examination of the specimen showed three synchronous colon carcinomas.
The 31-year-old son carrying the pathogenic mutation refused to be
included in the HNPCC surveillance program. One year later he presented
with symptoms of bowel obstruction, and a carcinoma of the descending
colon was diagnosed. Intraoperatively, in addition to the colon cancer,
a small bowel cancer and peritoneal carcinomatosis were found. In
another family fulfilling the Amsterdam criteria without known germline
mutation a woman presented with synchronous cancer of the ascending
colon and the lower rectum at the age of 49 years. Proctocolectomy and
prophylactic hysterectomy were performed, which revealed an additional
colon cancer and endometrial cancer. We discuss approaches for
individual decision making for surgery in HNPCC patients. Is a subtotal
colectomy indicated in the case of first colon cancer in HNPCC patients,
or if the first tumor occurs in the lower rectum, should a
proctocolectomy or a restorative proctocolectomy be considered? The aim
of prospective clinical studies should be to assess acceptability,
survival rates, mortality, and the quality of life in HNPCC patients who
have undergone surveillance and standard oncological resections versus
extended or prophylactic surgery.
14
UI - 11807990
AU - Yamamoto H; Min Y; Itoh F; Imsumran A; Horiuchi S; Yoshida M; Iku S;
TI -
Fukushima H; Imai K
Differential involvement of the hypermethylator phenotype in hereditary
and sporadic colorectal cancers with high-frequency microsatellite
instability.
SO - Genes Chromosomes Cancer 2002 Mar;33(3):322-5
AD - First Department of Internal Medicine, Sapporo Medical University,
Sapporo, Japan. h-yama@sapmed.ac.jp
High-frequency microsatellite instability (MSI-H) due to defective DNA
mismatch repair occurs in the majority of hereditary nonpolyposis
colorectal cancers (HNPCCs) and in a subset of sporadic malignant
tumors. Clinicopathologic and genotypic features of MSI-H colorectal
tumors in HNPCC patients and those in sporadic cases are very similar
but not identical. Correlation between the MSI phenotype and aberrant
DNA methylation has been highlighted recently. A strong association
between MSI and CpG island methylation has been well characterized in
sporadic colorectal cancers with MSI-H but not in those of hereditary
origin. To address the issue, we analyzed hereditary and sporadic
colorectal cancers for aberrant DNA methylation of target genes using
methylation-specific polymerase chain reaction. DNA methylation of the
MLH1, CDKN2A, MGMT, THBS1, RARB, APC, and p14ARF genes was found in 0%,
23%, 10%, 3%, 73%, 53%, and 33% of 30 MSI-H cancers in HNPCC patients
and in 80%, 55%, 23%, 23%, 58%, 35%, and 50% of 40 sporadic colorectal
cancers with MSI-H, respectively. Cases showing methylation at three or
more loci of six genes other than MLH1 were defined as CpG island
methylator phenotype-positive (CIMP +), and 23% of HNPCC tumors and 53%
of sporadic cancers with MSI-H were CIMP+ (P = 0.018). Differences in
the extent of CpG island methylation, coupled with the differential
involvement of several genes by methylation, in HNPCC tumors and
sporadic MSI-H colorectal cancers may be associated with diverging
developmental pathways in hereditary and sporadic cancers despite
similar MSI-H phenotypes. Copyright 2002 Wiley-Liss, Inc.
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