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Familial Colorectal Cancers
Francis M. Giardiello, M.D.
The Johns Hopkins University
COLORECTAL CANCER
Sporadic
Familial
Familial Syndromes
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Hereditary nonpolyposis colorectal cancer
Familial adenomatous polyposis
Attenuated FAP
I 1307K mutation of the APC gene
Hereditary Nonpolyposis
Colorectal Cancer
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Autosomal dominant disease
Due to mismatch repair gene mutation
Proximal location of colorectal cancer
Early age of onset
Multiple primary malignancies
Other family cancer
Hereditary Nonpolyposis
Colorectal Cancer
• Warthin-Lynch syndrome
• Lynch I syndrome
– hereditary site specific colorectal cancer
• Lynch II syndrome
– cancer family syndrome
Amsterdam Criteria
3 or more with CRC
65
2 generations
70
1 diagnosed age < 50 yrs
49
SITE OF COLORECTAL CANCER
HNPCC
right sided
Sporadic
left sided
Age of Diagnosis of Colorectal
Cancer in HNPCC
45
40
35
No.
30
25
age
20
15
10
5
0
<20
20-29 30-39 40-49 50-59 60-69 70-79 80-89
Age in Years
Cancer Risks in HNPCC
100
80
%
with
cancer
Colorectal 78%
60
Endometrial 43%
40
Stomach 19%
Biliary tract 18%
Urinary tract 10%
Ovarian 9%
20
0
0
20
40
Aarnio M et al. Int J Cancer 64:430, 1995
60
80
Age (years)
Screening
• At-risk family members
– colonoscopy 1-2 yr. starting age 20 to 25, and
annually after age 40
– gyn exams in women annually with aspiration
of endometrium and/or transvaginal ultrasound
– screen for gastric or urologic cancer
Screening: Genetic Testing
• Mutation of the mismatch repair genes
• hMSH2, hMLH1, hPMS1, hPMS2, hMSH6
HNPCC Results From Failure of
Mismatch Repair (MMR) Genes
Base pair
mismatch
Normal
DNA repair
TCGAC
AGCTG
T CT A C
AGCTG
Defective DNA
repair (MMR+)
T CT A C
TCTAC
AGCTG
AGATG
HNPCC GENETIC TESTING
Germline
Somatic
MSH2
MLH1
MSH6
Microsatellite Instability/
Immunohistochemistry
Blood
Cancer
Mismatch Repair Failure Leads
to Microsatellite Instability (MSI)
Normal
Microsatellite
instability
Addition of
nucleotide repeats
Immunohistochemistry
• Stain tumor for gene proteins
• Pursue absent proteins
Bethesda Criteria
• Adenoma < 40 or CRC < 45 yo
– right-sided undifferentiated, cribiform; signet cell
• Endometrial Cancer < 45 yo
• 2 HNPCC cancers including met/syn CRC
• CRC and FDR with CRC or HNPCC extra
colonic cancer (< 45 , adenoma <40)
• ICG criteria
Familial Adenomatous
Polyposis
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Autosomal dominant disease
Mutation of APC gene
Hundreds of adenomas in colorectum
Presence/absence extracolonic lesions
Colorectal cancer inevitable
Cause of FAP
• Mutation of APC gene (Adenomatous
Polyposis Coli)
• Located chromosome 5q 21
• Discovered 1991
Clinical Course
Puberty - polyps appear
15 y.o. - average age onset of polyps
33 y.o. - symptoms appear
36 y.o. - average age of diagnosis
39 y.o. - average age of colorectal cancer dx
42 y.o. - death from colorectal cancer
Treatment
• Proctocolectomy with ileostomy
• Proctocolectomy with ileoanal pull through
• Colectomy with ileorectal anastomosis
Cause of FAP
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APC gene mutation
Located chromosome 5q21
Tumor suppressor gene
300 different mutations identified
APC protein - cell adhesion, signal
transduction, and transcription activation
APC GENE
CLASSIC FAP
5’
codons 0 158
1596
RNA
PROTEIN
3’
2843
APC GENE
CLASSIC FAP
5’
codons 0 158
1596
RNA
PROTEIN
3’
2843
Attenuated FAP
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5’ and 3’ APC gene mutations
6% of FAP pedigrees
Oligopolyposis (<100 adenomas), R-sided
Heterogeneous phenotype
Later development of CRC (51 vs 39 y.o.)
Screening
• At-risk persons (1st degree relatives)
• Sigmoidoscopy q yr. starting age 12, then q
2 yrs after age 25, then q 3 yrs after age 35,
then average risk guidelines after age 50
Screening: APC Gene Testing
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Gene test for mutation of APC gene by PTT
Start at-risk persons age 10-12
Pretest genetic counseling/informed consent
Test affected pedigree member first
APC Gene Testing - At Risk
APC mutation
APC Gene Test Result
• Positive - FAP- sigmoidoscopy yearly
• Negative - No FAP- sigmoidoscopy age 25
Multiple Adenomas
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Mutation of MYH gene
Base excision gene
Phenotype: multiple adenomas or polyposis
Autosomal recessive
Familial Colorectal Cancer
• I1307K APC gene mutation
– Mutation in codon 1307 of the APC gene
– T to A mutation
APC
I1307K Mutation
*
5’
AGAAA[TAA]AA
3’
isoleucine
*
AGAAA[AAA]A
mutations
* * *
*
lysine
predisposing CRC
APC I1307K Mutation
30
25
20
15
Risk CRC
10
5
0
Gen Pop
Jewish
J. CRC CRC<66 CRC+FH
Lifetime Risk of Colorectal
Cancer
• Ashkenazi Jew
• Gene Pos
• Gene Pos + FH
10-15%
20-30%
> 50%
I1307K Genetic Testing
Allele-Specific Oligonucleotide Analysis
Normal
Mutant
X
Screening
• Consideration of genetic counseling and
genetic testing in Ashkenazi Jewish person
with family history of colorectal cancer
• Colonoscopy q 2 yrs starting age 35 in gene
positive patients
Summary
Summary
• Hereditary Nonpolyposis Colorectal Cancer
– colonoscopic screening
– MSI testing, MMR gene testing
Summary
• Hereditary Nonpolyposis Colorectal Cancer
– colonoscopic screening
– MSI testing, MMR gene testing
• Familial adenomatous polyposis
– APC gene testing/ MYH gene testing
– sigmoid/colonoscopy screening
Summary
• Hereditary Nonpolyposis Colorectal Cancer
– colonoscopic screening
– MSI testing, MMR gene testing
• Familial adenomatous polyposis
– APC gene testing/ MYH gene testing
– sigmoid/colonoscopy screening
• Familial Colorectal Cancer
– family history/ I1307K