Transcript GI Grand Rounds

Medicine Grand Rounds
March 9, 2005
Yoshi Makino, M.D.
USC Department of Internal Medicine
Andrew Stolz, M.D.
Faculty Moderator
Case Presentation
Patient F.B. is a 64 year old AfricanAmerican male, referred from an outside
M.D. for OB(+) stool and anemia. Patient
was scheduled for colonoscopy based on
the above indications.
PSH: none
PMH:
– HTN
– hyperlipidemia
Case Presentation
SH:
– EtOH: 1-2 beers/day,
6-pack on weekends x 40 years
– Tobacco: ¾ ppd x 40 years
– Drugs: Marijuana in youth; without h/o IVDA
ROS:
– Denies h/o BRBPR, melena, stool caliber
changes, nor weight loss. Without h/o GERD
or other upper GI complaints.
Case Presentation
Allergies: NKDA
Medications
–
–
–
–
–
–
–
–
Pravachol 40 mg PO daily
HCTZ 25 mg PO daily
Atenolol/Chlorthalidone 50 mg / 25 mg PO daily
Quinapril 40 mg PO daily
Norvasc 10 mg PO daily
Cardura 2 mg PO daily
EC ASA 81 mg PO daily
Darvocet or Tylenol 500 mg prn pain/HA
Laboratories
5.3
MCV
RDW
Ferr
13.0
39.1
81.6
17.6
191
TIBC
Fe
%Sat
278
Alk P
TProt
Alb
TBili
55
DBili
140
103
14
3.8
20
0.8
129
7.9
4.3
0.5
0.1
AST
ALT
78
29
18
Colonoscopy
Poor prep
Anus: small IH
Sigmoid: 2 cm flat polyp, s/p bx
Transverse colon: one diminutive polyp
and a 1.5 cm sessile polyp, s/p bx
Ascending colon: multiple 2-9mm sessile
polyp, s/p bx
Biopsy Results
8 of 11 polyps biopsied showed tubular
adenoma
Of these 8 polyps, 2 also showed areas of
focal increased glandular complexity and
high grade dysplasia
Colonoscopy Images
Colonoscopy Images
Family History
Colon CA; Age 70’s
Colon CA; Age 68
“Bone” CA; Age 64
Colon CA; dx age 46;
Presently 66
Multiple adenomatous polyps
@ age 42, now 46
Familial Colorectal Cancers
Objectives
Overview
Types of familial colorectal cancers
– Clinical Features
– Diagnostic Criteria
– Genetics
Genetic Testing
Surveillance
Management/Treatment
Colon Cancer Overview
Annual Statistics
– 150,000 new cases diagnosed
– 56,000 deaths
Second leading cause of cancer deaths
Lifetime incidence rate of 5%
Most cases occurring after age 50
Lifetime Risk of CRC
General Population
Prior History of CRC
Family History
Colorectal Adenomas
HNPCC
Ulcerative colitis
FAP
3.5 - 6%
15%
15%
15-25%
80%
50-90%
100%
Pucciarelli. 21st ICLAM Congress. Venice, April 2004.
Familial Colorectal Cancers
Familial clustering
studies suggest
20%-30% of colon
cancers may have a
genetic cause
Johns LE et al. Am J Gasteoenterol
2001;96:2992-3003.
The causative genes
have been identified in
only <5% of cases
UC
HNPCC
FAP
AFAP
Cao et al. AJG 2002;97(7)1822-1827
Familial Adenomatous Polyposis
Familial Adenomatous Polyposis (FAP) was first
described by Lockhart-Mummery in 1925 as a
disease with clear dominant inheritance
Adenomatous Polyposis Coli (APC: 5q21) gene
identified by Kinzer and Groden in 1991
Courtesy of Florida State University and Pucciarelli 2004
Clinical Features of FAP
Greater than 100 colonic adenomatous polyps,
frequently exceeding 1000 polyps
Polyps can develop throughout the colon and
rectum
90% of patient will have duodenal and
periampullary polyps
100% lifetime risk for colorectal carcinoma
Polyps appear at a mean age of 16 years, and
colon cancer develops at a mean of 39 years,
and invariably by 50 years
Extracolonic Manifestations
High association with gastric fundic polyps
Extracolonic cancers include:
–
–
–
–
duodenal and periampullary tumors (5-10%)
pancreatic (2%)
thyroid (2%)
Gastric (0.5%)
Osteomas, desmoid tumors and soft tissue
tumors of the skin
Congenital hypertrophy of the retinal pigment
epithelium (CHRPE)
Hernegger et al. Dis Colon Rectum. 2002 Jan;45(1):127-136.
Gastric Fundic Gland Polyps
Fundic gland polyps account for 50% of all
gastric polyps and are observed in 0.8-1.9% of
all patients undergoing EGD
Studies estimate 52-88% of FAP patients have
gastric fundic glands polyps
Lifetime risk of gastric cancer is estimated to be
0.6%
Burt. Gastro 2003;125:1462-1469.
Gastric Fundic Gland Polyps
FAP
AFAP
Burt. Gastro 2003;125:1462-1469.
CHRPE
Edward S. Harkness Eye Institute, Columbia University
Clinical Criteria for FAP
Clinical diagnosis of FAP can be made if…
– Presence of >100 colon adenomas
– Multiple adenomas, with both of the following
criteria
a first-degree relative is diagnosed with FAP
the patient is on the affected side of the family
Groden et al. Cell 1991;66:589–600
However, genetic testing is now standard
of care for those meeting the above
criteria
Giardiello FM. JAMA 1997;278:1278–1281
Attenuated FAP
In 1990, Lynch et al described two families
with “right-sided colonic flat adenomas”
with more polyps than HNPCC but fewer
than FAP
Lynch also observed later age of onset of
colon cancer, and a paucity of rectal
adenomas
Lynch et al. Cancer. 1990 Sep 1;66(5):909-15.
Initially called “hereditary flat adenoma
syndrome”, later called attenuated FAP
Clinical Features of AFAP
Less than 100 adenomas, typically
morphologically flat
Polyps primarily located proximal to the splenic
flexure, sparing the rectum
Diagnosed at mean age of 44 years, and
cancers at a mean of 56 years
Extracolonic malignancies similar to FAP, but
CHRPE, desmoid tumors and, osteomas are not
seen
Hernegger et al. Dis Colon Rectum. 2002 Jan;45(1):127-136.
Clinical Criteria for AFAP
Leppert et al suggest a set of diagnostic criteria
for the disease
– A positive family history of colorectal cancer with…
at least one of the following criteria
CRC at any age
> 5 colorectal adenomas
2-4 adenomas and multiple gastric fundic polyps
Leppert et al. N Engl J Med 1990; 322:9.
Later studies suggest a fourth criteria
– Number of colorectal adenomas must be < 100
Knudsen et al. Familial Cancer. 2003;2:43-55.
The Genetics of FAP and AFAP
Primary defect is in the adenomatous polyposis
coli (APC) gene, located on 5q21
APC gene is a classic tumor suppressor gene,
primarily down-regulating intercellular β-catenin
activity and ultimately slowing cell cycle entry
and progression
“Dominant negative model” suggests that the
mutated gene product forms dimers with the
wild-type protein, causing lowered or abolished
tumor suppressor activity
30% of FAP/AFAP cases are due to de novo
mutations of the APC gene
Burt. Gastro. 2000;119:837-853
APC, β-catenin and E-cadherin
Fearnhead et al. Hum Mol Gen. 2001;10(7):721-733.
APC Gene Mutations
Fearnhead et al. Hum Mol Gen. 2001;10(7):721-733.
APC Mutation Phenotypes
Colored = distinct protein domains / Boxed = areas of mutation
Fearnhead et al. Hum Mol Gen. 2001;10(7):721-733.
Extreme Phenotypic Variability
Burt et al. Gastro. 2004;127:444-451.
HNPCC / Lynch Syndrome
Hereditary Nonpolyposis Colorectal
Cancer was first described in 1913 by
Warthin, and formally characterized as an
autosomal dominant condition by Lynch et
al. in 1966
Lynch et al. Arch Intern Med 1966;117:206–212.
Mismatch Repair (MMR) gene defects
identified by 3 independent groups in 1993
Ionov et al. Nature 1993. / Thibodeau et al. Science 1993.
Peltomaki et al. Science 1993
Clinical Features of HNPCC
Sporadic colonic polyps (<10 polyps)
Despite the name “non-polyposis,”
accelerated transformation of
flat polyps  carcinoma is suspected
70-80% lifetime risk for colorectal
carcinoma, at a mean age of 44 years
Extracolonic Manifestations
Numerous extracolonic cancers including
–
–
–
–
–
–
–
Endometrium (43%)
Stomach (19%)
Biliary tract (18%)
Urinary tract (10%)
Ovary (9%)
Brain (1%)
Small bowel (rare)
Specific MMR mutations are associated with varying
rates of the above cancers
– MSH2 mutations have higher incidences of cancer than MLH1
mutations
– MSH6 mutations have highest rate of endometrial cancers
Grady. Gastro. 2003;124:1574–1594
Clinical Criteria for HNPCC
Amsterdam criteria (All criteria must be met)
– One member diagnosed with colorectal cancer before
age 50 years
– Two affected generations
– Three affected relatives, one of them a first-degree
relative of the other two
– FAP should be excluded
– Tumors should be verified by pathologic examination
Amsterdam II and Bethesda criteria are more
lenient, however there is no consensus on which
criteria should be used for genetic testing
Grady. Gastro. 2003;124:1574–1594
The Genetics of HNPCC
A defect in one of several MMR genes has been
associated with HNPCC
– MLH1 (59%)
– MSH2 (38%)
– MSH6 (1.3%), PMS2 (0.8%), PMS1 (0.4%), TGFBR2,
EXO1, MLH3
MMR genes are vital in the repair of
microsatellites (short, repeated DNA sequences)
Microsatellite instabilities (MSI) are expansion or
contraction of these repeated sequences
MSI and MMR
Yangming et al. AJG. 2002;97(7):1822-1827.
Summary of Familial CRCs
FAP
AFAP
HNPCC
Inheritance
Dominant
Dominant
Dominant
Incidence
1:10,000
1:100,000
1:2,000
Gene Defect
APC
APC / MYH ?
MMR genes
Colonic Polyps
Always > 100,
often >1000
10 - 100, usually
proximal
Few, sporadic
Lifetime CRC Risk
Near 100%
70-80%
> 80%
Average age of CRC
39
49
44
Adapted from Grady. Gastro. 2003;124:1574–1594
Overview of Genetic Testing
Should be offered to patients…
– With strong family history
– Where test results can be adequately interpreted
– If results would influence screening and management
ASCO Statement. J Clin Onc 1996;14:1730-1736.
Patients should at least meet the clinical criteria
for the disease in question
A genetic counselor should be involved to
provide both pretest and post-test counseling
Who to Test for FAP
Clinical criteria for FAP met
– >100 colon adenomas, or
– Multiple adenomas in first degree relative of a known
FAP case, on the affected side of family
First-degree relatives of a person with a known
APC mutation, regardless of polyp status
A person with multiple adenomas who is a
relative of a person with a known APC mutation
Grady. Gastro. 2003;124:1574–1594.
Who to Test for AFAP
Clinical criteria for AFAP met
– Greater than 5 to 10 and less than 100 colorectal
adenomas
– 2-4 adenomas and multiple gastric fundic polyps
First-degree relatives of a person with a known
APC mutation, regardless of polyp status
A person with multiple adenomas who is a
relative of a person with a known APC mutation
Grady. Gastro. 2003;124:1574–1594.
Genetic Testing in AFAP/FAP
Testing involves direct DNA sequencing of APC gene
– 95% mutation detection rate
– Most expensive (~$800/test)
Other tests are less expensive but also less sensitive
– Confirmation strand electrophoresis with protein
truncation (80-90%)
– Protein truncation alone (80%)
– Linkage analysis
Detection rate dependent on accuracy of family tree
Cannot be performed if only one member is affected (25% of FAP
cases are de novo)
Grady. Gastro. 2003;124:1574–1594.
Who to Test for HNPCC
Amsterdam criteria met
– Greater than 5 to 10 and less than 100 colorectal adenomas
– 2-4 adenomas and multiple gastric fundic polyps
First-degree relatives of a person with a known
MMR mutation
Complex algorithm using Bethesda criteria and
other predictors (e.g. CRC case at <35 years of
age) has also been proposed
Grady. Gastro. 2003;124:1574–1594.
Genetic Testing in HNPCC
Direct DNA sequencing of MSH2, MLH1,
+/- MSH6 is highest yielding approach
– >95% of HNPCC cases MSH2 and MLH1
– Extremely expensive ($800-$3000)
MSI Testing
95% of HNPCC tumors have MSI
13% of all CRC have MSI
1%-6% of CRC are associated with HNPCC
MSI testing can be conducted for
$300-$500
Serves as a useful screening test prior to full
MSH2, MLH1 testing
Pucciarelli. 21st ICLAM Congress. Venice, April 2004.
Summary of Costs
FAP/AFAP
– APC Full Sequence: $800
– Single site mutation analysis: $200
HNPCC
– MLH/MSH2 Full Sequence: $800-$3000
– MSI Testing: $300-500
Pricing from American Gastroenterology Association 2001.
Surveillance for FAP
Surveillance may initially be by sigmoidoscopy
– Annually, starting at age 10-12
Annual colonoscopy from mid-teens until age 30
– Every 3-5 years past age 30
EGD starting at 30 years, every 1-3 years,
depending on polyp status in duodenum
Consider AFP and liver imaging from infancy to
age 5
Grady. Gastro. 2003;124:1574–1594.
Surveillance for AFAP
Surveillance must be by colonoscopy
– Due to lesions proximal to splenic flexure
– Contrasts with screening by flexible
sigmoidoscopy in classic FAP
Colonoscopy starting at 10–17 years,
annually
EGD starting at 30 years, every 1–3 years,
depending on polyp status in duodenum
Grady. Gastro. 2003;124:1574–1594.
Surveillance for HNPCC
Surveillance must be by colonoscopy, as lesions
are usually located in ascending colon
Colonoscopy starting at age 25
– May be conducted every 2-3 years
Annual colonoscopy after age 40
until age 75 **
EGD starting at 30 to 50 years, every 2 years,
until age 75
All above studies should be conducted 5 years
earlier than youngest affected person in family
Grady. Gastro. 2003;124:1574–1594.
Distinguishing Flat Polyps
Eisen et al. Gastrointest Endosc 2002;55:687-94.
High-resolution Chromoendoscopy
Hyperplastic Polyp
Adenomatous Polyp
“Pit” pattern
“Grooves”
Eisen et al. Gastrointest Endosc 2002;55:687-94.
High-resolution Chromoendoscopy
Conventional dyes (e.g. 0.9% indigo carmine) or
florescent dyes used in conjunction with a highresolution endoscope (410k – 850k pixels
vs standard scopes 100k – 200k pixels)
Hyperplastic polyps
– a characteristic “pit” pattern of orderly arranged circular “dots,”
morphologically similar to surrounding normal mucosa.
Adenomatous Polyps
– surface “grooves” occasionally with a sulcus-like appearance
In a recent multicenter trial by Eisen et al.,
chromoendoscopy had a sensitivity of 82% and
specificity of 82% in distinguishing the above polyps
Eisen et al. Gastrointest Endosc 2002;55:687-94.
2D Axial Image Acquisition
http://itswww.epfl.ch/~cuisenai/endoscopy.shtml
3D Virtual Reconstruction
http://itswww.epfl.ch/~cuisenai/endoscopy.shtml
FAP in Virtual Colonoscopy
Clinical Application of 3D Virtual Colonoscopy
myweb.hinet.net/ home7/r2207759/
Management of FAP/AFAP
100% lifetime risk of CRC in FAP
Exact risk of CRC in AFAP remains unknown (general
consensus is roughly 60-80%)
Disease progression from adenoma to carcinoma is not
accelerated
Colonoscopy
– In AFAP, there is a sufficiently low number of colonic
polyps to make polypectomy practical
Burt et all. Gastro. 2004;127:444-451.
EGD
– Best treatment of gastric fundic gland polyps is
presently unknown
Burt. Gastro 2003;125:1462-1469.
When to Perform Colectomy?
In FAP patients, The American Society of Colon
and Rectal Surgeons recommends colectomy
between ages 15 to 18
Church and Simmang. Dis Colon Rectum, August 2003.
No clear consensus exists for AFAP
– 15 year delay in onset of disease would
suggest colectomy at age 30
– In a series of 120 patient with AFAP by Burt et
al., first CRC was at a mean age of 58 years
(range of ages 29 to 81), with 12 patients over
the age of 60 with intact colons
Burt et all. Gastro. 2004;127:444-451.
Type of Surgery
Three main surgical options
– Colectomy and ileorectal anastomosis (IRA),
– Proctocolectomy with ileostomy (TPC)
– Proctocolectomy with ileal pouch-anal anastomosis
(IPAA)
As AFAP almost always spares the rectum,
present consensus is for IRA, with subsequent
surveillance by flexible sigmoidoscopy annually
Bülow et al. Gastro. 2000;119:1454–1460.
Church and Simmang. Dis Colon Rectum, August 2003.
Pharmacologic Therapy
Treatment with sulindac and celecoxib may also
reduce polyp burden
Giardiello et al. N Engl J Med 1993;328:1313-1316.
Steinbach et al. N Engl J Med 2000;342:1946–52.
In 1999, FDA approves celecoxib as a treatment
for patients with FAP
– Dosage: celecoxib 400 mg PO BID
– “To reduce the number of adenomatous colorectal
polyps in familial adenomatous polyposis (FAP), as
an adjunct to usual care (e.g., endoscopic
surveillance, surgery).”
FDA Application NDA 21-156 & 20-998/S007
Celecoxib and FAP
Steinbach et al. N Engl J Med 2000;342:1946–52.
Management of HNPCC
Life time risk of colon cancer is >80%
Disease progression from adenoma to
carcinoma is accelerated
Burt. Gastro 2003;125:1462-1469.
Given high prevalence of extracolonic
malignancies, consider
– Pap smears, transvaginal ultrasound,
endometrial aspiration biopsy every 1-2 years
– Urinalysis, urine cytology, and if abnormal,
ultrasound +/- cystoscopy every 1-2 years
Surgical Management of HNPCC
If colorectal cancer found, subtotal
colectomy with ileorectal anastamosis is
recommended, as metachronous lesions
are common
Prophylactic colectomy is recommended,
but no consensus exists on timing
Procotocolectomy should be considered in
MSH2 mutation, given higher rates of
rectal involvement
Kouraklis et al. Dig Dis Sci. 2005 Feb;50(2):336-44.
CRC Survival Rates in HNPCC
5 year survival rates for patients with
HNPCC CRC is significantly better than for
sporadic cases of CRC
Sankila et al. in 1996 followed 175 patients
with genetically proven HNPCC CRC,
compared to 14,086 patients with sporadic
CRC
– 5 year survival rate in HNPCC: 65% versus
sporadic: 44%
Sankila et al. Gastro. 110:682-687, 1997.
Conclusions
Genetic and familiar factors may account for up
to 30% of colorectal cancers
While specific genetic defects are rarely
identified (5% of cases), given the high
malignant potential (80-100% lifetime risk of
CRC), early recognition is vital
Many polyps  think FAP
Few polyps  think HNPCC (more common),
but do not discount AFAP
Involve a genetic counselor early, and use
genetic testing judiciously
Patient Follow-up
Patient had an EGD on 9/20/2004 to evaluate for
gastric fundic gland polyps and periampullary
disease
– No significant lesions found
Patient underwent genetic counseling at Norris
Comprehensive Cancer Center on 9/24/2004
Ultimately, the proband (the sister) underwent
genetic testing via the Kaiser Permanente
system
MLH1 mutation found
Acknowledgements
Dr. Andrew Stolz
Rebecca Zemetra
Roche Pharmaceuticals
This presentation is available at:
http://www.makino.net/gastro
Questions?
Oh no! Is that
a short call?
I have two
questions.
Hmm.. it’s almost
8 o’clock
Genetic Testing and
Counseling
Dr. Andrew Stolz
Associate Professor of Medicine
USC Department of Internal Medicine
Division of Gastrointestinal and Liver Diseases
Risk - Benefits for Genetic Testing
+
Non-invasive test
 Preventive treatment
 Highly predictive

Fails to identify all cases
 Social implication
 Psychological
implications

Genetic Testing Strategy for BRC1/2
Pre-Test counseling session
Pt declines BRCA 1/2
+
Reinforce medical management
Counsel as needed.
Post genetic testing session
- Discuss option for medical management
- Coping strategy for family members
Nature Cancer Rev 4:153, 2004
Potential Outcomes of Genetic Testing
Interpretation of
result in at-risk
family member
Result in index
case
Result in at-risk
family member
Significant mutation
found
Same mutation found Positive
Significant mutation
found
No mutation found
Negative
No mutation found
Do not test
Not informative
Variant of unknown
significance found
Do not test
Not informative
Screening Recommendation for
APC Patients
Annual screening for hepatoblastoma up to age 5
Sigmoidoscopy every one to two years after age 10
Colonoscopy once polyps are detected.
Annual colonoscopy if colectomy is delayed more than a
year after polyps emerge.
Esophagogastroduodenoscopy (EGD) beginning when
colonic polyposis is detected or by age 25.
Small bowel X-ray (small bowel enteroclysis or
abdominal and pelvic CT with orally administered
contrast) when duodenal adenomas are detected or prior
to colectomy,
Attention to extraintestinal manifestations, usually for
cosmetic concerns.
Annual physical examination including palpation of the
thyroid.
Screening Recommendation for
HNPCC Patients
Colon cancer. Colonoscopy every one to two years
beginning between age 20-25 years or ten years
before the earliest age of diagnosis in the family.
Gynecological cancer. Endometrial cancer and
ovarian cancer surveillance is less well established
than that for colon cancer. In addition to an annual Pap
smear and pelvic examination, annual transvaginal
ultrasound examination, endometrial biopsy, and CA125 blood test beginning between 25-30 years of age
can be considered.
Stomach and duodenum. Upper endoscopy
surveillance is available to for gastric and duodenal
cancers. However, one study suggested no benefit
from this because of the lack of identifiable precursor
lesions.
References
Al Tassan et al. Inherited variants of MYH associated with somatic G:C->T:A mutations in colorectal tumors. Nat Genet. 2002 Feb;30(2):227-32.
Bülow et al. Ileorectal anastomosis is appropriate for a subset of patients
with familial adenomatous polyposis. Gastroenterology. 2000
Dec;119(6):1454-60.
Burt et al. Genetic testing and phenotype in a large kindred with attenuated
familial adenomatous polyposis. Gastroenterology. 2004 Aug;127(2):444-51.
Burt. Gastric fundic gland polyps. Gastroenterology. 2003 Nov;125(5):14629.
Cao et al. Challenge in the differentiation between attenuated familial
adenomatous polyposis and hereditary nonpolyposis colorectal cancer:
case report with review of the literature. Am J Gastroenterol. 2002
Jul;97(7):1822-7.
Church and Simmang. Practice parameters for the treatment of patients
with dominantly inherited colorectal cancer (familial adenomatous polyposis
and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum. 2003
Aug;46(8):1001-12.
References
Eisen et al. High-resolution chromoendoscopy for classifying colonic polyps:
a multicenter study. Gastrointest Endosc. 2002 May;55(6):687-94.
Fearnhead et al. The ABC of APC. Hum Mol Genet. 2001 Apr;10(7):721-33.
Giardiello et al. Primary chemoprevention of familial adenomatous polyposis
with sulindac. N Engl J Med. 2002 Apr 4;346(14):1054-9.
Giardiello et al. Treatment of colonic and rectal adenomas with sulindac in
familial adenomatous polyposis. N Engl J Med. 1993 May 6;328(18):1313-6.
Grady. Genetic testing for high-risk colon cancer patients. Gastroenterology.
2003 May;124(6):1574-94.
Hawk et al. Colorectal cancer chemoprevention--an overview of the science.
Gastroenterology. 2004 May;126(5):1423-47.
Hernegger et al. Attenuated familial adenomatous polyposis: an evolving
and poorly understood entity. Dis Colon Rectum. 2002 Jan;45(1):127-34;
discussion 134-6.
Jones et al. Biallelic germline mutations in MYH predispose to
multiple colorectal adenoma and somatic G:C-->T:A mutations. Hum
Mol Genet. 2002 Nov 1;11(23):2961-7.
References
Knudsen et al. Attenuated familial adenomatous polyposis (AFAP). A review
of the literature. Fam Cancer. 2003;2(1):43-55.
Kouraklis G, Misiakos EP. Hereditary nonpolyposis colorectal cancer (Lynch
syndrome): criteria for identification and management.
Dig Dis Sci. 2005 Feb;50(2):336-44.
Leppert et al. Genetic analysis of an inherited predisposition to colon cancer
in a family with a variable number of adenomatous polyps. N Engl J Med.
1990 Mar 29;322(13):904-8.
Lynch et al. Phenotypic variation in colorectal adenoma/cancer expression
in two families. Hereditary flat adenoma syndrome. Cancer. 1990 Sep
1;66(5):909-15.
Spirio et al. Alleles of the APC gene: an attenuated form of familial
polyposis. Cell. 1993 Dec 3;75(5):951-7.
Steinbach et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in
familial adenomatous polyposis. N Engl J Med. 2000 Jun 29;342(26):194652.
Wang et al. MYH mutations in patients with attenuated and classic polyposis
and with young-onset colorectal cancer without polyps. Gastroenterology.
2004 Jul;127(1):9-16.
Acknowledgements
Dr. Andrew Stolz
Rebecca Zemetra
Roche Pharmaceuticals
This presentation is available at:
http://www.makino.net/gastro