Transcript Inherited Susceptibility to Cancer

Lecture 22
Cancer Genetics II:
Inherited Susceptibility to Cancer
Stephen B. Gruber, MD, PhD
November 19, 2002
Cancer Genetics: II
Summary
•
•
•
•
Inherited susceptibility to cancer due to germline mutations
Causes of inherited susceptibility to colorectal cancer
Familial Adenomatous Polyposis
Hereditary Non-Polyposis Colorectal Cancer
Causes of Hereditary
Susceptibility to CRC
Sporadic
(65%–85%)
Familial
(10%–30%)
Rare CRC
syndromes
(<0.1%)
Familial adenomatous
polyposis (FAP) (1%)
Hereditary nonpolyposis
colorectal cancer
(HNPCC) (5%)
Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996
Multi-Step Carcinogenesis
Loss of
APC
Normal
epithelium
Hyperproliferative
epithelium
Activation Loss of
of K-ras
18q
Early
adenoma
Intermediate
adenoma
Loss of
TP53
Late
adenoma
Other
alterations
Carcinoma
Metastasis
Adapted from Fearon ER. Cell 61:759, 1990
ASCO
Risk of Colorectal Cancer (CRC)
6%
General population
Personal history of
colorectal neoplasia
15%–20%
Inflammatory
bowel disease
15%–40%
70%–80%
HNPCC mutation
>95%
FAP
0
20
40
60
Lifetime risk (%)
80
100
Clinical Features of FAP
• Estimated penetrance for
adenomas >90%
• Risk of extracolonic tumors
(upper GI, desmoid,
osteoma, thyroid, brain,
other)
• CHRPE may be present
• Untreated polyposis leads
to 100% risk of cancer
ASCO
Some FAP Manifestations Correlate
With Specific APC Gene Regions
5'
12 3 4 5 6 7 8
3'
9 10 111213 14
15
Attenuated FAP
Classic FAP
CHRPE
Attenuated FAP
• Later onset (CRC ~age 50)
• Fewer colonic adenomas
• Not associated with CHRPE
• UGI lesions
• Associated with mutations at
5' and 3' ends of APC gene
ASCO
Clinical Features of HNPCC
• Early but variable age at
CRC diagnosis (~45 years)
• Tumor site in proximal colon
predominates
• Extracolonic cancers:
endometrium, ovary,
stomach, urinary tract, small
bowel, bile ducts, sebaceous
skin tumors
Amsterdam Criteria

3 or more relatives with verified CRC in family
- One case a first-degree relative of the other two



2 or more generations
1 CRC by age 50
FAP excluded
Failure to meet these criteria
does not exclude HNPCC
Vasen HFA et al. Dis Colon Rect 34:424, 1991
Genetic Features of HNPCC
• Autosomal dominant inheritance
• Penetrance ~80%
• Genes belong to DNA mismatch repair (MMR)
family
• Genetic heterogeneity (MLH1, MSH2, MSH6,
PMS1, PMS2)
Genetic Heterogeneity in HNPCC
MSH6
MSH2
MLH1
PMS2
PMS1
Chr 7
Chr 3
Chr 2
HNPCC is associated with germline mutations
in any one of at least five genes
Contribution of Gene Mutations
to HNPCC Families
Sporadic
Familial
Unknown ~30%
MSH2 ~30%
HNPCC
Rare CRC
syndromes
FAP
MSH6 (rare)
Liu B et al. Nat Med 2:169, 1996
PMS1 (rare)
PMS2 (rare)
MLH1
~30%
Cancer Risks in HNPCC
100
% with 80
cancer
60
Colorectal 78%
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)
ASCO
HNPCC Results From Failure of
Mismatch Repair (MMR) Genes
Normal DNA
repair
Base pair
mismatch
TCGAC
AGCTG
T CT A C
AGCTG
Defective DNA
repair (MMR+)
T CT A C
TCTAC
AGCTG
AGATG
Structure of Mismatch Repair
Obmolova G, Nature 407;703, 2000
Lamers et al, Nature 407;711, 2000
Mismatch Repair Failure Leads
to Microsatellite Instability (MSI)
Normal
Microsatellite
instability
Addition of
nucleotide repeats
Microsatellite Instability (MSI)
• 10%–15% of sporadic tumors have MSI
• 95% of HNPCC tumors have MSI at multiple loci
NEJM 342:71, 2000
Surveillance Options for Carriers
of HNPCC-Associated Mutations
Malignancy
Intervention
Recommendation
Colorectal cancer
Colonoscopy
Begin at age 20–25,
repeat every 1–2 years
Endometrial cancer
•
Transvaginal
ultrasound
•
Endometrial aspirate
Annually, starting at
age 25–35
Cancer Genetics Studies Consortium Task Force Recommendations
Modified from Burke W et al. JAMA 277:915, 1997
Surveillance Reduces Risk of Colorectal
Cancer in HNPCC Families
30
No surveillance
Surveillance
% of
subjects 20
with CRC
11.9%
10
4.5%
0
0
Jarvinen HJ et al. Gastro 108:1405, 1995
3
6
Years of follow-up
9
ASCO
Surveillance Improves
HNPCC Survival
Surveillance
No surveillance
1.0
0.9
0.8
Survival
0.7
65% reduction in mortality
0.6
p = 0.05
0.5
0
3
6
9
12
Years of follow-up
Jarvinen H et al Gastroenterology 118;829, 2000
15
Cancer Genetics: II
Summary
• Inherited susceptibility to cancer due to germline mutations
• Familial Adenomatous Polyposis
• Hereditary Non-Polyposis Colorectal Cancer
– Amsterdam criteria
• Surveillance reduces the risk of cancer
• Genetic counseling / testing plays an important role in the
management of families with inherited susceptibility to
cancer
Special thanks to David Barrett
Please check out his latest CD,
“It’s a long, long story”
www.DavidBarrett.com
or in concert at the
Greenwood Café Acoustic Series
December 6, 7:30pm