Familial Risk and Surveillance of Colon and Rectum Malcolm Dunlop Academic Coloproctology & Colon...
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Transcript of Familial Risk and Surveillance of Colon and Rectum Malcolm Dunlop Academic Coloproctology & Colon...
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