1. Diverticular Disease Genetics and correlation to cancer Tryggvi Stefánsson Centrallasarettet in Västerås and Landspítali University Hospital Reykjavík/Iceland

2. Diverticular disease Non-Symptomatic diverticular disease Non-Symptomatic diverticular disease = Diverticulosis Symptomatic diverticular disease = Diverticulosis + Diverticulitis Hemorrage Motility disorders

3. Diverticular disease and CRC Many similarities. Many similarities. Cancer and diverticulosis: Cancer and diverticulosis: No known association. Cancer and symptomatic diverticular disease: Association. Cancer and symptomatic diverticular disease: Association.

4. Diverticulosis and CRC Prevalence for diverticulosis and for CRC increases as age increases and is the same in men and women. Prevalence for diverticulosis and for CRC increases as age increases and is the same in men and women.

5. Diverticulosis and CRC Low prevalens of Diverticulosis in populations with low risk for CRC and Polyps. Low prevalens of Diverticulosis in populations with low risk for CRC and Polyps. Lack of fiber in the diet causes diverticulosis. Lack of fiber in the diet causes diverticulosis. Painter and Burkitt, BMJ,1971 Fiber in the diet decreases the risk for colon cancer Howe GR et al, J Nat Ca Inst, 1992 Fiber in the diet decreases the risk for colon cancer Howe GR et al, J Nat Ca Inst, 1992 Potter JD, Ca Causes and Control 1996

6. Diverticulosis and CRC Diverticulosis increases in migrating populations when moving from low risk areas to high risk areas. Diverticulosis increases in migrating populations when moving from low risk areas to high risk areas. Painter and Burkitt, BMJ,1971 Stemmermann GN, Cancer, 1973 CRC increases in migrating populations when moving from low risk areas to high risk areas. CRC increases in migrating populations when moving from low risk areas to high risk areas. Stazewski J, J Nat Ca Inst, 1965 Haenszel W, J Nat Ca Inst, 1968 Stemmermann GN, Cancer, 1973

7. Diverticulosis and CRC One small study on the association between non- symptomatic diverticular disease and CRC One small study on the association between non- symptomatic diverticular disease and CRC 119 cases with CRC 40% of men had diverticulosis 39% of women had diverticulosis 119 age-matched controls without CRC 50% of men had diverticulosis 36% of women had diverticulosis There was no significant difference in number of patients with diverticulosis in the two groups Mc Callum et al, Scand J Gastro, 1988

8. Symptomatic Diverticular Disease and CRC Physical activity lowers the risk of symptomatic diverticular disease in men. WH Aldoori et al, Gut, 1995 Physical activity lowers the risk of symptomatic diverticular disease in men. WH Aldoori et al, Gut, 1995 Physical activity lowers the risk of CRC. Physical activity lowers the risk of CRC. Garabrant DH et al, Am J Epid, 1984 Vena JE et al, Am J Epid, 1985 Gerhardson M, Int J Epid, 1988

9. Symptomatic Diverticular Disease and CRC High intake of fat and low intake of fiber is associated with increased risk of Symptomatic Diverticular Disease High intake of fat and low intake of fiber is associated with increased risk of Symptomatic Diverticular Disease Aldoori WH et al, Am J Clin Nutr, 1994 High intake of fat is associated with increased risk of CRC High intake of fat is associated with increased risk of CRC Howe et al, Ca Causes and Control, 1997

10. Symptomatic Diverticular Disease and CRC High intake of red meat and low intake of fiber is associated with increased risk of Symptomatic Diverticular Disease. High intake of red meat and low intake of fiber is associated with increased risk of Symptomatic Diverticular Disease. Aldoori WH et al, Am J Clin Nutr, 1994 High intake of red meat is associated with increased risk of CRC High intake of red meat is associated with increased risk of CRC Potter JD, J Natl Ca Inst, 1999

11. Symptomatic Diverticular Disease and CRC Uppsala Health Care Region 1965-1983 Uppsala Health Care Region 1965-1983 Total7159 patients with diverticular disease Total7159 patients with diverticular disease Men2478 Men2478 Women4681 Women4681 <60 years1410 <60 years1410 60-69 years1665 60-69 years1665 >70 years4084 >70 years4084

12. First year after the diagnosis Diverticular Disease SiteObsSIR95% CI Colon578.66.5-11.1 Colon578.66.5-11.1 Pancreas339.06.2-12.6 Pancreas339.06.2-12.6 Prostate303.32.2-4.7 Prostate303.32.2-4.7 Stomach274.22.7-6.0 Stomach274.22.7-6.0 Blood203.82.3-5.9 Blood203.82.3-5.9 Rectum164.42.5-7.2 Rectum164.42.5-7.2 Liver143.72.1-6.3 Liver143.72.1-6.3 Ovary134.13.2-10.3 Ovary134.13.2-10.3 Lung102.21.0-4.0 Lung102.21.0-4.0 Stefánsson T et al, Eur J Surg, 1995

13. First year after the diagnosis Diverticular Disease All ColonRight ColonLeft Colon obs SIR CIobs SIR CIobs SIR CI 57 8.6 (6.5-11)10 2.9 (1.4-5.4)41 17.8 (8-14.1) During 2 years after the diagnosis symptomatic DD there were 75 colon cancers among 7159 Sympt DD patients  1/100 FOBT screening in average risk>50 years  1/300 Stefánsson T et al, Eur J Surg, 1995

14. Symptomatic Diverticular Disease and CRC 7159 patients with symptomatic diverticular disease 1965-1983. Followed up untill 1985. The first two years excluded. 7159 patients with symptomatic diverticular disease 1965-1983. Followed up untill 1985. The first two years excluded. Obs= Observed numbers of CRC. obsSIR95%CI All Colon431.2(0.9-1.6) Right and Transv160.9(0.5-1.4) Desc and Sigm211.8(1.1-2.7) Rectum221.1 (0.7-1.7) Stefansson T et al, Gut, 1993

15. Symptomatic Diverticular Disease and CRC 7159 patients with symptomatic diverticular disease 1965-1983. Followed up untill 1991. The first two years excluded. 7159 patients with symptomatic diverticular disease 1965-1983. Followed up untill 1991. The first two years excluded. A nested case control study A nested case control study 64 cases of colon cancer x 123 controls, matched by age, sex and year of discharge Patients with sigmoid diverticulitis had four-fold risk of colon cancer compared to those with only diverticulosis Patients with sigmoid diverticulitis had four-fold risk of colon cancer compared to those with only diverticulosis OR= 4.2 (95% CI 1.3-13.0) OR= 4.2 (95% CI 1.3-13.0) Stefánsson T et al, Scand J Gastroenterol, 2004

16. Summary Diverticulosis and Colon cancer Diverticulosis and Colon cancer Many things in common. No known association Diverticular Disease and Colon Cancer Diverticular Disease and Colon Cancer The first year after diagnosis RR= 18 in left colon Diverticular Disease and Colon Cancer Diverticular Disease and Colon Cancer The first two years excluded RR=1.8 in left colon Diverticulitis and Colon Cancer Diverticulitis and Colon Cancer The first two years excluded OR=4 in left colon

17. Conclusion Many similarities. Many similarities. Cancer and diverticulosis: Cancer and diverticulosis: No known association. Cancer and Diverticulitis Cancer and DiverticulitisAssociation.

18. Genetics and Diverticular Disease x

19. Diverticulosis In European and US populations In European and US populations Distal Colon 90% with sigmoidal involvement 15% in right colon Parks TG, Clin Gastroenterol, 1975 Hughes LE, Gut, 1969 In Asian populations In Asian populations Right sided involvement of Diverticula Lee YS, Dis Colon Rectum, 1986 Chia JG, Dis Colon Rectum, 1991

20. Diverticulosis Prevalence is high in Europe, USA and Australia Prevalence is high in Europe, USA and Australia but low in rural Africa and Asia. Painter NS and Burkitt DP, BMJ, 1971

21. Diverticulosis The incidence of diverticula can vary in ethnic groups within a given country. The incidence of diverticula can vary in ethnic groups within a given country.Singapore: Chinese :1,4/100000/year Europeans:54,1/100000/year Kyle J et al, Scand J Gastroent, 1967 Israel 1969-741979-84 Ashkenazy Jews16,2%17,3% Sephardi Jews3,8%12,9% Arabs0,7%5,4% Levy N, Dis Colon Rectum, 1985

22. Diverticulosis Smooth Muscle Abnormality Smooth Muscle Abnormality Taenia Coli Appear thick with a cartilagenous consistency The circular musle is thick Corrugated concertina like appearance Morson BC, Proceedings of the Royal Society of Medicine 1963 Elastin Depositions Elastin Depositions The diverticular colonic wall contains normal muscle cells, but muscle cells in the taenia coli contains 200% more elastin compared with those without diverticula. Whiteway J, Morson BC, Gut, 1985

23. Diverticulosis Increase in type III collagen synthesis Increase in type III collagen synthesis Bode MK, Scand J Gastroenterol, 2000 Stumpf M, Int J Colorectal Dis, 2001

24. Diverticulosis Increased Diverticulosis in Marfans and Ehler Danlos syndromes Increased Diverticulosis in Marfans and Ehler Danlos syndromes Simpson J, Br J Surg, 2002

25. Diverticulosis Interstitial cells of Cajal and Glial cells are significantly reduced in Colonic Diverticular Disease. Interstitial cells of Cajal and Glial cells are significantly reduced in Colonic Diverticular Disease. Bassotti G et al, Journal of Clinical Pathology, 2005

26. Genetics of Diverticular Disease Discharged from hospital in Iceland 1985-2000 with the diagnosis Diverticular disease. Discharged from hospital in Iceland 1985-2000 with the diagnosis Diverticular disease. Genealogy register at deCode in Reykjavík containing all Icelanders living in Iceland from the settlement of the island. Genealogy register at deCode in Reykjavík containing all Icelanders living in Iceland from the settlement of the island. RR of relatives, mates and relatives of mates of being in the discharged group. RR of relatives, mates and relatives of mates of being in the discharged group.

27. Genetics of Diverticular Disease All3065 All3065 Operated488 Operated488 Not Operated2577 Not Operated2577

28. 1°rel-5°rel All OperatedNot-op RR (95% CI) RR (95% CI)RR (95% CI) 1°relatives1.77(1.67-1.87) 6.02(5.36-6.72)1.54(1.42-1.65) 1°relatives1.77(1.67-1.87) 6.02(5.36-6.72)1.54(1.42-1.65) 2°relatives1.17(1.09-1.27) 1.30(0.82-1.39)1.09(0.99-1.19) 2°relatives1.17(1.09-1.27) 1.30(0.82-1.39)1.09(0.99-1.19) 3°relatives1.17(1.11-1.22) 1.38(1.06-1.73)1.17(1.11-1.24) 3°relatives1.17(1.11-1.22) 1.38(1.06-1.73)1.17(1.11-1.24) 4°relatives1.14(1.10-1.19) 1.55(1.32-1.79)1.18(1.13-1.23) 4°relatives1.14(1.10-1.19) 1.55(1.32-1.79)1.18(1.13-1.23) 5°relatives1.05(1.02-1.09) 0.93(0.77-1.10)1.43(1.17-1.72) 5°relatives1.05(1.02-1.09) 0.93(0.77-1.10)1.43(1.17-1.72)

29. All Aunts & uncles 1.22 (1.09-1.37) Index 3065 Children 1.81 (1.56-2.06) parents 2.20(1.92-2.50) Grandparents 1.48 (0.97-2.10) Cousin 1.18 (1.12-1.25) Siblings 1.60 (1.49-1.71) Nephews & nieces 1.14 (1.02-1.28) Mates 1.42(1.19-1.67) Parents 1.33(1.08-1.61) Children 1.66(1.44-1.89) Cousin 1.15(1.09-1.21) Siblings 0.99(0.89-1.10) Nephews & nieces 1.06(0.95-1.19) Aunts & uncles 1.12(1.00-1.25)

30. Not Operated Aunts & uncles 1.13 (0.97-1.30) Index 2577 Children 1.56 (1.28-1.87) parents 1.96(1.64-2.31) Grandparents 1.45 (0.82-2.26) Cousin 1.20 (1.13-1.26) Siblings 1.41 (1.29-1.53) Nephews & nieces 1.05 (1.02-1.28) Mates 1.42(1.19-1.67) Parents 1.41(1.11-1.74) Children 1.45(1.21-1.73) Cousin 1.17(1.11-1.24) Siblings 1.07(0.95-1.19) Nephews & nieces 1.09(0.95-1.24) Aunts & uncles 1.14(1.00-1.28)

31. Operated Aunts & uncles 1.34 (0.64-2.28) Index 488 Children 2.94 (1.60-4.68) parents 3.26(1.82-5.12) Grandparents 4.45 (1.45-9.08) Cousin 1.39 (1.05-1.76) Siblings 6.28 (5.51-7.11) Nephews & nieces 1.29 (0.64-2.18) Mates 0.00(0.00-1.49) Parents 0.61(0.03-3.01) Children 2.39(1.18-4.03) Cousin 0.99(0.69-1.34) Siblings 0.52(0.05-1.47) Nephews & nieces 1.49(0.84-2.31) Aunts & uncles 1.02(0.43-1.86)

32. Discussion Diverticular Disease both genetic and environmental. Diverticular Disease both genetic and environmental. Diverticulosis more environmental ? Diverticulosis more environmental ? Complicated diverticular disease more genetic ? Complicated diverticular disease more genetic ?