familial risk and surveillance of colon and rectum malcolm dunlop academic coloproctology &...
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![Page 1: Familial Risk and Surveillance of Colon and Rectum Malcolm Dunlop Academic Coloproctology & Colon Cancer Genetics Group University of Edinburgh & Western](https://reader035.vdocuments.site/reader035/viewer/2022062517/56649ec55503460f94bcf712/html5/thumbnails/1.jpg)
Familial Risk and Surveillance of Colon and Rectum
Malcolm Dunlop
Academic Coloproctology & Colon Cancer Genetics GroupUniversity of Edinburgh & Western General Hospital
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Providing benefit
Doing harm
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Know your enemy!
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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
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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+
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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 (%
)
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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
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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
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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%
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HNPCC kindred
Bowel cancer
Uterine cancer
Stomach cancer
50% risk
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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
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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%
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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
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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
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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
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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
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Empiric FH Criteria to Guide Surveillance
71
53
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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
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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
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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
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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.
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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%)
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Accuracy of FH Reporting Reporting of Colorectal Cancer in Relatives
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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
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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
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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
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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
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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
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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%
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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
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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 - +/-
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Edinburgh FH Genetic Database
High
Moderate
Low
Unclear
18%
40%
33%
9%
N = 882
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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
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Possession of a technology requires that you keep your eye on the horizon!
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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
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