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

Diverticular Diverticular DiseaseDisease

Genetics and correlation to cancerGenetics and correlation to cancerTryggvi StefánssonTryggvi Stefánsson

Centrallasarettet in VästeråsCentrallasarettet in Västeråsand and

Landspítali University HospitalLandspítali University HospitalReykjavík/IcelandReykjavík/Iceland

Diverticular diseaseDiverticular disease Non-Symptomatic Non-Symptomatic

diverticular diverticular diseasedisease

= Diverticulosis= Diverticulosis

Symptomatic Symptomatic diverticular diverticular diseasedisease

= Diverticulosis += Diverticulosis +DiverticulitisDiverticulitisHemorrageHemorrageMotility Motility

disordersdisorders

Diverticular disease and Diverticular disease and CRCCRC

Many similarities.Many similarities. Cancer and diverticulosis: Cancer and diverticulosis:

No known association.No known association. Cancer and symptomatic diverticular Cancer and symptomatic diverticular

disease: disease: Association.Association.

Diverticulosis and CRCDiverticulosis and CRC

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

Diverticulosis and CRCDiverticulosis and CRC Low prevalens of Diverticulosis in Low prevalens of Diverticulosis in

populations with low risk for CRC and populations with low risk for CRC and Polyps.Polyps.

Lack of fiber in the diet causes Lack of fiber in the diet causes diverticulosis.diverticulosis.Painter and Burkitt, BMJ,1971Painter and Burkitt, BMJ,1971

Fiber in the diet decreases the risk for Fiber in the diet decreases the risk for colon cancercolon cancer Howe GR et al, J Nat Ca Inst, 1992Howe GR et al, J Nat Ca Inst, 1992

Potter JD, Ca Causes and Control 1996Potter JD, Ca Causes and Control 1996

Diverticulosis and CRCDiverticulosis and CRC Diverticulosis increases in migrating Diverticulosis increases in migrating

populations when moving from low risk populations when moving from low risk areas to high risk areas.areas to high risk areas.Painter and Burkitt, BMJ,1971Painter and Burkitt, BMJ,1971Stemmermann GN, Cancer, 1973Stemmermann GN, Cancer, 1973

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

Diverticulosis and CRCDiverticulosis and CRC One small study on the association between One small study on the association between

non-symptomatic diverticular disease and CRCnon-symptomatic diverticular disease and CRC

119 cases with CRC119 cases with CRC40% of men had diverticulosis40% of men had diverticulosis39% of women had diverticulosis39% of women had diverticulosis

119 age-matched controls without CRC119 age-matched controls without CRC50% of men had diverticulosis50% of men had diverticulosis36% of women had diverticulosis36% of women had diverticulosis

There was no significant difference in number of There was no significant difference in number of patients with diverticulosis in the two groupspatients with diverticulosis in the two groupsMc Callum et al, Scand J Gastro, 1988Mc Callum et al, Scand J Gastro, 1988

Symptomatic Diverticular Symptomatic Diverticular Disease and CRCDisease and CRC

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


High intake of fat and low intake of High intake of fat and low intake of fiber is associated with increased fiber is associated with increased risk of Symptomatic Diverticular risk of Symptomatic Diverticular DiseaseDisease

Aldoori WH et al, Am J Clin Aldoori WH et al, Am J Clin Nutr, 1994Nutr, 1994

High intake of fat is associated with High intake of fat is associated with increased risk of CRCincreased risk of CRC

Howe et al, Ca Causes and Howe et al, Ca Causes and Control, 1997Control, 1997


High intake of red meat and low High intake of red meat and low intake of fiber is associated with intake of fiber is associated with increased risk of Symptomatic increased risk of Symptomatic Diverticular Disease.Diverticular Disease.

Aldoori WH et al, Am J Clin Aldoori WH et al, Am J Clin Nutr, 1994Nutr, 1994

High intake of red meat is associated High intake of red meat is associated with increased risk of CRCwith increased risk of CRC

Potter JD, J Natl Ca Inst, 1999Potter JD, J Natl Ca Inst, 1999


Uppsala Health Care Region 1965-1983Uppsala Health Care Region 1965-1983

TotalTotal 7159 patients with diverticular 7159 patients with diverticular diseasedisease

MenMen 24782478 WomenWomen 46814681

<60 years<60 years 14101410 60-69 years60-69 years 16651665 >70 years>70 years 40844084

First year First year after the diagnosis Diverticular after the diagnosis Diverticular

DiseaseDisease SiteSite ObsObs SIRSIR 95% CI95% CI

ColonColon5757 8.68.6 6.5-11.16.5-11.1 PancreasPancreas 3333 9.09.0 6.2-12.66.2-12.6 ProstateProstate 3030 3.33.3 2.2-4.72.2-4.7 StomachStomach 2727 4.24.2 2.7-6.02.7-6.0 BloodBlood2020 3.83.8 2.3-5.92.3-5.9 RectumRectum 1616 4.44.4 2.5-7.22.5-7.2 LiverLiver 1414 3.73.7 2.1-6.32.1-6.3 OvaryOvary 1313 4.14.1 3.2-10.33.2-10.3 LungLung 1010 2.22.2 1.0-4.01.0-4.0

Stefánsson T et al, Eur J Surg, 1995Stefánsson T et al, Eur J Surg, 1995

First year First year after the diagnosis Diverticular after the diagnosis Diverticular

DiseaseDisease

All ColonAll Colon Right ColonRight Colon Left ColonLeft Colonobs SIR CIobs SIR CI obs SIR CIobs SIR CI obs SIR CIobs SIR CI57 8.6 (6.5-11)57 8.6 (6.5-11) 10 2.9 (1.4-5.4)10 2.9 (1.4-5.4) 41 41 17.817.8 (8-14.1)(8-14.1)

During 2 years after the diagnosis symptomatic DD During 2 years after the diagnosis symptomatic DD there were 75 colon cancers among 7159 Sympt DD there were 75 colon cancers among 7159 Sympt DD patientspatients 1/100 1/100

FOBT screening in average risk>50 yearsFOBT screening in average risk>50 years 1/300 1/300

Stefánsson T et al, Eur J Surg, 1995Stefánsson T et al, Eur J Surg, 1995


7159 patients with symptomatic diverticular 7159 patients with symptomatic diverticular disease 1965-1983. Followed up untill 1985. The disease 1965-1983. Followed up untill 1985. The first two years excluded. first two years excluded. Obs= Observed numbers of CRC.Obs= Observed numbers of CRC.obsobs SIRSIR 95%CI95%CIAll ColonAll Colon 4343 1.21.2 (0.9-1.6)(0.9-1.6)Right and TransvRight and Transv 1616 0.90.9 (0.5-1.4)(0.5-1.4)Desc and SigmDesc and Sigm 2121 1.81.8 (1.1-2.7)(1.1-2.7)RectumRectum 2222 1.1 1.1 (0.7-1.7)(0.7-1.7)

Stefansson T et al, Gut, 1993Stefansson T et al, Gut, 1993


7159 patients with symptomatic diverticular disease 7159 patients with symptomatic diverticular disease 1965-1983. Followed up untill 1991. The first two 1965-1983. Followed up untill 1991. The first two years excluded. years excluded.

A nested case control studyA nested case control study64 cases of colon cancer x 123 controls, 64 cases of colon cancer x 123 controls, matched by age, sex and year of dischargematched by age, sex and year of discharge

Patients with sigmoid Patients with sigmoid diverticulitisdiverticulitis had had four-fold risk of colon cancer compared four-fold risk of colon cancer compared to those with only diverticulosisto those with only diverticulosis

OR= OR= 4.24.2 (95% CI 1.3-13.0) (95% CI 1.3-13.0)Stefánsson T et al, Scand J Gastroenterol, 2004Stefánsson T et al, Scand J Gastroenterol, 2004

SummarySummary Diverticulosis and Colon cancerDiverticulosis and Colon cancer

Many things in common. No known associationMany things in common. No known association Diverticular Disease and Colon CancerDiverticular Disease and Colon Cancer

The first year after diagnosis The first year after diagnosis RR= 18 in left colonRR= 18 in left colon Diverticular Disease and Colon CancerDiverticular Disease and Colon Cancer

The first two years excluded The first two years excluded RR=1.8 in left colonRR=1.8 in left colon Diverticulitis and Colon CancerDiverticulitis and Colon Cancer

The first two years excluded The first two years excluded OR=4 in left colonOR=4 in left colon

ConclusionConclusion Many similarities.Many similarities. Cancer and diverticulosis: Cancer and diverticulosis:

No known No known association.association.

Cancer and DiverticulitisCancer and DiverticulitisAssociation.Association.

Genetics and Genetics and Diverticular Diverticular

DiseaseDiseasexx

DiverticulosisDiverticulosis In European and US populationsIn European and US populations

Distal Colon Distal Colon 90% with sigmoidal involvement90% with sigmoidal involvement15% in right colon15% in right colonParks TG, Clin Gastroenterol, 1975Parks TG, Clin Gastroenterol, 1975Hughes LE, Gut, 1969Hughes LE, Gut, 1969

In Asian populationsIn Asian populationsRight sided involvement of DiverticulaRight sided involvement of DiverticulaLee YS, Dis Colon Rectum, 1986Lee YS, Dis Colon Rectum, 1986Chia JG, Dis Colon Rectum, 1991Chia JG, Dis Colon Rectum, 1991

DiverticulosisDiverticulosis Prevalence is high in Europe, USA Prevalence is high in Europe, USA

and Australiaand Australiabut low in rural Africa and Asia.but low in rural Africa and Asia.

Painter NS and Burkitt DP, BMJ, Painter NS and Burkitt DP, BMJ, 19711971

DiverticulosisDiverticulosis The incidence of diverticula can vary in ethnic The incidence of diverticula can vary in ethnic

groups within a given country.groups within a given country.

Singapore:Singapore:Chinese :Chinese : 1,4/100000/year1,4/100000/yearEuropeans:Europeans: 54,1/100000/year54,1/100000/year

Kyle J et al, Scand J Gastroent, 1967Kyle J et al, Scand J Gastroent, 1967

IsraelIsrael1969-741969-74 1979-841979-84

Ashkenazy JewsAshkenazy Jews 16,2%16,2% 17,3%17,3%Sephardi JewsSephardi Jews 3,8%3,8% 12,9%12,9%ArabsArabs 0,7%0,7% 5,4%5,4%

Levy N, Dis Colon Rectum, 1985Levy N, Dis Colon Rectum, 1985

DiverticulosisDiverticulosis Smooth Muscle AbnormalitySmooth Muscle Abnormality

Taenia Coli Appear thick with a cartilagenous Taenia Coli Appear thick with a cartilagenous consistencyconsistencyThe circular musle is thickThe circular musle is thickCorrugated concertina like appearanceCorrugated concertina like appearanceMorson BC, Proceedings of the Royal Society of Medicine 1963Morson BC, Proceedings of the Royal Society of Medicine 1963

Elastin DepositionsElastin Depositions The diverticular colonic wall contains normal The diverticular colonic wall contains normal muscle cells, but muscle cells in the taenia coli muscle cells, but muscle cells in the taenia coli contains 200% more elastin compared with those contains 200% more elastin compared with those without diverticula.without diverticula.Whiteway J, Morson BC, Gut, 1985Whiteway J, Morson BC, Gut, 1985

DiverticulosisDiverticulosis Increase in type III collagen Increase in type III collagen

synthesissynthesisBode MK, Scand J Gastroenterol, 2000Bode MK, Scand J Gastroenterol, 2000Stumpf M, Int J Colorectal Dis, 2001Stumpf M, Int J Colorectal Dis, 2001

DiverticulosisDiverticulosis Increased Diverticulosis in Marfans Increased Diverticulosis in Marfans

and Ehler Danlos syndromesand Ehler Danlos syndromesSimpson J, Br J Surg, 2002Simpson J, Br J Surg, 2002

DiverticulosisDiverticulosis Interstitial cells of Cajal and Glial Interstitial cells of Cajal and Glial

cells are significantly reduced in cells are significantly reduced in Colonic Diverticular Disease.Colonic Diverticular Disease.

Bassotti G et al, Journal of Clinical Bassotti G et al, Journal of Clinical Pathology, 2005Pathology, 2005

Genetics of Diverticular Genetics of Diverticular DiseaseDisease

Discharged from hospital in Iceland Discharged from hospital in Iceland 1985-2000 with the diagnosis 1985-2000 with the diagnosis Diverticular disease.Diverticular disease.

Genealogy register at deCode in Genealogy register at deCode in Reykjavík containing all Icelanders Reykjavík containing all Icelanders living in Iceland from the settlement of living in Iceland from the settlement of the island.the island.

RR of relatives, mates and relatives of RR of relatives, mates and relatives of mates of being in the discharged group.mates of being in the discharged group.

Genetics of Diverticular Genetics of Diverticular DiseaseDisease

AllAll 30653065 OperatedOperated 488488 Not OperatedNot Operated 25772577

1°rel-5°rel1°rel-5°relAllAll OperatedOperated Not-opNot-opRR (95% CI)RR (95% CI) RR (95% CI) RR (95% CI) RR (95% CI)RR (95% CI)

1°relatives1°relatives 1.77(1.67-1.87)1.77(1.67-1.87) 6.02(5.36-6.72) 6.02(5.36-6.72)1.54(1.42-1.65)1.54(1.42-1.65)





AllAll

Aunts & uncles1.22 (1.09-1.37)

Index3065

Children1.81 (1.56-2.06)

parents2.20(1.92-2.50)

Grandparents1.48 (0.97-2.10)

Cousin1.18 (1.12-1.25)

Siblings1.60 (1.49-1.71)

Nephews & nieces1.14 (1.02-1.28)

Mates1.42(1.19-1.67)

Parents1.33(1.08-1.61)

Children1.66(1.44-1.89)

Cousin1.15(1.09-1.21)

Siblings0.99(0.89-1.10)

Nephews & nieces1.06(0.95-1.19)

Aunts & uncles1.12(1.00-1.25)

Not OperatedNot Operated

Aunts & uncles1.13 (0.97-1.30)

Index2577

Children1.56 (1.28-1.87)

parents1.96(1.64-2.31)


Cousin1.20 (1.13-1.26)

Siblings1.41 (1.29-1.53)


Mates1.42(1.19-1.67)

Parents1.41(1.11-1.74)

Children1.45(1.21-1.73)

Cousin1.17(1.11-1.24)

Siblings1.07(0.95-1.19)


Aunts & uncles1.14(1.00-1.28)

OperatedOperated

Aunts & uncles1.34 (0.64-2.28)

Index488

Children2.94 (1.60-4.68)

parents3.26(1.82-5.12)


Cousin1.39 (1.05-1.76)

Siblings6.28 (5.51-7.11)


Mates0.00(0.00-1.49)

Parents0.61(0.03-3.01)

Children2.39(1.18-4.03)

Cousin0.99(0.69-1.34)

Siblings0.52(0.05-1.47)


Aunts & uncles1.02(0.43-1.86)

DiscussionDiscussion

Diverticular Disease both genetic Diverticular Disease both genetic and environmental.and environmental.

Diverticulosis more environmental ?Diverticulosis more environmental ? Complicated diverticular disease Complicated diverticular disease

more genetic ?more genetic ?

Documents

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