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Abramson Cancer CenterNCI CANCERLIT® Search: Familial Adenomatous Polyposis - April 2002
National Cancer Institute®
Last Modified: April 1, 2002
Table of Contents
1
UI - 11552476
AU - Carlomagno N; Scarano MI; Gargiulo S; De Rosa M; Panariello L; Izzo P;
TI -
Renda A
[Familial colonic polyposis: effect of molecular analysis on the
diagnostic-therapeutic approach]
SO - Ann Ital Chir 2001 Mar-Apr;72(2):207-14
AD - Chirurgia Generale ad Indirizzo Addominale, Universita Federico II,
Napoli. renda@unina.it
Germline mutations of the Adenomatous polyposis gene (APC) are
responsible for Familial Adenomatous Polyposis (FAP), an inherited
condition that predisposes to the development of hundreds to thousands
benign adenomas in the colo-rectum. If not surgically removed, they
inevitably progress into malignant adenocarcinoma. To date more than 450
germline mutations have been described allowing the establishment of
genotype/phenotype correlation between the site and type of molecular
defects and their morbid consequences. Authors reviewed their experience
concerning 22 FAP affected patients and their 26 first degree relatives,
in whom the mutational analysis of the APC gene had been carried out.
Site and type of mutations were associated with clinical parameters (age
of onset, rectal involvement, extracolonic manifestations, presence of
colorectal cancer) and treatments. The impact of mutational analyses on
the clinical approach could be very interesting in the future, modifying
both surveillance programs and therapeutical choices.
2
UI - 11905639
AU - Jass J R
TI -
Familial colorectal cancer: pathology and molecular characteristics.
SO - Lancet Oncol 2000 Dec;1():220-6
AD - Department of Pathology, University of Queensland, Mayne Medical School,
Herston, Australia. j.jass@mailbox.uq.edu.au
Appropriate management of familial colorectal cancer revolves around the
diagnosis of the underlying genetic syndrome. This necessitates an
interdisciplinary approach allowing integration of clinical,
morphological, and molecular evidence that may involve several members
of the same family. Genetic disorders express themselves over time,
whereas clinical investigation of family members is likely to be
episodic. Generic features of hereditary colorectal cancer syndromes
include a positive family history, early age at onset, multiple
neoplasms, and extracolonic lesions of either a developmental or
neoplastic nature. Deriving a complete description of a genetic disorder
is hampered by the need to trace and obtain tissue samples from many
institutions. This review examines the usefulness of tissue-based
investigations, both morphological and molecular, in raising the
suspicion of familial colorectal cancer, providing a definitive tissue
diagnosis and contributing to the larger body of diagnostic evidence.
The account focuses on the two most well-studied syndromes--familial
adenomatous polyposis (FAP) and hereditary non-polyposis colorectal
cancer (HNPCC)--but consideration is also given to less well-understood
syndromes. Some of these, notably hyperplastic polyposis and mixed
polyposis, may closely mimic FAP or HNPCC.
3
UI - 11899542
AU - Krutilkova V; Havlovicova M; Goetz P
TI -
[Specialized genetic counseling in pediatric and adult oncology
patients]
SO - Cas Lek Cesk 2002;141(1):23-7
AD - Ustav biologie a lekarske genetiky 2. LF UK a FNM, Praha.
vera.krutilkova@lfmotol.cuni.cz
Five to ten percent of oncological diseases exhibit monogenic mode of
inheritance. They occur as a consequence of the germline mutations of
tumor suppressor genes and of the genes engaged in reparative processes.
Most common monogenically determined oncological diseases are: AD form
of breast and ovarian cancer, hereditary nonpolyposis colorectal cancer
(HNPCC, Lynch sy.) and familiar adenomatous polyposis (FAP). The aim of
the genetic investigation is to evaluate whether the index family deals
with the hereditary form of tumor predisposition, than, if possible, to
perform DNA analysis in the family and to propose preventive screening
program (methods) for the probands in risk.
4
UI - 11809680
AU - Cheadle JP; Krawczak M; Thomas MW; Hodges AK; Al-Tassan N; Fleming N;
TI -
Sampson JR
Different combinations of biallelic APC mutation confer different growth
advantages in colorectal tumours.
SO - Cancer Res 2002 Jan 15;62(2):363-6
AD - Institute of Medical Genetics, University of Wales College of Medicine,
Heath Park, Cardiff CF14 4XN, United Kingdom.
New facets to Knudson's [corrected] "two-hit" hypothesis have been
proposed recently in relation to adenomatous polyposis coli (APC):
protein inactivation may be selected weakly, and the two hits may be
interdependent. We reviewed published data on 165 sporadic and 102
familial adenomatous polyposis-associated colorectal tumors with two
characterized mutations. Using a Poisson model, we redefined the
mutation cluster region (MCR) to residues 1281-1556 and confirmed that
the locations of pairs of APC mutations are interdependent (P < 0.0001).
A mathematical model, based on the data for sporadic tumors, implied
different growth advantages for different combinations of APC mutations:
genotype I/I (I: mutation inside MCR) was 3.9 times more likely to be
selected than IO or IL (O: mutation outside MCR, L: allelic loss), which
were 27.8 times more likely to be selected than OO or OL.
5
UI - 11113066
AU - Bulow C; Vasen H; Jarvinen H; Bjork J; Bisgaard ML; Bulow S
TI -
Ileorectal anastomosis is appropriate for a subset of patients with
familial adenomatous polyposis.
SO - Gastroenterology 2000 Dec;119(6):1454-60
AD - Danish Polyposis Register, Hvidovre University Hospital, Copenhagen,
Denmark.
BACKGROUND & AIMS: This study reevaluates the risk of rectal cancer and
the frequency of subsequent proctectomy for nonmalignant causes in
patients with familial adenomatous polyposis (FAP) who have undergone
colectomy with ileorectal anastomosis (IRA). Potential risk factors for
rectal cancer in this setting are also examined, and recommendations for
the choice of surgical procedure are made. METHODS: The national
polyposis registries in Denmark, Finland, The Netherlands, and Sweden
included 659 patients undergoing surgery with IRA in 1940-1997.
Kaplan-Meier analysis and Cox regression analysis were performed to
evaluate cumulative risk, survival, and predictive risk factors.
RESULTS: Rectal carcinoma was diagnosed in 47 patients, with a
cumulative 40-year risk of 0.32. The cumulative risk according to
chronologic age was 0.30 at age 60, and higher in patients undergoing
surgery above age 25 (P = 0.0016). Chronologic age was the only
independent risk factor (P = 0.0016). The cumulative 5-year survival
rate after rectal carcinoma was 0.60. The apc mutation was known in 167
patients, of whom 7 had rectal cancer. The cumulative 40-year risk of
secondary proctectomy was 0.70, and higher in patients with a mutation
in codon 1250-1500 than outside this region (P = 0.005). However, all 7
rectal cancers were found in the latter group. None of the 18 patients
with attenuated FAP (mutation in codon 0-200 or >1500) had a secondary
proctectomy. CONCLUSIONS: IRA is recommended in (1) young patients with
few rectal adenomas and a family history of a mild phenotype and (2)
patients with attenuated FAP (a mutation in codon 0-200 or >1500),
provided there is acceptance of life-long rectal surveillance. Patients
with many rectal polyps and/or a family history of severe polyposis
should be offered a restorative proctocolectomy with an ileal pouch-anal
anastomosis.
6
UI - 11494976
AU - Bertario L; Sala P; Radice P; Russo A
TI -
Ileorectal anastomosis in patients with familial adenomatous polyposis.
SO - Gastroenterology 2001 Aug;121(2):502-3
7
UI - 11494977
AU - Friedl W; Mangold E; Caspari R; Lamberti C; Propping P
TI -
Ileorectal anastomosis is appropriate for a subset of patients with
familial adenomatous polyposis.
SO - Gastroenterology 2001 Aug;121(2):503-4
8
UI - 11932472
AU - Giardiello FM; Yang VW; Hylind LM; Krush AJ; Petersen GM; Trimbath JD;
TI -
Piantadosi S; Garrett E; Geiman DE; Hubbard W; Offerhaus GJ; Hamilton SR
Primary chemoprevention of familial adenomatous polyposis with sulindac.
SO - N Engl J Med 2002 Apr 4;346(14):1054-9
AD - Department of Medicine, Johns Hopkins University School of Medicine,
Baltimore, USA.
BACKGROUND: Familial adenomatous polyposis is caused by a germ-line
mutation in the adenomatous polyposis coli gene and is characterized by
the development of hundreds of colorectal adenomas and, eventually,
colorectal cancer. Nonsteroidal antiinflammatory drugs can cause
regression of adenomas, but whether they can prevent adenomas is
unknown. METHODS: We conducted a randomized, double-blind,
placebo-controlled study of 41 young subjects (age range, 8 to 25 years)
who were genotypically affected with familial adenomatous polyposis but
phenotypically unaffected. The subjects received either 75 or 150 mg of
sulindac orally twice a day or identical-appearing placebo tablets for
48 months. The number and size of new adenomas and side effects of
therapy were evaluated every four months for four years, and the levels
of five major prostaglandins were serially measured in biopsy specimens
of normal-appearing colorectal mucosa. RESULTS: After four years of
treatment, the average rate of compliance exceeded 76 percent in the
sulindac group, and mucosal prostaglandin levels were lower in this
group than in the placebo group. During the course of the study,
adenomas developed in 9 of 21 subjects (43 percent) in the sulindac
group and 11 of 20 subjects in the placebo group (55 percent) (P=0.54).
There were no significant differences in the mean number (P=0.69) or
size (P=0.17) of polyps between the groups. Sulindac did not slow the
development of adenomas, according to an evaluation involving linear
longitudinal methods. CONCLUSIONS: Standard doses of sulindac did not
prevent the development of adenomas in subjects with familial
adenomatous polyposis.
9
UI - 11932478
AU - Chau I; Cunningham D
TI -
Cyclooxygenase inhibition in cancer--a blind alley or a new therapeutic
reality?
SO - N Engl J Med 2002 Apr 4;346(14):1085-7
10
UI - 11868006
AU - Saurin JC; Ligneau B; Ponchon T; Lepretre J; Chavaillon A; Napoleon B;
TI -
Chayvialle JA
The influence of mutation site and age on the severity of duodenal
polyposis in patients with familial adenomatous polyposis.
SO - Gastrointest Endosc 2002 Mar;55(3):342-7
AD - Federation des specialites digestives, Laboratoire de genetique, Hopital
E. Herriot, 5 place d'Arsonval, 64937 Lyon Cedex 03, France.
BACKGROUND: The present study was undertaken to identify factors
affecting the severity of the duodenojejunal polyposis in patients with
familial adenomatous polyposis. METHODS: Duodenojejunal polyposis was
evaluated in 41 consecutive patients with familial adenomatous polyposis
(mean age 41 years, range 21-63 years), 33 (80%) with known APC
mutation, by using a standardized endoscopic protocol. The severity of
the polyposis was graded with the Spigelman scoring system (0-12
points), the Spigelman score/age ratio, and the presence or absence of
advanced adenomas (>1 cm in diameter and/or high-grade dysplasia).
RESULTS: The Spigelman score (median 8, range 3-12) was higher in
patients older than 50 years (median 10, range 3-12) as compared with
younger patients (median 7.5, range 3-11; p = 0.043). A significant
association between age and the presence of advanced adenomas was also
observed. Patients with a mutation in the central part of the APC gene
(codons 279-1309) had a higher Spigelman score and Spigelman score/age
ratio as compared with patients with other mutations: median Spigelman
score/age ratio 0.21 (range 0.14-0.40) versus 0.10 (range 0.06-0.20) (p
< 0.001). CONCLUSIONS: Older age and APC mutation in the central part of
the gene are risk factors for the development of severe duodenojejunal
polyposis.
11
UI - 10223463
AU - Taylor MD; Perry J; Zlatescu MC; Stemmer-Rachamimov AO; Ang LC; Ino Y;
TI -
Schwartz M; Becker LE; Louis DN; Cairncross JG
The hPMS2 exon 5 mutation and malignant glioma. Case report.
SO - J Neurosurg 1999 May;90(5):946-50
AD - Department of Medicine, University of Toronto, Ontario, Canada.
Patients with Turcot syndrome (TS) are predisposed to colon tumors and
primary brain tumors, typically glioblastomas or medulloblastomas. The
authors describe a patient with TS featuring a known germline mutation
of exon 5 of the hPMS2 mismatch repair gene who developed two
metachronous glioblastomas, both with distinct oligodendroglial
features. Molecular genetic analysis revealed allelic loss of chromosome
19q in the patient's second tumor but no allelic loss of chromosome 1p.
Prominent microsatellite instability was also found in this tumor,
consistent with a germline mismatch repair defect. Because this patient
had an unusual underlying condition and his tumor had a unique
histological appearance for TS, it was hypothesized that this genetic
defect may predispose to malignant gliomas with oligodendroglial
features. The authors therefore evaluated whether sporadic glioblastomas
and oligodendrogliomas undergo mutations of this region of the hPMS2
gene. However, single-strand conformation polymorphism analysis of hPMS2
exon 5 failed to reveal mutations in 20 sporadic glioblastomas and 16
sporadic oligodendroglial gliomas. Thus, although it is possible that
the germline hPMS2 exon 5 mutation may predispose to glioblastomas with
an oligodendroglial component, the same genetic defect is not commonly
involved in sporadic oligodendrogliomas or glioblastomas.
12
UI - 10536173
AU - Arai T; Akiyama Y; Nagasaki H; Murase N; Okabe S; Ikeuchi T; Saito K;
TI -
Iwai T; Yuasa Y
EXTL3/EXTR1 alterations in colorectal cancer cell lines.
SO - Int J Oncol 1999 Nov;15(5):915-9
AD - First Department of Surgery, Medical Research Institute, Tokyo Medical
and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
We previously demonstrated that metastasis-related tumor suppressor
gene(s) may exist on chromosome 8p21-22 on allelotype analysis of early
colorectal carcinomas (CRC) with lymph node metastasis. Here, we
searched for target gene(s) in this chromosomal region in the UniGene
database. The EXTL3 (also called EXTR1) gene was selected as a candidate
because of its homology to EXT1 and EXT2, putative tumor suppressor
genes. We screened 12 CRC cell lines for mutations by means of
polymerase chain reaction (PCR)-single strand conformation polymorphism.
Three cell lines showed EXTL3 mutations, all of which were located
within exon 3 and caused amino acid substitutions. Reverse
transcription-PCR analysis showed that the EXTL3 expression was lacking
in 1 of the 12 colorectal cancer cell lines. Although there is still no
definitive evidence that EXTL3 is a tumor suppressor gene for CRC, these
data suggest that inactivation of the EXTL3 gene may at least offer a
selective growth advantage for some CRC cell lines.
13
UI - 10965758
AU - Matsumoto T; Iida M
TI -
[Genetic aspects of hereditary polyposis of the gastrointestinal tract]
SO - Nippon Shokakibyo Gakkai Zasshi 2000 Aug;97(8):1007-16
AD - Department of Endoscopic Diagnostics and Therapeutics, Kyushu University
Hospital.
14
UI - 11244511
AU - Tan C; Costello P; Sanghera J; Dominguez D; Baulida J; de Herreros AG;
TI -
Dedhar S
Inhibition of integrin linked kinase (ILK) suppresses
beta-catenin-Lef/Tcf-dependent transcription and expression of the
E-cadherin repressor, snail, in APC-/- human colon carcinoma cells.
SO - Oncogene 2001 Jan 4;20(1):133-40
AD - BC Cancer Agency and Jack Bell Research Centre, 2660 Oak Street,
Vancouver, BC V6H 3Z6, Canada.
Loss of functional adenomatous polyposis coli (APC) protein results in
the stabilization of cytosolic beta-catenin and activation of genes that
are responsive to Lef/Tcf family transcription factors. We have recently
shown that an independent cell adhesion and integrin linked kinase
(ILK)-dependent pathway can also activate beta-catenin/LEF mediated gene
transcription and downregulate E-cadherin expression. In addition, ILK
activity and expression are elevated in adenomatous polyposis and colon
carcinomas. To examine the role of this pathway in the background of APC
mutations we inhibited ILK activity in APC-/- human colon carcinoma cell
lines. In all cases, inhibition of ILK resulted in substantial
inhibition of TCF mediated gene transcription and inhibition of
transcription and expression of the TCF regulated gene, cyclin D1.
Inhibition of ILK resulted in decreased nuclear beta-catenin expression,
and in the inhibition of phosphorylation of GSK-3 and stimulation of its
activity, leading to accelerated degradation of beta-catenin. In
addition, inhibition of ILK suppressed cell growth in culture as well as
growth of human colon carcinoma cells in SCID mice. Strikingly,
inhibition of ILK also resulted in the transcriptional stimulation of
E-cadherin expression and correlated with the inhibition of gene
transcription of snail, a repressor of E-cadherin gene expression.
Overexpression of ILK caused a stimulation of expression of snail, but
snail expression was found not to be regulated by beta-catenin/Tcf.
These data demonstrate that ILK can regulate beta-catenin/TCF and snail
transcription factors by distinct pathways. We propose that inhibition
of ILK may be a useful strategy in the control of progression of colon
as well as other carcinomas. Oncogene (2001) 20, 133 - 140.
15
UI - 11381248
AU - Eng C
TI -
To be or not to BMP.
SO - Nat Genet 2001 Jun;28(2):105-7
16
UI - 11381269
AU - Howe JR; Bair JL; Sayed MG; Anderson ME; Mitros FA; Petersen GM;
TI -
Velculescu VE; Traverso G; Vogelstein B
Germline mutations of the gene encoding bone morphogenetic protein
receptor 1A in juvenile polyposis.
SO - Nat Genet 2001 Jun;28(2):184-7
AD - Department of Surgery, University of Iowa College of Medicine, Iowa
City, Iowa, USA. james-howe@uiowa.edu
Juvenile polyposis (JP; OMIM 174900) is an autosomal dominant
gastrointestinal hamartomatous polyposis syndrome in which patients are
at risk for developing gastrointestinal cancers. Previous studies have
demonstrated a locus for JP mapping to 18q21.1 (ref. 3) and germline
mutations in the homolog of the gene for mothers against
decapentaplegic, Drosophila, (MADH4, also known as SMAD4) in several JP
families. However, mutations in MADH4 are only present in a subset of JP
cases, and although mutations in the gene for phosphatase and tensin
homolog (PTEN) have been described in a few families, undefined genetic
heterogeneity remains. Using a genome-wide screen in four JP kindreds
without germline mutations in MADH4 or PTEN, we identified linkage with
markers from chromosome 10q22-23 (maximum lod score of 4.74, straight
theta=0.00). We found no recombinants using markers developed from the
vicinity of the gene for bone morphogenetic protein receptor 1A
(BMPR1A), a serine-threonine kinase type I receptor involved in bone
morphogenetic protein (BMP) signaling. Genomic sequencing of BMPR1A in
each of these JP kindreds disclosed germline nonsense mutations in all
affected kindred members but not in normal control individuals. These
findings indicate involvement of an additional gene in the transforming
growth factor-beta (TGF-beta) superfamily in the genesis of JP, and
document an unanticipated function for BMP in colonic epithelial growth
control.
17
UI - 11355940
AU - Woodford-Richens KL; Halford S; Rowan A; Bevan S; Aaltonen LA; Wasan H;
TI -
Bicknell D; Bodmer WF; Houlston RS; Tomlinson IP
CDX2 mutations do not account for juvenile polyposis or Peutz-Jeghers
syndrome and occur infrequently in sporadic colorectal cancers.
SO - Br J Cancer 2001 May 18;84(10):1314-6
AD - Molecular and Population Genetics Laboratory, Imperial Cancer Research
Fund, London, WC2A 3PX, UK.
Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JPS) are both
characterized by the presence of hamartomatous polyps and increased risk
of malignancy in the gastrointestinal tract. Mutations of the LKB1 and
SMAD4 genes have been shown recently to cause a number of PJS and JPS
cases respectively, but there remains considerable uncharacterized
genetic heterogeneity in these syndromes, particularly JPS. The mouse
homologue of CDX2 has been shown to give rise to a phenotype which
includes hamartomatous-like polyps in the colon and is therefore a good
candidate for JPS and PJS cases which are not accounted for by the SMAD4
and LKB1 genes. By analogy with SMAD4, CDX2 is also a candidate for
somatic mutation in sporadic colorectal cancer. We have screened 37 JPS
families/cases without known SMAD4 mutations, 10 Peutz-Jeghers cases
without known LKB1 mutations and 49 sporadic colorectal cancers for
mutations in CDX2. Although polymorphic variants and rare variants of
unlikely significance were detected, no pathogenic CDX2 mutations were
found in any case of JPS or PJS, or in any of the sporadic cancers.
Copyright 2001 Cancer Research Campaign.
18
UI - 11593435
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.
19
UI - 11896466
AU - Fuerer C; Iggo R
TI -
Adenoviruses with Tcf binding sites in multiple early promoters show
enhanced selectivity for tumour cells with constitutive activation of
the wnt signalling pathway.
SO - Gene Ther 2002 Feb;9(4):270-81
AD - Oncogene Group, Swiss Institute for Experimental Cancer Research
(ISREC), Epalinges, Switzerland.
Mutation of the adenomatous polyposis coli and beta-catenin genes in
colon cancer leads to constitutive activation of transcription from
promoters containing binding sites for Tcf/LEF transcription factors. We
have constructed adenoviruses with Tcf binding sites in the early
promoters, in order to target viral replication to colon tumours. Tcf
regulation of the E1A promoter confers a 100-fold selectivity for cells
with activated wnt signalling in viral burst and cytopathic effect
assays. p300 is a coactivator for beta-catenin, and E1A inhibits
Tcf-dependent transcription through sequestration of p300, but mutation
of the p300 binding site in E1A leads to a 10-fold reduction in
cytopathic effect of all of the Tcf-regulated viruses. When Tcf sites
are inserted in the E1A, E1B, E2 and E4 promoters the viruses show up to
100 000-fold selectivity for cells with activated wnt signalling.
20
UI - 11922570
AU - Batra S; Valdimarsdottir H; McGovern M; Itzkowitz S; Brown K
TI -
Awareness of genetic testing for colorectal cancer predisposition among
specialists in gastroenterology.
SO - Am J Gastroenterol 2002 Mar;97(3):729-33
AD - Department of Human Genetics, Mount Sinai School of Medicine, New York,
New York 10029, USA.
OBJECTIVES: Adult gastroenterologists practicing in New York State were
surveyed to determine their practice with regard to identifying family
histories consistent with inherited forms of colorectal cancer, and to
assess their awareness of cancer genetic counseling and molecular
genetic testing for familial adenomatous polyposis (FAP) and hereditary
nonpolyposis colorectal cancer (HNPCC). METHODS: A closed-ended
questionnaire was mailed to 815 gastroenterologists identified through
the membership Directory of the American Gastroenterological Association
(1998). Two mailings resulted in a response rate of 35%. RESULTS: In
all, 99% of the gastroenterologists obtained a family history from their
patients, and 95% were aware of cancer genetic counseling. However, only
51% would routinely refer patients for genetic counseling before
providing cancer predisposition testing. In addition, only 52% were
aware of the availability of genetic tests for FAP and 34% for HNPCC.
Presented with a family history consistent with HNPCC, 79% could
identify the syndrome, 26% recommended genetic counseling for the
consultand, and 16% advised appropriate screening, according to current
recommendations. CONCLUSIONS: The majority of gastroenterologists do
obtain a family history on their patients. However, there is a need for
physician education regarding the recognition of pedigrees consistent
with inherited colorectal cancer, the genetic counseling process, and
the availability of mutation testing for FAP and HNPCC.
21
UI - 11889072
AU - Hardy RG; Tselepis C; Hoyland J; Wallis Y; Pretlow TP; Talbot I; Sanders
TI -
DS; Matthews G; Morton D; Jankowski JA
Aberrant P-cadherin expression is an early event in hyperplastic and
dysplastic transformation in the colon.
SO - Gut 2002 Apr;50(4):513-9
AD - Department of Surgery, University of Birmingham, Birmingham, UK.
r.g.hardy@bham.ac.uk
BACKGROUND: Colorectal adenomatous and, probably, hyperplastic polyp
development requires epithelial remodelling and stratification, with
loss of E-cadherin expression implicated in adenoma formation. We have
shown that P-cadherin, normally expressed in stratified epithelia and
placenta, is aberrantly expressed in disturbed epithelial architecture
associated with colitis. AIMS: (i) To investigate the role of P-cadherin
in colonic polyp formation. (ii) To ascertain whether expression of
P-cadherin is independent of or correlated with expression of its
associated proteins--E-cadherin, beta-catenin, and gamma-catenin. (iii)
To determine if P-cadherin is functional regarding catenin binding in
polyps. METHODS: Expression and localisation of cadherins (E- and P-)
and their associated catenins (beta- and gamma-) were determined in
aberrant crypt foci (ACF), in polyps with hyperplastic morphology
(hyperplastic polyps and serrated adenomas), and in adenomatous polyps
by immunohistochemistry, western blotting, and mRNA in situ
hybridisation. Assessment of cadherin-catenin binding was evaluated by
co-immunoprecipitation. Adenomatous polyposis coli (APC) mutation was
assessed in adenomatous polyps. RESULTS: P-cadherin was expressed from
ACF through to hyperplastic and adenomatous polyps. Alterations in
E-cadherin and catenin expression occurred later, with variant patterns
in (i) ACF, (ii) hyperplastic polyps and serrated adenomas, and (iii)
adenomatous polyps. P-cadherin present in adenomas was functional with
regard to catenin binding, and its expression was independent of APC
mutational status. CONCLUSIONS: P-cadherin is aberrantly expressed from
the earliest morphologically identifiable stage of colonocyte
transformation, prior to changes in E-cadherin, catenin, and APC
expression/mutation. P-cadherin expression alone does not predict tissue
morphology, and such expression is independent of that of associated
cadherins and catenins.
22
UI - 11957250
AU - Wakhisi J
TI -
Lessons learned from colorectal model of tumourigenesis.
SO - East Afr Med J 2001 Jul;78(7 Suppl):S48-9
AD - Department of Medical Biochemistry, Faculty of Health Sciences, Moi
University, P.O. Box 3900, Eldoret, Kenya.
Genetic analytical techniques were carried out to identify mutations in
adenomatous polyposis coli (APC) gene and K-ras oncogene in colorectal
tumourigenesis. These two genes are said to be early mutation genes
among other mutation genes that constitute the model for colorectal
tumourigenesis. To do this analysis, DNA was isolated from colorectal
formalin fixed paraffin-embedded tumour tissue sections. The sections
were deparaffinised, digested in proteinase-K, followed by DNA
isolation. The DNA was amplified by Polymerase Chain Reaction (PCR),
screened by using Denaturing Gradient Gel Electrophoresis (DGGE) or
Single Strand Conformation Polymorphism (SSCP) and then sequenced. These
results lend support to the fact that colorectal cancer and indeed
cancer in general develops through a multi-step process; also that
accumulation of genetic mutations underlie the development of neoplasia.
We are in the process of extending this study to cancer of oesophagus to
see if a similar or parallel model of carcinogenesis holds and in what
sequence it is.
23
UI - 11896079
AU - Young J; Barker M; Robertson T; Nasioulas S; Tannenberg A; Buttenshaw
TI -
RL; Knight N; Jass JR; Leggett BA
A case of myoepithelial carcinoma displaying biallelic inactivation of
the tumour suppressor gene APC in a patient with familial adenomatous
polyposis.
SO - J Clin Pathol 2002 Mar;55(3):230-1
AD - Conjoint Gastroenterology Laboratory, Clinical Research Centre, Royal
Brisbane Hospital Research Foundation, Bancroft Centre, 300 Herston
Road, Herston Q4029, Australia.
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder
caused by mutation of the APC gene. It is characterised by the
appearance of hundreds to thousands of colorectal adenomas in
adolescence and the subsequent development of colorectal cancer. Various
extracolonic malignancies are associated with FAP, including desmoids
and neoplasms of the stomach, duodenum, pancreas, liver, and brain. We
present a family affected by FAP with an exon 14 APC mutation displaying
two rare extracolonic lesions, a hepatoblastoma and a myoepithelial
carcinoma. The hepatoblastoma was found in a male patient aged 2 years.
The second lesion, a myoepithelial carcinoma of the right cheek, was
found in a female patient aged 14 years. Inactivation of the normal APC
allele was demonstrated in this lesion by loss of heterozygosity
analysis, thus implicating APC in the initiation or progression of this
neoplasm. This is the first reported case of this lesion in a family
affected by FAP.
24
UI - 10359544
AU - Potter JD
TI -
Colorectal cancer: molecules and populations.
SO - J Natl Cancer Inst 1999 Jun 2;91(11):916-32
AD - Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
jpotter@fhcrc.org
The epidemiology and molecular biology of colorectal cancer are reviewed
with a view to understanding their interrelationship. Risk factors for
colorectal neoplasia include a positive family history, meat
consumption, smoking, and alcohol consumption. Important inverse
associations exist with vegetables, nonsteroidal anti-inflammatory drugs
(NSAIDs), hormone replacement therapy, and physical activity. There are
several molecular pathways to colorectal cancer, especially the APC
(adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a
transcriptional activator) pathway and the pathway involving
abnormalities of DNA mismatch repair. These are important, both in
inherited syndromes (familial adenomatous polyposis [FAP] and hereditary
nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic
cancers. Other less well defined pathways exist. Expression of key genes
in any of these pathways may be lost by inherited or acquired mutation
or by hypermethylation. The roles of several of the environmental
exposures in the molecular pathways either are established (e.g.,
inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat
and tobacco smoke as sources of specific blood-borne carcinogens;
vegetables as a source of folate, antioxidants, and inducers of
detoxifying enzymes). The roles of other factors (e.g., physical
activity) remain obscure even when the epidemiology is quite consistent.
There is also evidence that some metabolic pathways, e.g., those
involving folate and heterocyclic amines, may be modified by
polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate
reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least
some evidence that the general host metabolic state can provide a milieu
that enhances or reduces the likelihood of cancer progression.
Understanding the roles of environmental exposures and host
susceptibilities in molecular pathways has implications for screening,
treatment, surveillance, and prevention.
25
UI - 11867715
AU - Sieber OM; Lamlum H; Crabtree MD; Rowan AJ; Barclay E; Lipton L; Hodgson
TI -
S; Thomas HJ; Neale K; Phillips RK; Farrington SM; Dunlop MG; Mueller
HJ; Bisgaard ML; Bulow S; Fidalgo P; Albuquerque C; Scarano MI; Bodmer
W; Tomlinson IP; Heinimann K
Whole-gene APC deletions cause classical familial adenomatous polyposis,
but not attenuated polyposis or "multiple" colorectal adenomas.
SO - Proc Natl Acad Sci U S A 2002 Mar 5;99(5):2954-8
AD - Molecular and Population Genetics Laboratory, Imperial Cancer Research
Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Familial adenomatous polyposis (FAP) is a dominantly inherited
colorectal tumor predisposition that results from germ-line mutations in
the APC gene (chromosome 5q21). FAP shows substantial phenotypic
variability: classical polyposis patients develop more than 100
colorectal adenomas, whereas those with attenuated polyposis (AAPC) have
fewer than 100 adenomas. A further group of individuals, so-called
"multiple" adenoma patients, have a phenotype like AAPC, with 3-99
polyps throughout the colorectum, but mostly have no demonstrable
germ-line APC mutation. Routine mutation detection techniques fail to
detect a pathogenic APC germ-line mutation in approximately 30% of
patients with classical polyposis and 90% of those with AAPC/multiple
adenomas. We have developed a real-time quantitative multiplex PCR assay
to detect APC exon 14 deletions. When this technique was applied to a
set of 60 classical polyposis and 143 AAPC/multiple adenoma patients
with no apparent APC germ-line mutation, deletions were found
exclusively in individuals with classical polyposis (7 of 60, 12%).
Fine-mapping of the region suggested that the majority (6 of 7) of these
deletions encompassed the entire APC locus, confirming that
haploinsufficiency can result in a classical polyposis phenotype.
Screening for germ-line deletions in APC mutation-negative individuals
with classical polyposis seems warranted.
26
UI - 10614178
AU - Taketo MM
TI -
[Intestinal polyposis in APC knockout mice: mechanism of tumorigenesis
and chemotherapy]
SO - Seikagaku 1999 Nov;71(11):1299-308
AD - Laboratory of Biomedical Genetics, Graduate School Pharmaceutical
Science, University of Tokyo.
27
UI - 11953860
AU - Chiang JM; Chou YH; Chen TC; Ng KF; Lin JL
TI -
Nuclear beta-catenin expression is closely related to ulcerative growth
of colorectal carcinoma.
SO - Br J Cancer 2002 Apr 8;86(7):1124-9
AD - Division of Colon and Rectal Surgery, Human Molecular Genetics
Laboratory, Chang Gung Memorial Hospital, 199 Tung Hwa North Road,
Taipei, Taiwan 333. jmjiang@ms34.hinet.net
Although most colorectal cancer develops based on the
adenoma-adenocarcinoma sequence, morphologically, colorectal cancer is
not a homogeneous disease entity. Generally, there are two distinct
morphological types: polypoid and ulcerative colorectal tumours.
Previous studies have demonstrated that K-ras codon 12 mutations are
preferentially associated with polypoid growth of colorectal cancer;
however, little is known about the molecular mechanism that determines
ulcerative growth of colorectal cancer. beta-catenin complex plays a
critical role both in tumorigenesis and morphogenesis. We examined the
differential expression of beta-catenin and its related factors among
different types of colorectal cancer in order to determine any
relationship with gross tumour morphology. Immunohistochemical staining
of beta-catenin, E-cadherin and MMP-7 was performed on 51 tumours,
including 26 polypoid tumours and 25 ulcerative tumours. Protein
truncation tests and single-strand conformational polymorphism for
mutation of the adenomatous polyposis coli tumour suppressor gene, as
well as single-strand conformational polymorphism for the mutation of
beta-catenin exon 3 were also done. Nuclear expression of beta-catenin
was observed in 18 out of 25 (72%) cases of ulcerative colorectal cancer
and seven out of 26 (26.9%) cases of polypoid colorectal cancer. A
significant relationship of nuclear beta-catenin expression with
ulcerative colorectal cancer was found (P<0.001). However, this finding
was independent of adenomatous polyposis coli tumour suppressor gene
mutation and E-cadherin expression. Together with previous data, we
propose that different combinations of genetic alterations may underlie
different morphological types of colorectal cancer. These findings
should be taken into consideration whenever developing a new genetic
diagnosis or therapy for colorectal cancer.
The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.
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