For personal use only. Reproduce with permission from The Lancet Publishing Group. Is colitis-associated colorectal cancer secondary to the inflammatory process? Or is there a common inherited susceptibility underlying both the inflammatory and the neoplastic process in patients with inflammatory bowel disease? If the latter explanation were correct, the prevalence of colorectal cancer would be expected to be increased among relatives of patients with inflammatory bowel disease. In today’s Lancet, Johan Askling and colleagues report that first-degree relatives of patients with this disease do not have an increased risk of colorectal cancer, but relatives of patients with the disease and colorectal cancer did. The researchers studied a large population-based cohort of patients with inflammatory bowel disease and identified over 100 000 first-degree relatives who were followed up for occurrence of cancer through linkage with Swedish national health registries. They stratified risk for colorectal cancer in relatives according to disease type, extent at diagnosis, and presence of colitis-associated cancer. Earlier studies had indicated similar results but had limited statistical power. The interpretation of the Swedish findings is clear; the findings do not support the idea of a genetic link between inflammation and neoplasia in the colon. Colitis and colorectal cancer are more likely to have a cause-and-effect relation, which implies that optimum anti-inflammatory therapy will provide effective cancer prevention. Indeed, there is evidence that regular treatment with amino- salicylates reduces the risk of colorectal cancer in patients with ulcerative colitis. 6 Molecular mechanisms of tumorigenesis secondary to chronic inflammation are emerging. The increased frequency of p53 mutant cells in chronic colitis has been linked to oxidative stress from reactive oxygen and nitrogen species generated during inflammation in non-dysplastic mucosal tissue. 7 Cytokines may also influence the p53 tumour-suppressor pathway. 8,9 For example, the pro- inflammatory cytokine, macrophage migration inhibitory factor, can functionally inactivate p53. 9 In inflamed tissue, this effect would create an anti-apoptosis feedback loop and limit responses of host cells to genetic damage and facilitate accumulation of oncogenic mutations. As the molecular details linking inflammatory and neoplastic pathways become clear, they promise not only improved strategies for cancer prevention, but also markers for early identification of patients at greatest risk of progression to cancer. 10 Finally, although colitis and cancer do not share a common genetic cause, environmental factors such as smoking and the enteric bacterial flora may contribute to the pathogenesis of both processes. Fergus Shanahan Department of Medicine, Cork University Hospital, Cork, Ireland (e-mail: fshanahan@ucc.ie) 1 Shanahan F, O’Sullivan GC, O’Leary C. Colorectal cancer: still a major killer despite progress on many fronts. Q J Med 2000; 93: 131–34. 2 Rhodes JM. Lectins, colitis and colon cancer. J R Coll Physicians Lond 2000; 34: 191–96. 3 Rhodes JM. Unifying hypothesis for inflammatory bowel disease and associated colon cancer: sticking the pieces together with sugar. Lancet 1996; 347: 40–44. 4 Itzkowitz SH, Greenwald B, Meltzer SJ. Colon carcinogenesis in inflammatory bowel disease. Inflamm Bowel Dis 1995; 1: 142–58. 5 Walsh S, Murphy M, Silverman M, et al. p27 expression in inflammatory bowel disease-associated neoplasia: further evidence of a unique molecular pathogenesis. Am J Pathol 1999; 155: 1511–18. 6 Eaden J, Abrams K, Ekbom A, Jackson E, Mayberry J. Colorectal cancer prevention in ulcerative colitis: a case control study. Aliment Pharmacol 2000; 14: 145–53. 7 Hussain SP, Amstad P, Raja K, et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 2000; 60: 3333–37. 3 Priest ND. The distribution and behaviour of metals in the skeleton and body: studies with bone seeking radionuclides. In: Priest ND, Van de Vyver F, eds. Trace metals and fluoride in bones and teeth. Boca Raton: CRC Press, 1990: 83–140. 4 Friberg L, Nordberg GF, Vouk VB. Handbook on the toxicology of metals, volume II. Elsevier: Amsterdam, 1986: 623–37. 5 Hodge HC, Stannard JN, Hursh JB. Handbook of experimental pharmacology, vol. 36, uranium, plutonium, transplutonic elements. New York: Springer-Verlag, 1973: 165–95. 6 Internationl Commission on Radiation Protection. Age-dependent doses to members of the public from intake of radionuclides: part 3. ICRP publication 69. Ann ICRP 1994; 25: 57–74. 7 Westlakes Research Institute, Cumbria. Press release, Jan 12, 2001. 8 Ellender M, Harrison JD, Pottinger H, Thomas JM. Induction of osteosarcoma and acute myeloid leukaemia in CBA/H mice by the alpha-emitting nuclides, uranium-233, plutonium-239 and americium- 241. Int J Radiat Biol 2001; 77: 41–52. 9 Polednak AP, Frome EL. Mortality among men employed between 1943 and 1947 at a uranium-processing plant. J Occup Med 1981; 23: 169–78. 10 McGeoghegan D, Spinks K. The mortality and cancer morbidity experience of workers at Springfields uranium production facility, 1946-95. J Radiol Protect 2000; 20: 111–37. 11 Checkoway H. Pearce N, Crawford-Brown DJ, Cragle DL. Radiation doses and cause-specific mortality among workers at a nuclear materials fabrication plant. Am J Epidemiol 1988; 127: 255–66. 12 Ritz B. Radiation exposure and cancer mortality in uranium processing workers. Epidemiology 1999; 10: 531–38. 246 THE LANCET • Vol 357 • January 27, 2001 COMMENTARY Relation between colitis and colon cancer See page 262 Genetic and environmental factors contribute to the pathogenesis of inflammatory bowel disease and colorectal cancer. 1,2 Since both Crohn’s colitis and ulcerative colitis are associated with an increased risk of colorectal cancer, it is reasonable to ask whether the inflammatory and cancer processes share a common cause. An inherited factor influencing glycosylation of mucin and other glycoproteins has been proposed as a link between both forms of inflammatory bowel disease and susceptibility to cancer, with environmental factors determining the phenotype (Crohn’s or ulcerative colitis) and progression to cancer. 3 This plausible hypothesis is supported by impressive but mainly circumstantial evidence. 2,3 Understanding the precise relation between inflammatory bowel disease and colorectal cancer is clinically important, because it may influence counselling, preventive strategies, screening for cancer and surveillance for dysplasia, and the timing of colectomy in patients with chronic colitis. In addition, there is a need for a reliable method to distinguish colitis- associated dysplasia from sporadic colorectal adenomas or cancers occurring coincidentally with colitis. Studies of molecular markers suggest divergent oncogenic pathways for colitis-associated and sporadic colorectal cancer. 4 Although most of the molecular alterations associated with sporadic colon cancer also occur in colitis-associated cancer, albeit with less frequency, there is a difference between the two pathways of carcinogenesis in the timing of molecular events. Alterations of the p53 tumour-suppressor gene appear relatively early and may precede dysplasia in patients with chronic colitis, but represent a late event in the molecular pathogenesis of sporadic colorectal carcinoma. By contrast, mutation or deletion of the APC tumour-suppressor gene tends to be late and uncommon in colitis-associated cancer, but is thought to be the earliest alteration in sporadic colon cancer. In addition, differences in expression of the p27 protein, which regulates the cell cycle, promotes epithelial differentiation, and protects the cell from inflammatory injury, have been cited as evidence for a distinct molecular pathogenesis for colitis-associated cancer. 5