1. Familial Risk and Surveillance of Colon and Rectum Malcolm Dunlop Academic Coloproctology & Colon Cancer Genetics Group University of Edinburgh & Western General Hospital

2. Providing benefit Doing harm

3. Know your enemy!

4. 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

5. Colorectal cancer age distribution

6. Absolute 5-year Colorectal Cancer Risk

7. Age-specific incidence rate (per 100,000 person-years) 204 326 OR = 1.6, M vs F

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

9. 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%

10. HNPCC kindred Bowel cancer Uterine cancer Stomach cancer 50% risk

11. 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

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

13. Age (years) Cumulative risk % MMR gene penetrance * * Dunlop et al 1997

14. 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

15. Effectiveness of Polypectomy by Risk Group

16. 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

17. Empiric FH Criteria to Guide Surveillance 71 53

18. 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

19. Heterogeneity of CRC Risk Aggregate 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 Pop n risk

20. Population Prevalence of Colorectal Cancer FH Published data* Any affected relative 4 - 10% 1 affected under 45yrs0.4% 2 affected relatives0.2% Combined0.5% *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

21. Edinburgh FH Study Population 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.

22. 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 13221250 (95%) “Second degree relatives 1968713 (36%) Controls (n=133)First degree relatives 1037991 (96%) “Second degree relatives 1310671 (51%)

23. Accuracy of FH Reporting Reporting of Colorectal Cancer in Relatives

24. 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 = 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 Reporting PPV and sensitivity for ACP criteria

25. 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

26. Degree of empirical lifetime CRC risk RR and OR

27. Absolute 10yr Risk Current age 30-3940-4950-5960-69 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

28. Absolute 10yr Colorectal Cancer Risk Current age 0.6 0.17 4.0 1.11.0 30 26 18 UK Population Moderate risk FH MMR carrier

29. 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%

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

31. 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 - +/-

32. Edinburgh FH Genetic Database High Moderate Low Unclear 18% 40% 33% 9% N = 882

33. Prevalence colonoscopy screen (n=448 consultands. 176 Medium/High Risk) Bradshaw et al. Gut 2003; 52: 1748-51

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

35. 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 35-45 and at 55yrs u Whole colon should be imaged u People assigned low risk can be reassured and population interventions advised