Diverticular Disease Genetics and correlation to cancer Tryggvi

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

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

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

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

Diverticulosis and CRC Low prevalens of Diverticulosis in populations with low risk for CRC and Polyps. n Lack of fiber in the diet causes diverticulosis. n Painter and Burkitt, BMJ, 1971 n 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

Diverticulosis and CRC n Diverticulosis increases in migrating populations when moving from low risk areas to high risk areas. Painter and Burkitt, BMJ, 1971 Stemmermann GN, Cancer, 1973 n 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

Diverticulosis and CRC n One small study on the association between nonsymptomatic 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

Symptomatic Diverticular Disease and CRC n Physical activity lowers the risk of symptomatic diverticular disease in men. WH Aldoori et al, Gut, 1995 n 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

Symptomatic Diverticular Disease and CRC n 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 n High intake of fat is associated with increased risk of CRC Howe et al, Ca Causes and Control, 1997

Symptomatic Diverticular Disease and CRC n 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 n High intake of red meat is associated with increased risk of CRC Potter JD, J Natl Ca Inst, 1999

Symptomatic Diverticular Disease and CRC n Uppsala Health Care Region 1965 -1983 n Total 7159 patients with diverticular disease n Men Women 2478 4681 n n <60 years 60 -69 years >70 years 1410 1665 4084

First year after the diagnosis Diverticular Disease n n n n n Site Colon Pancreas Prostate Stomach Blood Rectum Liver Ovary Lung Obs 57 33 30 27 20 16 14 13 10 SIR 8. 6 9. 0 3. 3 4. 2 3. 8 4. 4 3. 7 4. 1 2. 2 95% CI 6. 5 -11. 1 6. 2 -12. 6 2. 2 -4. 7 2. 7 -6. 0 2. 3 -5. 9 2. 5 -7. 2 2. 1 -6. 3 3. 2 -10. 3 1. 0 -4. 0 Stefánsson T et al, Eur J Surg, 1995

First year after the diagnosis Diverticular Disease All Colon obs SIR CI 57 8. 6 (6. 5 -11) Right Colon obs SIR CI 10 2. 9 (1. 4 -5. 4) Left Colon obs SIR CI 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

Symptomatic Diverticular Disease and CRC n 7159 patients with symptomatic diverticular disease 1965 -1983. Followed up untill 1985. The first two years excluded. Obs= Observed numbers of CRC. All Colon Right and Transv Desc and Sigm Rectum obs 43 16 21 22 SIR 1. 2 0. 9 1. 8 1. 1 95%CI (0. 9 -1. 6) (0. 5 -1. 4) (1. 1 -2. 7) (0. 7 -1. 7) Stefansson T et al, Gut, 1993

Symptomatic Diverticular Disease and CRC n 7159 patients with symptomatic diverticular disease 1965 -1983. Followed up untill 1991. The first two years excluded. n 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 n OR= 4. 2 (95% CI 1. 3 -13. 0) n Stefánsson T et al, Scand J Gastroenterol, 2004

Summary n Diverticulosis and Colon cancer Many things in common. No known association n Diverticular Disease and Colon Cancer The first year after diagnosis n Diverticular Disease and Colon Cancer The first two years excluded n RR= 18 in left colon RR=1. 8 in left colon Diverticulitis and Colon Cancer The first two years excluded OR=4 in left colon

Conclusion n Many similarities. n Cancer and diverticulosis: No known association. n Cancer and Diverticulitis Association.

Genetics and Diverticular Disease x

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

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

Diverticulosis n The incidence of diverticula can vary in ethnic groups within a given country. Singapore: Chinese : Europeans: 1, 4/100000/year 54, 1/100000/year Kyle J et al, Scand J Gastroent, 1967 Israel Ashkenazy Jews Sephardi Jews Arabs 1969 -74 16, 2% 3, 8% 0, 7% 1979 -84 17, 3% 12, 9% 5, 4% Levy N, Dis Colon Rectum, 1985

Diverticulosis n 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 n 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

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

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

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

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

Genetics of Diverticular Disease All n Operated 488 n Not Operated n 3065 2577

1°rel-5°rel n n n 1°relatives 2°relatives 3°relatives 4°relatives 5°relatives All RR (95% CI) 1. 77(1. 67 -1. 87) 1. 17(1. 09 -1. 27) 1. 17(1. 11 -1. 22) 1. 14(1. 10 -1. 19) 1. 05(1. 02 -1. 09) Operated RR (95% CI) 6. 02(5. 36 -6. 72) 1. 30(0. 82 -1. 39) 1. 38(1. 06 -1. 73) 1. 55(1. 32 -1. 79) 0. 93(0. 77 -1. 10) Not-op RR (95% CI) 1. 54(1. 42 -1. 65) 1. 09(0. 99 -1. 19) 1. 17(1. 11 -1. 24) 1. 18(1. 13 -1. 23) 1. 43(1. 17 -1. 72)

All Grandparents 1. 48 (0. 97 -2. 10) Aunts & uncles 1. 22 (1. 09 -1. 37) parents 2. 20(1. 92 -2. 50) Parents 1. 33(1. 08 -1. 61) Aunts & uncles 1. 12(1. 00 -1. 25) Cousin 1. 15(1. 09 -1. 21) Cousin 1. 18 (1. 12 -1. 25) Siblings 1. 60 (1. 49 -1. 71) Nephews & nieces 1. 14 (1. 02 -1. 28) Index 3065 Mates 1. 42(1. 19 -1. 67) Siblings 0. 99(0. 89 -1. 10) Children 1. 81 (1. 56 -2. 06) Children 1. 66(1. 44 -1. 89) Nephews & nieces 1. 06(0. 95 -1. 19)

Not Operated Grandparents 1. 45 (0. 82 -2. 26) Aunts & uncles 1. 13 (0. 97 -1. 30) parents 1. 96(1. 64 -2. 31) Parents 1. 41(1. 11 -1. 74) Aunts & uncles 1. 14(1. 00 -1. 28) Cousin 1. 17(1. 11 -1. 24) Cousin 1. 20 (1. 13 -1. 26) Siblings 1. 41 (1. 29 -1. 53) Nephews & nieces 1. 05 (1. 02 -1. 28) Index 2577 Mates 1. 42(1. 19 -1. 67) Siblings 1. 07(0. 95 -1. 19) Children 1. 56 (1. 28 -1. 87) Children 1. 45(1. 21 -1. 73) Nephews & nieces 1. 09(0. 95 -1. 24)

Operated Grandparents 4. 45 (1. 45 -9. 08) Aunts & uncles 1. 34 (0. 64 -2. 28) parents 3. 26(1. 82 -5. 12) Parents 0. 61(0. 03 -3. 01) Aunts & uncles 1. 02(0. 43 -1. 86) Cousin 0. 99(0. 69 -1. 34) Cousin 1. 39 (1. 05 -1. 76) Siblings 6. 28 (5. 51 -7. 11) Nephews & nieces 1. 29 (0. 64 -2. 18) Index 488 Mates 0. 00(0. 00 -1. 49) Siblings 0. 52(0. 05 -1. 47) Children 2. 94 (1. 60 -4. 68) Children 2. 39(1. 18 -4. 03) Nephews & nieces 1. 49(0. 84 -2. 31)

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