Familial Risk and Surveillance of Colon and Rectum

Malcolm Dunlop

Academic Coloproctology & Colon Cancer Genetics GroupUniversity of Edinburgh & Western General Hospital

Providing benefit

Doing harm

Know your enemy!

Colorectal Cancer Aetiology

Diet

Age/Sex

Lifestyle factors

Chronic inflammatory bowel disease

Genetic factors

High penetrance dominant/recessive gene disorders

Low penetrance dominant/recessive alleles

Genetic risk factors, gene-environment & gene-gene interaction

Colorectal cancer age distribution

0

100

200

300

400

500

600

25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Absolute 5-year Colorectal Cancer Risk

0.050.2

0.7

1.4

2.1

0

0.5

1

1.5

2

2.5

40 50 60 70 80Current age

5yr

abso

lute

ris

k (%

)

Age-specific incidence rate(per 100,000 person-years)

1

10

100

1000

30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

MaleFemale

204

326

OR = 1.6, M vs F

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Non- shared environmental

Shared environment

Heritable

Heritable mutations in knowngenes

Relative Contributions to Colorectal Cancer Incidence

35% -

Lichtenstein NEJ M 2000

Gene Contribution

Familial adenomatous polyposis APC 0.07%

Rare dominant genetic syndromes <0.01%

Peutz-Jegher’s Syndrome STK11/LKB1

Juvenile polyposis SMAD4, BMPR1A, PTEN

HNPCC MMR 2.8%

Recessive disorders

Multiple adenoma phenotype MUTYH ~0.05%

Familial E-Cadherin, TGF-BRII, ?15q ?

Low penetrance alleles EpHx, GSTMI, GSTTI, NAT, CCND1

MTHFR, CYP1A1, CYP1A1 ?

APC-I1307K, APC-E1317Q, Hras

Gene-environment interaction APC-D1822V/fat RR 0.2

MTHFR-A226V/folate RR 0.8

Gene defects contributing to incidence

Gene Contribution

Familial adenomatous polyposis APC 0.07%

Rare dominant genetic syndromes <0.01%

Peutz-Jegher’s Syndrome STK11/LKB1

Juvenile polyposis SMAD4, BMPR1A, PTEN

HNPCC MMR 2.8%

Recessive disorders

Multiple adenoma phenotype MUTYH ~0.05%

HNPCC kindred

Bowel cancer

Uterine cancer

Stomach cancer

50% risk

HNPCC is due to mutations in DNA mismatch repair genes

DNA mismatch Localisation Proportion of repair gene all mutations

identified

MLH1 3p21 54%

MSH2 2p16 36%

MSH6 2p16 ~10%

? Contribution of PMS2, MLH3, MSH3

Lifetime cancer risk for people with HNPCC gene mutations

Large bowel Male 80%

Female 30%

Uterus (endometrium) 40%

Ovary 9%

Stomach 19%

Upper Urinary Tract 10%

Small intestine 1%

0

Colorectal,

All cancers,

20

40

60

80

100

All cancers,

Uterine,

Colorectal,

0 20 40 60 80 Age (years)

Cu

mu

lati

ve r

isk

%MMR gene penetrance

*

*

Dunlop et al 1997

Effect of Surveillance on Colorectal Cancer Incidence and Mortality

Retrospective case-control study

colonoscopic surveillance vs no screen

62% colorectal cancer incidence

65% colorectal cancer mortality Jarvinen 2000

Sporadic CRC (Winawer)

HNPCC (Jarvinen)

Polypectomies 1178 22

Expected CRC 20-48 12.8

Observed CRC 5 5

CRC prevented 15-43 7.8

PolypX/CRC prevented 48 2.8

Effectiveness of Polypectomyby Risk Group

Evidence Base for Cancer Surveillance in HNPCC/MMR Carriers

Beneficial? Grade of evidence

Colorectal cancer Yes B/C

Endometrial No B/C

Ovarian ? C

Urothelial ? C

Gastric No B/C

Brain ? C

Empiric FH Criteria to Guide Surveillance

71

53

Familial aggregation due to chance

Familial aggregation due shared environment

Recall inaccuracy (+ve or –ve)

Effect of family size

Inability to determine risk at the individual level

Inherent limitations of FH information

Heterogeneity of CRC RiskAggregate risk 1:10

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8 Several modest

risk subjects

3 cases from HNPCC

families

Single MMR gene carrier

Popn risk

Population Prevalence of Colorectal Cancer FH

Published data*

Any affected relative 4 - 10%

1 affected under 45yrs 0.4%

2 affected relatives 0.2%

Combined 0.5%

*St John. Ann Int Med 1993. Fuchs NEJM 1994. Bonelli Int J C 1988. Slattery JNCI 1994. Ponz de Leon Cancer 1987. Stephenson. BJS 1991

Edinburgh FH StudyPopulation Prevalence of Family History

All relatives traced of healthy control subjects (n = 160)

(age 30-70 years)

Family History Criteria

Any affected relative 46 28.8% (95% CI = 21.7, 35.8)

Affected first degree relative 15 9.4% (95% CI = 4.9, 13.9)

More than one affected relative 14 8.8% (95% CI = 4.4, 13.1)

Mitchell & Dunlop 2004 unpublished.

Accuracy of FH ReportingKnowledge of Family Member’s Health

Interviewee Group Relative Group Total Number of Relatives

Number (%) For Whom Interviewee Could Supply Any Health Information

Cases (n=199) First degree relatives

1322 1250 (95%)

“ Second degree relatives

1968 713 (36%)

Controls (n=133) First degree relatives

1037 991 (96%)

“ Second degree relatives

1310 671 (51%)

Accuracy of FH Reporting Reporting of Colorectal Cancer in Relatives

FH Criteria (ACP/BSG) Two affected first degree relatives or

One first degree relative affected at <45yrs

Families meeting criteria on interview data alone 5

Validated by record linkage 2

Positive Predictive Value 0.40(95% CI = 0.12-0.77)

Record linkage identified families not reported at interview 4

Sensitivity of interview 0.33(95% CI = 0.10-0.70)

Accuracy of FH ReportingPPV and sensitivity for ACP criteria

Family history of colorectal cancer is common in population

FH of colorectal cancer is substantially under-reported

Interviewee reports are subject to considerable inaccuracy

Interview data should be interpreted with caution

FH Reporting at InterviewConclusions

Risk group Houlston (lifetime risk CRC death)

St John (OR)

Fuchs (RR)

Slattery (OR) Male Female

Population 1:50 - - - -

Any FH 1:17 1.8 1.72 2.1 2.43

One affected relative <45yrs

1:10 3.7 N/A 3.61 7.18

Two affected relatives

1:6 5.7 2.75 9.24 5.00

Degree of empirical lifetime CRC risk

RR and OR

Absolute 10yr Risk

Current age 30-39 40-49 50-59 60-69

Population CRC risk 1/3,000 1/600 1/170 1/73

CRC risk if FH++ 1/500 1/100 1/90 1/36

Chance of 2yrly colonoscopy 1/900 1/180 1/160 1/65preventing CRC death (FH++)

Cumulative risk for each age group

Absolute 10yr Colorectal Cancer Risk

0

5

10

15

20

25

30

40 50 75 40 50 30 40 50

Ris

k o

f C

RC

in

ne

xt

10

yrs

(%

)

Current age

0.60.17

4.0

1.11.0

30

26

18

UK Population

Moderate risk FH

MMR carrier

Competing Causes of Death10-year risks by age-group

50-69yrs 70yrs+

All cause death 17% 41%

Developing CRC 1.7% 4.2%

Death from CRC 0.95% 2.6%

Colonoscopy adverse events

Outcome Risk/examination

Adenoma miss rate

(Rex et al 1997) Overall 27%

6-9mm 13%>1cm 6%

Serious morbidity 0.3%

Mortality 1/5000-1/10,000

Projected effect of surveillanceACP/BSG Moderate Risk Guidelines

Projected benefit Single colonoscopy

35-45yrs 55yrs

Early CRC detection 1:1660 1:180

Prevention CRC death 1:3600 1:220

Detect polyposis syndromes ++ +/-

Reduce anxiety ++ +/-

Identify polyp formers for surveillance + ++

Sporadic CRC incidence reduction - +/-

Edinburgh FH Genetic Database

High

Moderate

Low

Unclear

18%

40%

33%

9%

N = 882

High Risk Median Age

Moderate Risk

Median Age

Screened 53 43 123 43

Normal 45 41 104 43

Any Polyp 8 49 19 45

adenoma 4 (8%) 46 5 (4%) 54

hyperplastic 4 (8%) 54 14 (11%) 44

Prevalence colonoscopy screen(n=448 consultands. 176 Medium/High Risk)

Bradshaw et al. Gut 2003; 52: 1748-51

Possession of a technology requires that you keep your eye on the horizon!

Conclusions

Limited high quality data available to inform practice

Centralised management of FH+ cases facilitates risk assignment and audit of outcomes

People fulfilling moderate risk criteria merit surveillance on two occasions, aged 35-45 and at 55yrs

Whole colon should be imaged

People assigned low risk can be reassured and population interventions advised