Familial Risk and Surveillance of Colon and Rectum Malcolm Dunlop Academic Coloproctology & Colon Cancer Genetics Group University 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

Absolute 5-year Colorectal Cancer Risk

Age-specific incidence rate (per 100,000 person-years) OR = 1.6, M vs F

Relative Contributions to Colorectal Cancer Incidence 35% - Lichtenstein NEJ M 2000

GeneContribution Familial adenomatous polyposis APC0.07% Rare dominant genetic syndromes <0.01% Peutz-Jegher’s Syndrome STK11/LKB1 Juvenile polyposis SMAD4, BMPR1A, PTEN HNPCCMMR 2.8% Recessive disorders Multiple adenoma phenotypeMUTYH~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/fatRR 0.2 MTHFR-A226V/folateRR 0.8 Gene defects contributing to incidence GeneContribution Familial adenomatous polyposis APC0.07% Rare dominant genetic syndromes <0.01% Peutz-Jegher’s Syndrome STK11/LKB1 Juvenile polyposis SMAD4, BMPR1A, PTEN HNPCCMMR 2.8% Recessive disorders Multiple adenoma phenotypeMUTYH~0.05%

HNPCC kindred Bowel cancer Uterine cancer Stomach cancer 50% risk

HNPCC is due to mutations in DNA mismatch repair genes DNA mismatch LocalisationProportion of repair gene all mutations identified MLH13p2154% MSH22p1636% MSH62p16 ~10% ? Contribution of PMS2, MLH3, MSH3

Lifetime cancer risk for people with HNPCC gene mutations Large bowel Male80% Female30% Uterus (endometrium)40% Ovary9% Stomach19% Upper Urinary Tract10% Small intestine1%

Age (years) Cumulative risk % 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

Effectiveness of Polypectomy by Risk Group

Evidence Base for Cancer Surveillance in HNPCC/MMR Carriers Beneficial?Grade of evidence Colorectal cancerYesB/C EndometrialNoB/C Ovarian?C Urothelial?C GastricNoB/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 Risk Aggregate risk 1: Several modest risk subjects 3 cases from HNPCC families Single MMR gene carrier Pop n risk

Population Prevalence of Colorectal Cancer FH Published data* Any affected relative % 1 affected under 45yrs0.4% 2 affected relatives0.2% Combined0.5% *St John. Ann Int Med Fuchs NEJM Bonelli Int J C Slattery JNCI Ponz de Leon Cancer Stephenson. BJS 1991

Edinburgh FH Study Population Prevalence of Family History All relatives traced of healthy control subjects (n = 160) (age years) Family History Criteria Any affected relative % ( 95% CI = 21.7, 35.8 ) Affected first degree relative % ( 95% CI = 4.9, 13.9 ) More than one affected relative % ( 95% CI = 4.4, 13.1 ) Mitchell & Dunlop 2004 unpublished.

Accuracy of FH Reporting Knowledge of Family Member’s Health Interviewee GroupRelative GroupTotal Number of Relatives Number (%) For Whom Interviewee Could Supply Any Health Information Cases (n=199)First degree relatives (95%) “Second degree relatives (36%) Controls (n=133)First degree relatives (96%) “Second degree relatives (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 alone5 Validated by record linkage2 Positive Predictive Value 0.40 (95% CI = ) Record linkage identified families not reported at interview 4 Sensitivity of interview 0.33 (95% CI = ) Accuracy of FH Reporting PPV 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 Interview Conclusions

Degree of empirical lifetime CRC risk RR and OR

Absolute 10yr Risk Current age Population CRC risk 1/3,0001/6001/1701/73 CRC risk if FH++1/5001/1001/901/36 Chance of 2yrly colonoscopy 1/9001/1801/1601/65 preventing CRC death (FH++) Cumulative risk for each age group

Absolute 10yr Colorectal Cancer Risk Current age UK Population Moderate risk FH MMR carrier

Competing Causes of Death 10-year risks by age-group 50-69yrs70yrs+ All cause death17%41% Developing CRC 1.7%4.2% Death from CRC0.95%2.6%

Colonoscopy adverse events OutcomeRisk/examination Adenoma miss rate (Rex et al 1997) Overall27% 6-9mm13% >1cm6% Serious morbidity0.3% Mortality1/5000-1/10,000

Projected effect of surveillance ACP/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

Prevalence colonoscopy screen (n=448 consultands. 176 Medium/High Risk) Bradshaw et al. Gut 2003; 52:

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

Conclusions u Limited high quality data available to inform practice u Centralised management of FH+ cases facilitates risk assignment and audit of outcomes u People fulfilling moderate risk criteria merit surveillance on two occasions, aged and at 55yrs u Whole colon should be imaged u People assigned low risk can be reassured and population interventions advised