Familial Risk and Surveillance of Colon and Rectum

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

2. Doing harm Providing benefit

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) 326 204 OR = 1.6, M vs F

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

9. Gene defects contributing to incidence Gene Contribution Familial adenomatous polyposisAPC 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% FamilialE-Cadherin, TGF-BRII, ?15q? Low penetrance allelesEpHx, GSTMI, GSTTI, NAT, CCND1 MTHFR, CYP1A1, CYP1A1 ? APC-I1307K, APC-E1317Q, Hras Gene-environment interactionAPC-D1822V/fat RR 0.2 MTHFR-A226V/folate RR 0.8 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%

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

11. DNA mismatch Localisation Proportion of repair gene all mutations identified MLH1 3p21 54% MSH2 2p16 36% MSH6 2p16 ~10% ? Contribution of PMS2, MLH3, MSH3 HNPCC is due to mutations in DNA mismatch repair genes

12. 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%

13. MMR gene penetrance * Cumulative risk % * Age (years) 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 cancer Yes B/C Endometrial No B/C Ovarian ? C Urothelial ? C Gastric No B/C Brain ? C

17. 71 53 Empiric FH Criteria to Guide Surveillance

18. Inherent limitations of FH information 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

19. 0.8 0.7 0.6 Several modest risk subjects 0.5 3 cases from HNPCC 0.4 families Popn risk 0.3 Single MMR gene carrier 0.2 0.1 0 Heterogeneity of CRC RiskAggregate risk 1:10

20. 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

21. Edinburgh FH StudyPopulation Prevalence of Family History All relatives traced of healthy control subjects (n = 160) (age 30-70 years) Mitchell & Dunlop 2004 unpublished.

22. Accuracy of FH ReportingKnowledge of Family Member’s Health

23. Accuracy of FH ReportingReporting of Colorectal Cancer in Relatives

24. Accuracy of FH ReportingPPV and sensitivity for ACP criteria 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)

25. FH Reporting at InterviewConclusions 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

26. Degree of empirical lifetime CRC riskRR and OR

27. 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 1/65 preventing CRC death (FH++) Absolute 10yr Risk Cumulative risk for each age group

28. 30 26 MMR carrier UK Population 18 Moderate risk FH 4.0 0.6 1.0 1.1 0.17 Current age Absolute 10yr Colorectal Cancer Risk

29. Competing Causes of Death 10-year risks by age-group 50-69yrs 70yrs+ All cause death17% 41% Developing CRC 1.7% 4.2% Death from CRC0.95% 2.6%

30. 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

31. Projected effect of surveillanceACP/BSG Moderate Risk Guidelines Projected benefit Single colonoscopy 35-45yrs 55yrs Early CRC detection1:16601:180 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 9% 18% High Moderate N = 882 Low 33% Unclear 40%

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 • 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