Lecture 22 Cancer Genetics II: Inherited Susceptibility to Cancer

1
Lecture 22Cancer Genetics IIInherited
Susceptibility to Cancer

• Stephen B. Gruber, MD, PhD
• November 19, 2002

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Cancer Genetics IISummary

• Inherited susceptibility to cancer due to
  germline mutations
• Causes of inherited susceptibility to colorectal
  cancer
• Familial Adenomatous Polyposis
• Hereditary Non-Polyposis Colorectal Cancer

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Causes of Hereditary Susceptibility to CRC
Sporadic (6585)
Familial (1030)
Rare CRC syndromes (lt0.1)
Hereditary nonpolyposis colorectal cancer (HNPCC)
(5)
Familial adenomatous polyposis (FAP) (1)
Adapted from Burt RW et al. Prevention and Early
Detection of CRC, 1996
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Multi-Step Carcinogenesis
Loss of APC
Activation of K-ras
Loss of 18q
Loss of TP53
Other alterations
Normal epithelium
Hyper- proliferative epithelium
Early adenoma
Late adenoma
Carcinoma
Metastasis
Inter- mediate adenoma
Adapted from Fearon ER. Cell 61759, 1990
ASCO
5
Risk of Colorectal Cancer (CRC)
6
General population
Personal history of colorectal neoplasia
1520
Inflammatory bowel disease
1540
7080
HNPCC mutation
gt95
FAP
0
20
40
60
80
100
Lifetime risk ()
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Clinical Features of FAP

• Estimated penetrance for adenomas gt90
• Risk of extracolonic tumors (upper GI, desmoid,
  osteoma, thyroid, brain, other)
• CHRPE may be present
• Untreated polyposis leads to 100 risk of cancer

ASCO
7
Some FAP Manifestations Correlate With Specific
APC Gene Regions
5'
3'
Attenuated FAP
Classic FAP
CHRPE
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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
9
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

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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 34424, 1991
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Genetic Features of HNPCC

• Autosomal dominant inheritance
• Penetrance 80
• Genes belong to DNA mismatch repair (MMR) family
• Genetic heterogeneity (MLH1, MSH2, MSH6, PMS1,
  PMS2)

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Genetic Heterogeneity in HNPCC
MSH6
MLH1
MSH2
PMS2
PMS1
Chr 7
Chr 3
Chr 2
HNPCC is associated with germline mutations in
any one of at least five genes
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Contribution of Gene Mutations to HNPCC Families
Sporadic
Familial
MSH2 30
Unknown 30
HNPCC
Rare CRC syndromes
FAP
MLH1 30
PMS1 (rare)
MSH6 (rare)
PMS2 (rare)
Liu B et al. Nat Med 2169, 1996
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Cancer Risks in HNPCC
100
80
with cancer
Colorectal 78
60
Endometrial 43
40
Stomach 19
20
Biliary tract 18
Urinary tract 10
Ovarian 9
0
20
40
60
80
0
Age (years)
Aarnio M et al. Int J Cancer 64430, 1995
ASCO
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HNPCC Results From Failure of Mismatch Repair
(MMR) Genes
Normal DNA repair
Base pair mismatch
Defective DNA repair (MMR)
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Structure of Mismatch Repair
Obmolova G, Nature 407703, 2000
Lamers et al, Nature 407711, 2000
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Mismatch Repair Failure Leads to Microsatellite
Instability (MSI)
Normal
Microsatellite instability
Addition of nucleotide repeats
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Microsatellite Instability (MSI)

• 1015 of sporadic tumors have MSI
• 95 of HNPCC tumors have MSI at multiple loci

NEJM 34271, 2000
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Surveillance Options for Carriers of
HNPCC-Associated Mutations

• Intervention
• Colonoscopy
• Transvaginal ultrasound
• Endometrial aspirate

Recommendation Begin at age 2025, repeat every
12 years Annually, starting at age 2535

• Malignancy
• Colorectal cancer
• Endometrial cancer

Cancer Genetics Studies Consortium Task Force
Recommendations Modified from Burke W et al. JAMA
277915, 1997
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Surveillance Reduces Risk of Colorectal Cancer in
HNPCC Families
30
No surveillance
of subjects with CRC
Surveillance
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11.9
10
4.5
0
0
3
6
9
Years of follow-up
Jarvinen HJ et al. Gastro 1081405, 1995
ASCO
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Surveillance Improves HNPCC Survival
Surveillance
1.0
No surveillance
0.9
0.8
Survival
0.7
65 reduction in mortality p 0.05
0.6
0.5
9
3
6
12
15
0
Years of follow-up
Jarvinen H et al Gastroenterology 118829, 2000
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Cancer Genetics IISummary

• 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

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Special thanks to David BarrettPlease check out
his latest CD, Its a long, long
storywww.DavidBarrett.comor in concert at the
Greenwood Café Acoustic SeriesDecember 6,
730pm