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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

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lecture 22 cancer genetics ii inherited susceptibility to cancer

Lecture 22Cancer Genetics II:Inherited Susceptibility to Cancer

Stephen B. Gruber, MD, PhD

November 19, 2002

cancer genetics ii summary
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
causes of hereditary susceptibility to crc
Causes of Hereditary Susceptibility to CRC

Sporadic (65%–85%)

Familial (10%–30%)

Rare CRC syndromes (<0.1%)

Hereditary nonpolyposis colorectal cancer (HNPCC) (5%)

Familial adenomatous polyposis (FAP) (1%)

Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996

multi step carcinogenesis
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

Inter-

mediate

adenoma

Late

adenoma

Carcinoma

Metastasis

Adapted from Fearon ER. Cell 61:759, 1990

ASCO

risk of colorectal cancer crc
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

80

100

Lifetime risk (%)

clinical features of fap
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

15

3

7

14

1

2

4

5

6

8

9

10

12

13

11

Some FAP Manifestations Correlate With Specific APC Gene Regions

5'

3'

Attenuated FAP

Classic FAP

CHRPE

attenuated fap
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

Clinical Features of HNPCC
amsterdam criteria
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
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
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

contribution of gene mutations to hnpcc families
Contribution of Gene Mutations to HNPCC Families

Sporadic

Familial

Unknown ~30%

MSH2 ~30%

HNPCC

Rare CRC syndromes

FAP

MLH1

~30%

MSH6 (rare)

PMS1 (rare)

PMS2 (rare)

Liu B et al. Nat Med 2:169, 1996

cancer risks in hnpcc
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

0

20

40

60

80

Age (years)

Aarnio M et al. Int J Cancer 64:430, 1995

ASCO

hnpcc results from failure of mismatch repair mmr genes

T C G A C

A G C T G

T

C

A

T

C

A G C T G

T

T C T A C

C

A

T

C

A G AT G

A G C T G

HNPCC Results From Failure of Mismatch Repair (MMR) Genes

Normal DNA repair

Base pair mismatch

Defective DNA repair (MMR+)

structure of mismatch repair
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
Mismatch Repair Failure Leads to Microsatellite Instability (MSI)

Normal

Microsatellite instability

Addition of nucleotide repeats

microsatellite instability msi
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
Surveillance Options for Carriers of HNPCC-Associated Mutations
  • Malignancy
  • Colorectal cancer

Endometrial cancer

  • Intervention
  • Colonoscopy
  • Transvaginal ultrasound
  • Endometrial aspirate

Recommendation

Begin at age 20–25, repeat every 1–2 years

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
Surveillance Reduces Risk of Colorectal Cancer in HNPCC Families

30

Nosurveillance

% of subjects with CRC

Surveillance

20

11.9%

10

4.5%

0

0

3

6

9

Years of follow-up

Jarvinen HJ et al. Gastro 108:1405, 1995

ASCO

surveillance improves hnpcc survival
Surveillance Improves HNPCC Survival

Surveillance

1.0

Nosurveillance

0.9

0.8

Survival

0.7

65% reduction in mortality

p = 0.05

0.6

0.5

0

3

6

9

12

15

Years of follow-up

Jarvinen H et al Gastroenterology 118;829, 2000

cancer genetics ii summary22
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
slide23

Special thanks to David BarrettPlease check out his latest CD, “It’s a long, long story”www.DavidBarrett.comor in concert at the Greenwood Café Acoustic SeriesDecember 6, 7:30pm