Lecture 22Cancer Genetics II:

Inherited Susceptibility to Cancer

Stephen B. Gruber, MD, PhD

November 19, 2002

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

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

Sporadic Sporadic (65(65%–%–85%)85%)

Familial Familial (10(10%–%–30%)30%)

Hereditary nonpolyposis Hereditary nonpolyposis colorectal cancer colorectal cancer (HNPCC) (5%)(HNPCC) (5%)Familial adenomatous Familial adenomatous

polyposis (FAP) (1%)polyposis (FAP) (1%)

Rare CRC Rare CRC syndromes syndromes

(<0.1%)(<0.1%)

Multi-Step Carcinogenesis

Normal Normal epitheliumepithelium

Hyper-Hyper-proliferativeproliferativeepitheliumepithelium

EarlyEarlyadenomaadenoma

LateLateadenomaadenoma CarcinomaCarcinoma MetastasisMetastasis

Loss ofLoss ofAPCAPC

ActivationActivationof K-rasof K-ras

Loss ofLoss of18q18q

Loss ofLoss ofTP53TP53

Other Other alterationsalterations

Adapted from Fearon ER. Adapted from Fearon ER. CellCell 61:759, 1990 61:759, 1990

Inter-Inter-mediatemediate

adenomaadenoma

ASCO

Risk of Colorectal Cancer (CRC)

0 20 40 60 80 100

General populationGeneral population

Personal history of Personal history of colorectal neoplasiacolorectal neoplasia

Inflammatory Inflammatory bowel diseasebowel disease

HNPCC mutationHNPCC mutation

FAPFAP

6%6%

15%–20%15%–20%

15%–40%15%–40%

70%–80%70%–80%

>95%>95%

Lifetime risk (%)Lifetime risk (%)

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

Attenuated FAPAttenuated FAPClassic FAPClassic FAPCHRPECHRPE

1 2 3 4 5 6 7 8 9 10111213 14 15

5'5' 3'3'

Attenuated FAP

ASCO

• Later onset (CRC ~age 50)Later onset (CRC ~age 50)

• Fewer colonic adenomasFewer colonic adenomas

• Not associated with CHRPENot associated with CHRPE

• UGI lesionsUGI lesions

• Associated with mutations at Associated with mutations at 5' and 3' ends of 5' and 3' ends of APCAPC gene gene

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 33 or more relatives with verified CRC in family or more relatives with verified CRC in family

- - One case a first-degree relative of the other twoOne case a first-degree relative of the other two 22 or more generations or more generations 11 CRC by age 50 CRC by age 50 FAP excludedFAP excluded

Vasen HFA et al. Vasen HFA et al. Dis Colon RectDis Colon Rect 34:424, 1991 34:424, 1991

Failure to meet these criteria Failure to meet these criteria does does notnot exclude HNPCC exclude 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

HNPCC is associated with germline mutations HNPCC is associated with germline mutations in any one of at least five genesin any one of at least five genes

Chr 2Chr 2Chr 3Chr 3

Chr 7Chr 7

MSH2MSH2

PMS1PMS1

MLH1MLH1PMS2PMS2

MSH6MSH6

Contribution of Gene Mutations to HNPCC Families

MSH2 MSH2 ~30%~30%

MLH1MLH1~30%~30%

PMS1 PMS1 (rare)(rare)

PMS2PMS2 (rare) (rare)

MSH6 MSH6 (rare)(rare)

Unknown ~30%Unknown ~30%

SporadicSporadic FamilialFamilial

HNPCCHNPCC

FAPFAP

Rare CRC Rare CRC syndromessyndromes

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

Cancer Risks in HNPCC

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

% with % with cancercancer

100100

8080

6060

4040

2020

002020 4040 6060 808000

Age (years)Age (years)

Colorectal 78%Colorectal 78%

Endometrial 43% Endometrial 43%

Stomach 19%Stomach 19%Biliary tract 18%Biliary tract 18%Urinary tract 10%Urinary tract 10%Ovarian 9%Ovarian 9%

ASCO

HNPCC Results From Failure of Mismatch Repair (MMR) Genes

Base pair Base pair mismatchmismatch

Normal DNA Normal DNA repairrepair

Defective DNA Defective DNA repair (MMR+)repair (MMR+)

TT CC TT AA CC

A G C T GA G C T G

T C G A CT C G A C

A G C T GA G C T G

TT CC TT AA CC

A G C T GA G C T G A G A G AA T GT G

T C T C TT A C A C

Structure of Mismatch Repair

Obmolova G, Nature 407;703, 2000Lamers et al, Nature 407;711, 2000

Mismatch Repair Failure Leads to Microsatellite Instability (MSI)

NormalNormal

Microsatellite Microsatellite instabilityinstability Addition of Addition of

nucleotide repeatsnucleotide repeats

NEJMNEJM 342:71, 2000 342:71, 2000

Microsatellite Instability (MSI)

• 10%–15% of sporadic tumors have MSI10%–15% of sporadic tumors have MSI• 95% of HNPCC tumors have MSI at multiple loci95% of HNPCC tumors have MSI at multiple loci

Surveillance Options for Carriers of HNPCC-Associated Mutations

Cancer Genetics Studies Consortium Task Force RecommendationsCancer Genetics Studies Consortium Task Force RecommendationsModified from Burke W et al. Modified from Burke W et al. JAMAJAMA 277:915, 1997 277:915, 1997

InterventionIntervention

ColonoscopyColonoscopy

• Transvaginal Transvaginal ultrasound ultrasound

• Endometrial aspirateEndometrial aspirate

RecommendationRecommendation

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

Annually, starting at Annually, starting at age 25–35age 25–35

MalignancyMalignancy

Colorectal cancerColorectal cancer

Endometrial cancerEndometrial cancer

Surveillance Reduces Risk of Colorectal Cancer in HNPCC Families

Jarvinen HJ et al. Jarvinen HJ et al. GastroGastro 108:1405, 1995 108:1405, 1995

% of % of subjects subjects

with CRCwith CRC

3030

2020

1010

4.5%4.5%

11.9%11.9%

00 33 66 99Years of follow-upYears of follow-up

SurveillanceSurveillanceNoNo surveillancesurveillance

00

ASCO

Surveillance Improves HNPCC Survival

9

0.6

0.7

0.8

0.9

1.0

0.5

3 6 12 150

Jarvinen H et al Gastroenterology 118;829, 2000Jarvinen H et al Gastroenterology 118;829, 2000

Years of follow-upYears of follow-up

SurvivalSurvival

65% reduction in mortality

p = 0.05

SurveillanceSurveillanceNoNo surveillancesurveillance

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

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