Table of Contents
1
UI - 11551102
AU - Shtoyerman-Chen R; Friedman E; Figer A; Carmel M; Patael Y; Rath P;
TI -
Fidder HH; Bar-Meir S; Theodor L
The I1307K APC polymorphism: prevalence in non-Ashkenazi Jews and
evidence for a founder effect.
SO - Genet Test 2001 Summer;5(2):141-6
AD - Department of Gastroenterology, Chaim Sheba Medical Center,
Tel-Hashomer, Israel. kiffa@post.tau.ac.il
A missense mutation within the APC gene, I1307K, was described in
Ashkenazi individuals at risk for colorectal cancer (CRC) and in the
general population. The anecdotal reporting of the occurrence of this
mutation in some non-Ashkenazi individuals led us to hypothesize that
within the Jewish people, the I1307K polymorphism may reflect a founder
mutation, and that the mutation is not restricted to ethnic Ashkenazis.
To test that notion, and to establish the occurrence rate of the I1307K
polymorphism in non-Ashkenazi Jewish populations, we screened Iraqi and
Moroccan Jews and consecutive Jewish CRC patients and performed
haplotype analysis with APC-linked markers in two I1307K carrier
families. We analyzed Jewish individuals: 210 Moroccans, 160 Iraqis, 148
Ashkenazi, and 349 CRC patients (227 Ashkenazi and 122 non-Ashkenazi).
The mutation detection scheme included PCR followed by denaturing
gradient gel electrophoresis (DGGE) or modified restriction analysis
(MRA). Haplotypes were assessed using three intragenic and three
flanking markers. The I1307K polymorphism was detected in 29/227
Ashkenazi (12.8%), 2/122 (1.6%) non-Ashkenazi CRC patients, and in 2
individuals each (approximately 1%) within the Moroccan and Iraqi
populations. Allelic pattern analysis in all our I1307K carriers,
revealed a common haplotype for the three intragenic markers tested, in
all mutation carriers, regardless of ethnic origin. The I1307K
polymorphism, therefore, exists in all ethnic Jewish populations:
Ashkenazi and non-Ashkenazi, with or without colon cancer. Jewish I1307K
mutation carriers share a common allelic pattern with APC-linked
markers. This strongly supports the notion of a founder mutation for
I1307K.
2
UI - 11793475
AU - Kahmann S; Herter P; Kuhnen C; Muller KM; Muhr G; Martin D; Soddemann M;
TI -
Muller O
A non-radioactive protein truncation test for the sensitive detection of
all stop and frameshift mutations.
SO - Hum Mutat 2002 Feb;19(2):165-72
AD - Max-Planck-Institut fur molekulare Physiologie, Dortmund, Germany.
A new method for mutation detection is described, which is a technical
advancement of the protein truncation test. The new technique is
non-radioactive and highly sensitive for detection of virtually all
sequence mutations, which lead to a stop signal or to the shift of the
translation frame. The method includes four steps: 1) capture of the
interesting sequence copies out of the sample by binding to an
immobilized complementary sequence, 2) PCR amplification of the gene
fragment to be analyzed with primers coding both for amino- and
carboxy-terminal tags, 3) in vitro transcription and translation, and 4)
analysis of the translation products by Western blot. As an evaluation
of the new method, we detected mutated gene copies at a dilution of 1 to
40 compared to the non-mutated gene. Using the method, we were able to
detect a mutation in the adenomatous polyposis coli tumor suppressor
gene (APC) in a stool sample of a colorectal cancer patient. This
mutation could not be detected by direct sequencing of the amplified APC
gene fragment. Copyright 2002 Wiley-Liss, Inc.
3
UI - 11830528
AU - Huerta S; Irwin RW; Heber D; Go VL; Koeffler HP; Uskokovic MR; Harris DM
TI -
1alpha,25-(OH)(2)-D(3) and its synthetic analogue decrease tumor load in
the Apc(min) Mouse.
SO - Cancer Res 2002 Feb 1;62(3):741-6
AD - University of California-Los Angeles Center for Human Nutrition, Los
Angeles, CA 90095, USA.
Both calcium and vitamin D are thought to be able to inhibit colon
carcinogenesis. To better define the effects of vitamin D, we studied
1alpha,25-(OH)(2)-D(3) and a noncalcemic synthetic analogue of vitamin
D(3) (VD(3)) in the Apc(min) mouse. Female Apc(min) mice 4-5 weeks old
were randomized to four groups: a VD(3)-treated group (n = 11) were
given injections of 0.01 microg of 1alpha,25-(OH)(2)-D(3) i.p. three
times per week; an analogue-treated group (n = 10) received 5 microg of
1alpha,25-(OH)(2)-16-ene-19-nor-24-oxo-D(3) i.p. three times per week;
and a control group (n = 12) received sham injections of PBS. A
sulindac-treated group (n = 10) was used as a positive control. Doses of
these compounds were chosen based on previous toxicity studies in mice
and rats. After 10 weeks of treatment, mice were killed and two
observers (S. H., R. W. I.), blinded to treatment, scored polyp number
and size. Tumor number was not affected with 1alpha,25-(OH)(2)-D(3) or
vitamin D analogue administration. A significant decrease in total tumor
load (sum of all polyp areas) over the entire gastrointestinal tract was
seen in the analogue (36% decrease; P < 0.05) and the VD(3) groups (46%;
P < 0.001). There was a significant decrease in polyp number (49%; P <
0.001) and polyp area (70%; P < 0.001) in the sulindac group. Reverse
transcription-PCR of the total RNA derived from intestinal tissue
revealed expression of the vitamin D receptor throughout the small
intestine and the colon. Serum calcium levels in the analogue group were
not elevated at week 4 of treatment and only moderately elevated (22%)
by week 8 (P < or =0.001). In contrast, serum calcium in the VD(3) group
was significantly elevated (P < or =0.001) at weeks 4 (23%) and 8 (45%).
Food intake and growth rate were significantly lower in the VD(3) group
(26%, P < 0.001, and 27%, P < 0.001, respectively) at week 10. In
contrast, food intake and growth rate were similar for the control,
sulindac, and analogue groups. Our results indicate that a noncalcemic
analogue of vitamin D can significantly decrease intestinal tumor load
in Apc(min) mice without severe toxic side effects and suggest that
these compounds may have utility as chemopreventive agents in groups at
high-risk for colon cancer.
4
UI - 11852337
AU - Matsumoto T; Iida M; Kobori Y; Mizuno M; Nakamura S; Hizawa K
TI -
Progressive duodenal adenomatosis in a familial adenomatous polyposis
pedigree with APC mutation at codon 1556.
SO - Dis Colon Rectum 2002 Feb;45(2):229-33
AD - Department of Endoscopic Diagnostics and Therapeutics, Kyushu University
Hospital, Fukuoka, Japan.
PURPOSE: In familial adenomatous polyposis, genotype-duodenal phenotype
correlations have not been clearly understood. We identified the
adenomatous polyposis coli gene mutation in a family pedigree with
severe duodenal adenomatosis. METHODS: Among 53 familial adenomatous
polyposis families, we found a pedigree composed of five affected
members with severe duodenal adenomatosis. Clinical manifestations of
the family members were reviewed. The adenomatous polyposis coli gene of
four members were screened by polymerase chain reaction-based single
strand conformation polymorphism or protein truncation test. RESULTS:
The family was characterized by sparse colorectal polyposis, osteomas,
and epidermal cysts. However, there were intrafamilial variabilities in
the occurrence of fundic gland polyposis, congenital hypertrophy of the
retinal pigment epithelium, and desmoids. All the members had duodenal
adenomatosis in their second or third decades, and the adenomatosis in
three members progressed during surveillance. A frameshift mutation was
found at codon 1556 of the adenomatous polyposis coli gene in two
members, and the equivalent mutation was confirmed by protein truncation
test in another two. CONCLUSIONS: Distal 3' mutation of the adenomatous
polyposis coli gene seems to contribute to severe duodenal adenomatosis
in familial adenomatous polyposis. Specification of the adenomatous
polyposis coli gene mutation may be a clue for surveillance strategy for
duodenal adenomatosis in patients with familial adenomatous polyposis.
5
UI - 11748858
AU - Hutter P; Rey-Berthod C; Chappuis PO; Couturier A; Membrez V; Murphy A;
TI -
Joris F; Schorderet DF; Delozier-Blanchet C; Soravia C
Molecular and clinical characteristics in 32 families affected with
familial adenomatous polyposis.
SO - Hum Mutat 2001 Dec;18(6):550
AD - Unite de Genetique, Institut Central des Hopitaux Valaisans, Av.
Grand-Champsec, 1951 Sion, Switzerland. pierre.hutter@ichv.vsnet.ch.
Germ-line mutations in the 5' half of the Adenomatous Polyposis Coli
(APC) gene are found in about 80% of the patients affected with familial
adenomatous polyposis (FAP). The vast majority of these are nonsense or
frameshift mutations which result in the loss of the carboxyl terminus
of the APC protein. Using an in vivo assay in yeast, we have identified
pathogenic germ-line mutations in 26 of 32 (81%) unrelated Swiss
families affected with FAP. Nine mutations were novel and eight families
were shown to harbor two recurrent mutations. Correlations were
attempted between the location of APC germ-line mutations and clinical
manifestations of the disease. Copyright 2001 Wiley-Liss, Inc.
6
UI - 11768389
AU - Eccles D; Harvey J; Bateman A; Ross F
TI -
A novel 3' mutation in the APC gene in a family presenting with a
desmoid tumour.
SO - J Med Genet 2001 Dec;38(12):861-3
7
UI - 11768390
AU - Montera M; Piaggio F; Marchese C; Gismondi V; Stella A; Resta N; Varesco
TI -
L; Guanti G; Mareni C
A silent mutation in exon 14 of the APC gene is associated with exon
skipping in a FAP family.
SO - J Med Genet 2001 Dec;38(12):863-7
8
UI - 11818567
AU - Roberts RB; Min L; Washington MK; Olsen SJ; Settle SH; Coffey RJ;
TI -
Threadgill DW
Importance of epidermal growth factor receptor signaling in
establishment of adenomas and maintenance of carcinomas during
intestinal tumorigenesis.
SO - Proc Natl Acad Sci U S A 2002 Feb 5;99(3):1521-6
AD - Department of Cell Biology, Vanderbilt University, 1161 21st Avenue
South, Nashville, TN 37232, USA.
We used the hypomorphic Egfr(wa2) allele to genetically examine the
impact of impaired epidermal growth factor receptor (Egfr) signaling on
the Apc(Min) mouse model of familial adenomatous polyposis. Transfer of
the Apc(Min) allele onto a homozygous Egfr(wa2) background results in a
90% reduction in intestinal polyp number relative to Apc(Min) mice
carrying a wild-type Egfr allele. This Egfr effect is potentially
synergistic with the actions of the modifier-of-min (Mom1) locus.
Surprisingly, the size, expansion, and pathological progression of the
polyps appear Egfr-independent. Histological examination of the ilea of
younger animals revealed no differences in the number of microadenomas,
the presumptive precursor lesions to gross intestinal polyps.
Pharmacological inhibition with EKI-785, an Egfr tyrosine kinase
inhibitor, produced similar results in the Apc(Min) model. These data
suggest that normal Egfr activity is required for establishment of
intestinal tumors in the Apc(Min) model between initiation and
subsequent expansion of initiated tumors. The role of Egfr signaling
during later stages of tumorigenesis was examined by using nude mice
xenografts of two human colorectal cancer cell lines. Treatment with
EKI-785 produced a dose-dependent reduction in tumor growth, suggesting
that Egfr inhibitors may be useful for advanced colorectal cancer
treatment.
9
UI - 11848471
AU - Greco C; Alvino S; Buglioni S; Assisi D; Lapenta R; Grassi A; Stigliano
TI -
V; Mottolese M; Casale V
Activation of c-MYC and c-MYB proto-oncogenes is associated with
decreased apoptosis in tumor colon progression.
SO - Anticancer Res 2001 Sep-Oct;21(5):3185-92
AD - Clinical Pathology Service, Regina Elena Cancer Institute, Rome, Italy.
ayyctg@tin.it
BACKGROUND: An increasing amount of evidence suggests that progression
from normal mucosa to colorectal cancer is accompanied by morphological
and genetic alterations. Genetic abnormalities affect malignant
transformation via a gradual imbalance of normal tissue homeostasis
involving programmed cell death (PCD) or apoptosis. Therefore, it has
been hypothesized that alterations in apoptosis may contribute to
carcinogenesis. The aim of the present work was to investigate the
relationship between frequency of spontaneous apoptosis during
transition adenoma-to-carcinoma of the colorectal tract and the
incidence of activation of c-myc and c-myb proto-oncogenes, involved
both in colon tumorigenesis and apoptosis. MATERIALS AND METHODS:
Ninety-five tissue specimens (60 polyps and 35 adenocarcinomas) were
removed with autologous normal adjacent mucosa from colon cancer
patients. Genomic DNA was extracted and analyzed for both apoptosis
frequency (DNA fragmentation assay) and proto-oncogene activation
(Southern blot analysis). On the same samples, Bcl-2 protein expression
was evaluated by immunohistochemistry. RESULTS: Our results showed that:
i) a significant relationship exists between apoptosis and genesis of
colorectal cancer since, compared to adenomatous polyps and adjacent
normal mucosa, cell death is markedly inhibited in tumors (p = 0.01);
ii) during colon tumor progression, apoptosis and amplifications of
c-myc/c-myb genes are inversely related; iii) Bcl-2 expression is
retained in colon tumors even though at a significantly lower level with
respect to adenomatous polyps. CONCLUSION: These results indicate that
failure of the normal apoptotic process together with de-regulation of
c-myc and c-myb proto-oncogenes might promote the development of
colorectal tumors.
10
UI - 11848484
AU - Paulsen JE; Alexander J
TI -
Growth stimulation of intestinal tumours in Apc(Min/+) mice by dietary
L-methionine supplementation.
SO - Anticancer Res 2001 Sep-Oct;21(5):3281-4
AD - Department of Environmental Medicine, National Institute of Public
Health, Oslo, Norway. jan.erik.paulsen@folkehelsa.no
We studied the effects of extra dietary methionine on the formation and
growth of intestinal adenomas in the Min (Apc+/-) mouse, which is a
murine model of the human familial adenomatous syndrome. The AIN-76A
diet was supplemented with 0.7% L-methionine from week 4 after birth and
the animals were killed at week 8. The number of tumours in Min mice was
apparently not affected by the addition of extra methionine. However,
the dietary methionine supplementation increased the surface area of
small intestinal tumours by 41% (p=0.009). In the colon, extra
methionine did not affect tumour size. In conclusion, extra dietary
methionine promotes the growth of adenomas in the small intestine of Min
mice.
11
UI - 11815870
AU - de Chadarevian JP; Dunn S; Malatack JJ; Ganguly A; Blecker U; Punnett HH
TI -
Chromosome rearrangement with no apparent gene mutation in familial
adenomatous polyposis and hepatocellular neoplasia.
SO - Pediatr Dev Pathol 2002 Jan-Feb;5(1):69-75
AD - Department of Pathology and Laboratory Medicine. (Anatomical Pathology,
Cytogenetics), MCP Hahnemann University School of Medicine and St.
Christopher's Hospital for Children, Erie Avenue at Front Street,
Philadelphia, PA 19134, USA.
We have identified a constitutional inversion in chromosome 5 associated
with familial adenomatous polyposis in three generations of a Mexican
family. Two of three siblings developed hepatic neoplasia in infancy.
The gene truncation assay failed to demonstrate a truncated protein in
the segment harboring the adenomatous polyposis coli (APC) genes.
Polymerase chain reaction (PCR) amplification of APC gene coding exons
and sequencing of PCR products did not reveal any significant mutation.
The data suggest that in this family, the phenotype may be the result of
a "position effect."
12
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.
13
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.
14
UI - 11839722
AU - Matsumoto T; Iida M; Kobori Y; Mizuno M; Nakamura S; Hizawa K; Yao T
TI -
Serrated adenoma in familial adenomatous polyposis: relation to germline
APC gene mutation.
SO - Gut 2002 Mar;50(3):402-4
AD - Department of Endoscopic Diagnostics and Therapeutics, Kyushu University
Hospital, Fukuoka, Japan. matane@intmed2.med.kyushu-u.ac.jp
BACKGROUND: Serrated adenoma is a precursor of colorectal cancer. AIM:
To clarify possible genotype-phenotype correlations of serrated adenomas
in familial adenomatous polyposis (FAP). Patients: Eleven patients from
eight families with FAP. METHODS: We performed total colonoscopy with
multiple biopsies in patients. Neoplasia with a serrated glandular
structure was regarded as a serrated adenoma. In each patient, germline
mutations of the APC gene were determined. Colonic phenotype was
compared with germline mutations of the APC gene. RESULTS: Serrated
adenomas were found in three patients. These patients had macroscopic
polyps <100 in number. Pedigrees with serrated adenomas had the
truncating germline APC mutation at codon 161, 332, or 1556 while in the
other pedigrees mutations were found between codons 554 and 1324.
CONCLUSIONS: In FAP, serrated adenoma may be a phenotype characteristic
of the attenuated form.
15
UI - 11713587
AU - Humar B; D'Orazio D; Albrecht C; Bauerfeind P; Muller H; Dobbie Z;
TI -
Bendik I
Expression of putative anticancer targets in familial adenomatous
polyposis and its association with the APC mutation status.
SO - Int J Oncol 2001 Dec;19(6):1179-86
AD - Division of Medical Genetics, DKBW, Research Group Human Genetics,
University Hospital, Basel, Switzerland.
Several substances interfering with colorectal carcinogenesis may reduce
or prevent adenoma formation in familial adenomatous polyposis (FAP), an
inherited predisposition to colorectal cancer. This study determined the
expression of genes coding for putative anticancer targets (COX-2, iNOS,
MMP-7, ODC, PKCbeta, PPARgamma, RXRalpha, RXRbeta, RXRgamma) in FAP
patients to provide one of the rationales for the design of chemotherapy
and -prevention strategies. Gene expression was assessed by TaqMan
analysis in colonic tissue of 9 FAP patients with mutations in the APC
gene (APCpos), 5 FAP patients without identified genetic defect
(APCneg), and 3 healthy individuals. Among the examined genes, PKCbeta
and MMP-7 were most consistently altered in adenoma tissue relative to
matched mucosa. Intriguingly, ODC was clearly overexpressed in polyps
from APCpos but not APCneg patients. Furthermore, PKCbeta, MMP-7, ODC,
and COX-2 as well as all RXRs displayed altered expression in apparently
healthy FAP mucosa as opposed to that of healthy individuals. Our data
suggests PKCbeta and MMP-7 to be the most suited as anticancer targets
among the genes studied.
16
UI - 11773864
AU - Lamberti C; Jungck M; Laarmann M; Knapp M; Caspari R; Friedl W;
TI -
Sauerbruch T; Propping P; Kruse R
Arylamine N-acetyltransferase type 2 and glutathione S-transferases M1
and T1 polymorphisms in familial adenomatous polyposis.
SO - Pharmacogenetics 2002 Jan;12(1):49-54
AD - Institute of Human Genetics, University of Bonn, Bonn, Germany.
c.lamberti@uni-bonn.de
Familial adenomatous polyposis (FAP) exhibits a variable phenotype even
in carriers of the same adenomatous polyposis coli germline mutation.
Xenobiotic-metabolizing enzymes such as N-acetyltransferases (NATs) and
glutathione S-transferases (GSTs) were reported to modify the individual
risk for colorectal cancer. We examined whether the polymorphisms of the
NAT2, GSTM1, and GSTT1 enzymes affect age at diagnosis of first
colorectal adenomas or extracolonic manifestations in 411 FAP patients.
Neither age at diagnosis of colorectal adenomas nor occurrence of
extra-intestinal tumors differed significantly between genotypes at the
NAT2 and GSTM1 loci, whereas GSTT1 polymorphism showed an uncertain
association with extra-intestinal manifestations. Combinations of
supposed at risk genotypes of the three enzymes showed no significant
differences either. Thus, NAT2, GSTM1, or GSTT1 are unlikely to modify
the disease phenotype in FAP patients.
17
UI - 11751493
AU - Keller JJ; Offerhaus GJ; Drillenburg P; Caspers E; Musler A; Ristimaki
TI -
A; Giardiello FM
Molecular analysis of sulindac-resistant adenomas in familial
adenomatous polyposis.
SO - Clin Cancer Res 2001 Dec;7(12):4000-7
AD - Department of Pathology, Academic Medical Center, 1100 DD Amsterdam, the
Netherlands. j.j.keller@amc.uva.nl
PURPOSE: Sulindac causes the reduction of adenomas in familial
adenomatous polyposis (FAP) patients, but complete regression is
unusual, and breakthrough of colorectal carcinoma during sulindac
treatment has been described. The molecular features related to sulindac
resistance are unknown. Therefore, we investigated molecular alterations
in adenomas from FAP patients with complete adenoma regression on
sulindac (responsive patients) and from FAP patients with
sulindac-resistant adenomas (resistant patients). DESIGN: Fourteen
baseline adenomas (removed before sulindac treatment) from six
responsive patients were studied. Also, 9 baseline adenomas and 34
resistant adenomas (removed during sulindac treatment) from three
resistant patients were analyzed. Using immunohistochemistry, we
evaluated the expression of beta-catenin, cyclooxygenase-2 (Cox-2), p53,
Bcl-2, and Bax. K-ras codon 12 mutations, loss of heterozygosity at 5q
(APC locus), and microsatellite instability were studied with PCR-based
techniques. RESULTS: There were no significant differences between
baseline adenomas from sulindac-responsive and -resistant patients (P >
0.05). There was less loss of membranous beta-catenin staining and less
nuclear beta-catenin accumulation in resistant adenomas compared with
baseline adenomas from the same (sulindac-resistant) patients (P < 0.01)
or baseline adenomas from responsive patients (P < 0.01). Epithelial
Cox-2 expression was less, though not significant, in resistant adenomas
compared with baseline adenomas from resistant patients, but was
significantly less in baseline adenomas from responsive patients (P <
0.01). K-ras mutations were found in 8 of 34 resistant adenomas (24%)
and in none of the baseline adenomas (P < 0.05). Stromal Cox-2
expression, staining of p53 and Bcl-2, and loss of heterozygosity at 5q
were comparable in both groups. Loss of Bax staining and microsatellite
instability were not found in any adenoma. CONCLUSIONS:
Sulindac-resistant adenomas display less alteration in beta-catenin
staining and less epithelial Cox-2 expression when compared with
adenomas removed before sulindac treatment. K-ras mutations may
contribute to sulindac-resistance. Continued research is needed to
investigate molecular alterations related to sulindac resistance.
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