Table of Contents
1
UI - 21451200
AU - Burghes AH; Vaessin HE; de La Chapelle A
TI -
Genetics. The land between Mendelian and multifactorial inheritance.
SO - Science 2001 Sep 21;293(5538):2213-4
AD - Department of Molecular and Cellular Biochemistry, Ohio State
University, Columbus, OH 43210, USA. burghes.1@osu.edu
2
UI - 21274205
AU - Wittekind C; Tannapfel A
TI -
Adenoma of the papilla and ampulla--premalignant lesions?
SO - Langenbecks Arch Surg 2001 Apr;386(3):172-5
AD - Institute of Pathology, University of Leipzig, Germany.
tana@medizin.uni-leipzig.de
Ampullary adenomas arising in the papilla or the ampulla Vateri, are
rare, benign, neoplastic lesions. No specific aetiological factors, such
as diet, chemical or environmental causes, have been identified yet. An
established risk factor which is accompanied by the development of
adenoma is the presence of genetically inherited polyposis syndromes,
e.g. familial adenomatosis coli (FAP). Adenomas assume tubular,
tubulovillous, or villous architecture and are not different from
adenomas arising elsewhere in the gastrointestinal tract. The full
neoplastic spectrum, ranging from mild to high grade dysplasia, up to
invasive carcinoma, resembles the adenoma-carcinoma sequence of the
large bowels.
3
UI - 21437289
AU - Martin-Denavit T; Duthel S; Giraud S; Olschwang S; Saurin JC; Plauchu H
TI -
Phenotype variability of two FAP families with an identical APC germline
mutation at codon 1465: a potential modifier effect?
SO - Clin Genet 2001 Aug;60(2):125-31
AD - Service de Genetique Clinique, Hospices Civils de Lyon, Hotel Dieu,
69288 Lyon cedex 02, France. henri.plauchu@chu-lyon.fr
We report the cases of two familial adenomatous polyposis (FAP) families
who presented with the same 2 base pair deletion (AG) at codon 1465 of
the adenomatous polyposis coli (APC) gene, but showed phenotypic
variability. The mutation was revealed by a simple nonradioactive method
using a heteroduplex analysis and identified by a sequence analysis.
This observation suggests the responsibility of modifier genes in FAP
patients' phenotype.
4
UI - 21017799
AU - Hyer W; Beveridge I; Domizio P; Phillips R
TI -
Clinical management and genetics of gastrointestinal polyps in children.
SO - J Pediatr Gastroenterol Nutr 2000 Nov;31(5):469-79
AD - Department of Pediatrics, St. Mark's Hospital, Harrow, United Kingdom.
warrenhyer@aol.com
5
UI - 21408664
AU - Fodde R; Smits R
TI -
Disease model: familial adenomatous polyposis.
SO - Trends Mol Med 2001 Aug;7(8):369-73
AD - Dept. of Human and Clinical Genetics, Leiden University Medical Center,
Sylvius Laboratories, Wassenaarseweg 72, 2333 AL, Leiden, The
Netherlands. r.fodde@lumc.nl
Mutations in the APC gene are responsible for familial adenomatous
polyposis (FAP) and for the majority of sporadic colorectal cancers. The
establishment of genotype-phenotype correlations in FAP is often
complicated by the great clinical variability observed among carriers of
the same APC mutation even within the same kindred. This variability is
likely to arise from the interaction of genetic and environmental
modifying factors, the dissection of which ideally requires the
employment of mouse models where the effects of specific Apc mutations
are analyzed in an inbred, homogeneous genetic background and a
controlled environment. The availability of different Apc mouse models
allows not only the establishment of more precise genotype-phenotype
correlations but has also provided very important clues for the
understanding of the function of APC in homeostasis and tumorigenesis.
Also, the close phenotypic resemblance to the human disease makes these
mice unique preclinical models to test chemopreventive and therapeutic
interventions.
6
UI - 21424742
AU - Ryo A; Nakamura M; Wulf G; Liou YC; Lu KP
TI -
Pin1 regulates turnover and subcellular localization of beta-catenin by
inhibiting its interaction with APC.
SO - Nat Cell Biol 2001 Sep;3(9):793-801
AD - Cancer Biology Program, Division of Hematology/Oncology, Department of
Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue,
HIM 1047, Boston, MA 02215, USA.
Phosphorylation on a serine or threonine residue preceding proline
(Ser/Thr-Pro) is a key regulatory mechanism, and the conformation of
certain phosphorylated Ser/Thr-Pro bonds is regulated specifically by
the prolyl isomerase Pin1. Whereas the inhibition of Pin1 induces
apoptosis, Pin1 is strikingly overexpressed in a subset of human
tumours. Here we show that Pin1 regulates beta-catenin turnover and
subcellular localization by interfering with its interaction with
adenomatous polyposis coli protein (APC). A differential-display screen
reveals that Pin1 increases the transcription of several beta-catenin
target genes, including those encoding cyclin D1 and c-Myc. Manipulation
of Pin1 levels affects the stability of beta-catenin in vitro.
Furthermore, beta-catenin levels are decreased in Pin1-deficient mice
but are increased and correlated with Pin1 overexpression in human
breast cancer. Pin1 directly binds a phosphorylated Ser-Pro motif next
to the APC-binding site in beta-catenin, inhibits its interaction with
APC and increases its translocation into the nucleus. Thus, Pin1 is a
novel regulator of beta-catenin signalling and its overexpression might
contribute to the upregulation of beta-catenin in tumours such as breast
cancer, in which APC or beta-catenin mutations are not common.
7
UI - 21424793
AU - Sonoshita M; Takaku K; Sasaki N; Sugimoto Y; Ushikubi F; Narumiya S;
TI -
Oshima M; Taketo MM
Acceleration of intestinal polyposis through prostaglandin receptor EP2
in Apc(Delta 716) knockout mice.
SO - Nat Med 2001 Sep;7(9):1048-51
AD - Laboratory of Biomedical Genetics, Graduate School of Pharmaceutical
Sciences, University of Tokyo, Tokyo, Japan.
Arachidonic acid is metabolized to prostaglandin H(2) (PGH(2)) by
cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role
in intestinal polyposis. Among the metabolites of PGH(2), PGE(2) is
implicated in tumorigenesis because its level is markedly elevated in
tissues of intestinal adenoma and colon cancer. Here we show that
homozygous deletion of the gene encoding a cell-surface receptor of
PGE(2), EP2, causes decreases in number and size of intestinal polyps in
Apc(Delta 716) mice (a mouse model for human familial adenomatous
polyposis). This effect is similar to that of COX-2 gene disruption. We
also show that COX-2 expression is boosted by PGE(2) through the EP2
receptor via a positive feedback loop. Homozygous gene knockout for
other PGE(2) receptors, EP1 or EP3, did not affect intestinal polyp
formation in Apc(Delta 716) mice. We conclude that EP2 is the major
receptor mediating the PGE2 signal generated by COX-2 upregulation in
intestinal polyposis, and that increased cellular cAMP stimulates
expression of more COX-2 and vascular endothelial growth factor in the
polyp stroma.
8
UI - 21469634
AU - Buckhaults P; Rago C; St Croix B; Romans KE; Saha S; Zhang L;
TI -
Vogelstein B; Kinzler KW
Secreted and cell surface genes expressed in benign and malignant
colorectal tumors.
SO - Cancer Res 2001 Oct 1;61(19):6996-7001
AD - Howard Hughes Medical Institute, Johns Hopkins Medical Institution,
Baltimore, Maryland 21231, USA.
Serial analysis of gene expression was used to identify transcripts
encoding secreted or cell surface proteins that were expressed in benign
and malignant tumors of the colorectum. A total of 290,394 tags were
analyzed from normal, adenomatous, and cancerous colonic epithelium. Of
the 21,343 different transcripts observed, 957 were found to be
differentially expressed between normal tissue and adenoma or between
normal tissue and cancer. Forty-nine transcripts were elevated > or
=20-fold in adenomas, 40 transcripts were elevated > or =20-fold in
cancers, and 9 transcripts were elevated > or =20-fold in both. Products
of six of these nine transcripts (TGFBI, LYS, RDP, MIC-1, REGA, and
DEHL) were predicted to be secreted or to reside on the cell surface,
and these were analyzed in more detail. The abnormal expression levels
predicted by serial analysis of gene expression were confirmed by
quantitative PCR analyses of each of these six genes. Moreover, the cell
types responsible for the elevated expression were identified by in situ
hybridization and by PCR analyses of epithelial cells immunoaffinity
purified from primary tumors. This study extends knowledge of the
differences in gene expression that underlie various stages of neoplasia
and suggests specific diagnostic approaches that may be useful for the
early detection of colorectal neoplasia.
9
UI - 21217696
AU - Attard TM; Giardiello FM; Argani P; Cuffari C
TI -
Fundic gland polyposis with high-grade dysplasia in a child with
attenuated familial adenomatous polyposis and familial gastric cancer.
SO - J Pediatr Gastroenterol Nutr 2001 Feb;32(2):215-8
AD - Department of Pediatrics, The Johns Hopkins Hospital, Baltimore,
Maryland 21287-2631, USA.
10
UI - 21367432
AU - Olschwang S
TI -
[Intestinal polyposis]
SO - Ann Med Interne (Paris) 2001 Jun;152(4):267-72
AD - INSERM U434, Fondation Jean-Dausset-CEPH, 27, rue Juliette-Dodu, 75010
Paris, France. olschwang@cephb.fr
11
UI - 21481727
AU - Church J; Lowry A; Simmang C; The Standards Task Force; American Society
TI -
of Colon and Rectal Surgeons
Practice parameters for the identification and testing of patients at
risk for dominantly inherited colorectal cancer--supporting
documentation.
SO - Dis Colon Rectum 2001 Oct;44(10):1404-12
12
UI - 93278969
AU - Evans G
TI -
Ethical issues: the geneticist's view point.
SO - Dis Markers 1992 Jul-Aug;10(4):199-203; discussion 211-28
AD - Department of Medical Genetics, St Mary's Hospital, Manchester.
13
UI - 96282904
AU - Michie S; McDonald V; Bobrow M; McKeown C; Marteau T
TI -
Parents' responses to predictive genetic testing in their children:
report of a single case study.
SO - J Med Genet 1996 Apr;33(4):313-8
AD - Psychology and Genetics Research Group, United Medical School, Guy's
Hospital, London, UK.
There is a widely held view among health professionals that predictive
genetic testing of children for late onset diseases is not desirable
clinical practice. Yet, little is known about the views of parents, or
their responses, to predictive genetic testing in their children. Since
such testing is being carried out in some genetic centres, the
opportunity was taken to conduct a single case study of the parents of 2
and 4 year old sisters who were tested for the gene for familial
adenomatous polyposis. Interviews before testing, after, and 15 months
later showed a stable attitude, that parental responsibility included
making decisions about such testing, and that the role of health
professionals should be one of information giving rather than decision
making. These parents had no regrets about having their children tested
and reported no changes in their behaviour towards either the child who
tested positively or the child who tested negatively. Using standardised
scales, mood was found to be within the normal range both before and
after testing in the mother and father. This case study is a first step
towards systematic empirical studies determining the consequences of
acquiescing to parents' requests for genetic testing in their children.
14
UI - 97212608
AU - Giardiello FM; Brensinger JD; Petersen GM; Luce MC; Hylind LM; Bacon JA;
TI -
Booker SV; Parker RD; Hamilton SR
The use and interpretation of commercial APC gene testing for familial
adenomatous polyposis.
SO - N Engl J Med 1997 Mar 20;336(12):823-7
AD - Department of Medicine, Johns Hopkins University School of Medicine,
Baltimore, MD, USA.
BACKGROUND: The use of commercially available tests for genes linked to
familial cancer has aroused concern about the impact of these tests on
patients. Familial adenomatous polyposis is an autosomal dominant
disease caused by a germ-line mutation of the adenomatous polyposis coli
(APC) gene that causes colorectal cancer if prophylactic colectomy is
not performed. We evaluated the clinical use of commercial APC gene
testing. METHODS: We assessed indications for APC gene testing, whether
informed consent was obtained and genetic counseling was offered before
testing, and the interpretation of the results through telephone
interviews with physicians and genetic counselors in a nationwide sample
of 177 patients from 125 families who underwent testing during 1995.
RESULTS: Of the 177 patients tested, 83.0 percent had clinical features
of familial adenomatous polyposis or were at risk for the disease-both
valid indications for being tested. The appropriate strategy for
presymptomatic testing was used in 79.4 percent (50 of 63 patients).
Only 18.6 percent (33 of 177) received genetic counseling before the
test, and only 16.9 percent (28 of 166) provided written informed
consent. In 31.6 percent of the cases the physicians misinterpreted the
test results. Among the patients with unconventional indications for
testing, the rate of positive results was only 2.3 percent (1 of 44).
CONCLUSIONS: Patients who underwent genetic tests for familial
adenomatous polyposis often received inadequate counseling and would
have been given incorrectly interpreted results. Physicians should be
prepared to offer genetic counseling if they order genetic tests.
15
UI - 97212615
AU - Veatch RM
TI -
Consent, confidentiality, and research.
SO - N Engl J Med 1997 Mar 20;336(12):869-70
16
UI - 97192181
AU - Clarke A
TI -
Parents' responses to predictive genetic testing in their children.
SO - J Med Genet 1997 Feb;34(2):174-5
17
UI - 97297366
AU - DudokdeWit AC; Tibben A; Duivenvoorden HJ; Frets PG; Zoeteweij MW;
TI -
Losekoot M; van Haeringen A; Niermeijer MF; Passchier J
Psychological distress in applicants for predictive DNA testing for
autosomal dominant, heritable, late onset disorders. The
Rotterdam/Leiden Genetics Workgroup.
SO - J Med Genet 1997 May;34(5):382-90
AD - Department of Medical Psychology, Erasmus University Rotterdam, The
Netherlands.
In a comparative study on the effects of predictive DNA testing for late
onset disorders, pre-test psychological distress was assessed in people
at risk for Huntington's disease (HD, n = 41), cerebral haemorrhage
(HCHWA-D, n = 9), breast and ovarian cancer (HBOC, n = 24), and
polyposis coli (FAP, n = 45). Partners, if available, also participated
in the study. Distress was measured with the subscales Intrusion and
Avoidance of the Impact of Event Scale. People at risk for the
neurodegenerative disorders reported more avoidance than those at risk
for the cancer syndromes. People at risk for FAP and partners of those
at risk for HBOC reported less intrusion than the others at risk and the
other partners. Subjects who were more distressed reported more
experiences with the disease in close relatives, the disease having a
great impact on their lives, having considerations against predictive
testing, expecting that being identified as a gene carrier would have
adverse effects, and expecting relief after being identified as a
non-carrier. Test candidates who expected an increase of personal
problems showed higher avoidance, whereas those who could better
anticipate future life as a carrier had higher intrusion levels.
Generally, subjects with high distress levels are of more concern to the
healthcare professional than those with low distress levels. However,
high distress may reflect worrying as a mental preparation for the test
result, whereas low distress may indicate denial-avoidance behaviour and
poor anticipation of the test outcome. In pre-test counselling sessions,
this should be acknowledged and addressed.
18
UI - 21236249
AU - Joint Test and Technology Transfer Committee Working Group, American
TI -
College of Medical Genetics, 9650 Rockville Pike, Bethesda, MD
20814-3998, United States.
Genetic testing for colon cancer: joint statement of the American
College of Medical Genetics and American Society of Human Genetics.
Joint Test and Technology Transfer Committee Working Group.
SO - Genet Med 2000 Nov-Dec;2(6):362-6
19
UI - 21396470
AU - Liao PH; Lee TL; Yang LC; Yang SH; Chen SL; Chou MY
TI -
Adenomatous polyposis coli gene mutation and decreased wild-type p53
protein expression in oral submucous fibrosis: a preliminary
investigation.
SO - Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001 Aug;92(2):202-7
AD - Departmnent of Dentistry, Chung Shan Medical and Dental College,
Taichung, Taiwan, ROC.
OBJECTIVE: The purpose of this study was to identify the adenomatous
polyposis coli (APC) tumor suppressor gene mutation and level of
wild-type p53 protein expression in patients with oral submucous
fibrosis (OSF). STUDY DESIGN: Cells from OSF and control subjects were
cultured in Dulbecco modified Eagle medium with 10% fetal bovine serum
at 37 degrees C. Genomic DNA was extracted from cultured cells and used
as a template for polymerase chain reaction amplification of the APC
tumor suppressor gene. The presence of wild-type p53 protein in cell
lysates of cultured cells was analyzed by Western blot. Data were
analyzed by the sign test for nonparametric samples and by analysis of
variance. RESULTS: The results showed that the APC gene of explant
cultured cells from OSF patients (8/8) had a CGA-to-GGA transition
mutation at codon 498 that resulted in an Arg-to-Gly missense mutation
(P <.01). All (8/8) normal HGF cultures revealed expression of the
wild-type APC protein. Cells cultured from 7 of 8 OSF patients were also
found to have a single nucleotide deletion at nucleotide 1494 that
resulted in creating a stop codon (TGA) at codon 504 (P <.01). This
created a premature signal for the endpoint of translation and thus
resulted in the generation of a truncated protein product that encodes a
polypeptide of 503 amino acid residue. It was found that wild- type p53
protein in human gingival fibroblast cell cultures was significantly
higher than in OSF cells (P <.01). CONCLUSION: Alterations of the APC
and wild-type p53 tumor suppressor genes in OSF may imply a risk for
progression to oral cancer.
20
UI - 21443504
AU - Crabtree MD; Tomlinson IP; Talbot IC; Phillips RK
TI -
Variability in the severity of colonic disease in familial adenomatous
polyposis results from differences in tumour initiation rather than
progression and depends relatively little on patient age.
SO - Gut 2001 Oct;49(4):540-3
AD - Molecular and Population Genetics Laboratory, Imperial Cancer Research
Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
mitch.crabstix@lineone.net
INTRODUCTION: As large scale genetic analysis becomes increasingly
efficient, attention is turning to problems arising from inaccurate
measurement of the phenotype. We have investigated the underlying basis
of variation in disease severity in the large intestine of familial
adenomatous polyposis (FAP) patients. The development of objective and
reproducible measures may have future use in genetic studies, such as
analysis of modifier genes. METHODS: We examined the ratio of adenomas
to crypts from microscopic slides taken from all parts of the colon of
44 resected FAP specimens. These findings were compared with a carefully
reported macroscopic polyp count. Age dependency of adenoma counts (in
the period around colectomy) was also analysed. RESULTS: The
adenoma:crypt ratio strongly correlated with reported macroscopic polyp
count (r=0.82, p<0.001) with no significant residual variation. Polyp
density measured using the adenoma: crypt ratio did not vary
significantly within an individual colon. Apparent visible variation in
polyp density within any colon was not found at the microscopic level.
There was no detectable age related increase in macroscopic adenoma
count between siblings over the age range at which colectomies were
performed. DISCUSSION: The severity of colonic polyposis in FAP can be
determined accurately by counting the adenoma:crypt ratio in sections
derived from stored tissue blocks. Variation between patients-dependent
on APC genotype and, probably, modifier genes-is manifest at both the
microscopic and macroscopic levels. Thus variation in disease severity
is more likely to result from different rates of tumour initiation than
from differences in progression of microadenomas to macroscopic tumours.
The absence of a detectable relationship between adenoma number and age
(over the range studied) suggests that most tumours may be initiated
relatively early in the patient's life, perhaps at a time of particular
susceptibility.
21
UI - 21477322
AU - Marotta A; Tan C; Gray V; Malik S; Gallinger S; Sanghera J; Dupuis B;
TI -
Owen D; Dedhar S; Salh B
Dysregulation of integrin-linked kinase (ILK) signaling in colonic
polyposis.
SO - Oncogene 2001 Sep 27;20(43):6250-7
AD - Jack Bell Research Center, 2660 Oak Street, Vancouver, BC, Canada V6H
3Z6.
Mutation of the adenomatous polyposis coli (APC) gene and the subsequent
dysregulation of beta-catenin are well-documented abnormalities in
familial adenomatous polyposis (FAP), as well as sporadic polyposis.
Intriguingly, overexpression of the integrin-linked kinase (ILK) has
been shown to modulate beta-catenin subcellular localization and
function. However, the significance of this finding for human
carcinogenesis remains unclear. Here, we report the increased
biochemical activity and expression of ILK protein in polyps from FAP
patients. Furthermore, dramatic increases in ILK immunoreactivity were
observed in all abnormal crypts from sporadic polyps, when compared with
the normal appearing crypts within the same resected specimens. As
sulindac and aspirin are the two most important
therapeutic/chemopreventative agents demonstrated in colorectal
carcinogenesis, in both humans and animals, further investigation
revealed that these non-steroidal anti-inflammatory drugs (NSAIDs)
target ILK and ILK-mediated events in vivo. These include inhibition of,
both the biochemical activation of ILK, inhibition of serine 9 GSK3beta
phosphorylation and the enhancement of TCF-4 transcriptional activity.
In conclusion, ILK protein hyperexpression appears to be an early event
in colonic polyposis. Additionally, ILK signaling is shown to undergo
modulation by sulindac (and aspirin) for the first time, indicating that
it is likely to be one of the targets affected by these agents in vivo.
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