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Diverticular Disease Genetics and correlation to cancer

Diverticular Disease Genetics and correlation to cancer. Tryggvi Stefánsson Centrallasarettet in Västerås and Landspítali University Hospital Reykjavík/Iceland. Non-Symptomatic diverticular disease = Diverticulosis. Symptomatic diverticular disease = Diverticulosis + Diverticulitis

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Diverticular Disease Genetics and correlation to cancer

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

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

  3. Diverticular disease and CRC • Many similarities. • Cancer and diverticulosis: No known 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.

  5. Diverticulosis and CRC • Low prevalens of Diverticulosis in populations with low risk for CRC and Polyps. • 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 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. Painter and Burkitt, BMJ,1971 Stemmermann GN, Cancer, 1973 • 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 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 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 Aldoori WH et al, Am J Clin Nutr, 1994 • 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. Aldoori WH et al, Am J Clin Nutr, 1994 • 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 • Total 7159 patients with diverticular disease • Men 2478 • Women 4681 • <60 years 1410 • 60-69 years 1665 • >70 years 4084

  12. First year after the diagnosis Diverticular Disease Site Obs SIR 95% CI • Colon 57 8.6 6.5-11.1 • Pancreas 33 9.0 6.2-12.6 • Prostate 30 3.3 2.2-4.7 • Stomach 27 4.2 2.7-6.0 • Blood 20 3.8 2.3-5.9 • Rectum 16 4.4 2.5-7.2 • Liver 14 3.7 2.1-6.3 • Ovary 13 4.1 3.2-10.3 • Lung 10 2.2 1.0-4.0 Stefánsson T et al, Eur J Surg, 1995

  13. First year after the diagnosis Diverticular Disease All Colon Right Colon Left Colon obs SIR CI obs SIR CI obs 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. Obs= Observed numbers of CRC. obs SIR 95%CI All Colon 43 1.2 (0.9-1.6) Right and Transv 16 0.9 (0.5-1.4) Desc and Sigm 21 1.8 (1.1-2.7) Rectum 22 1.1 (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. • 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 • OR= 4.2 (95% CI 1.3-13.0) Stefánsson T et al, Scand J Gastroenterol, 2004

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

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

  18. Genetics and Diverticular Disease x

  19. Diverticulosis • 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 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 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. Singapore: Chinese : 1,4/100000/year Europeans: 54,1/100000/year Kyle J et al, Scand J Gastroent, 1967 Israel 1969-74 1979-84 Ashkenazy Jews 16,2% 17,3% Sephardi Jews 3,8% 12,9% Arabs 0,7% 5,4% Levy N, Dis Colon Rectum, 1985

  22. Diverticulosis • 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 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 Bode MK, Scand J Gastroenterol, 2000 Stumpf M, Int J Colorectal Dis, 2001

  24. Diverticulosis • 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. 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. • 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.

  27. Genetics of Diverticular Disease • All 3065 • Operated 488 • Not Operated 2577

  28. 1°rel-5°rel AllOperated Not-op RR (95% CI) RR (95% CI) RR (95% CI) • 1°relatives 1.77(1.67-1.87) 6.02(5.36-6.72) 1.54(1.42-1.65) • 2°relatives 1.17(1.09-1.27) 1.30(0.82-1.39) 1.09(0.99-1.19) • 3°relatives 1.17(1.11-1.22) 1.38(1.06-1.73) 1.17(1.11-1.24) • 4°relatives 1.14(1.10-1.19) 1.55(1.32-1.79) 1.18(1.13-1.23) • 5°relatives 1.05(1.02-1.09) 0.93(0.77-1.10) 1.43(1.17-1.72)

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

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

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

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

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