Selective COX-2 inhibition affects fatty acids, but not COX mRNA expression in patients with FAP.

Familial adenomatous polyposis (FAP) provides a model for sporadic colorectal cancer development. Cyclooxygenase (COX) inhibition may ameliorate polyp development, but rofecoxib was withdrawn due to cardiovascular side effects. Although this selective COX-2 inhibitor, like diet, may alter the fatty acid and eicosanoid pattern, data on the potential alteration in tissues after use, are scarce. The aims were to study if rofecoxib might influence the fatty acid distribution in serum phospholipids and duodenal lesions, mRNA for COX-1 and COX-2 in leucocytes and duodenal lesions, and finally plasma levels of PGE(2) in a randomized, double-blind, placebo controlled study (n = 38). Significant reductions were found for essential fatty acid index both in serum phospholipids (P = 0.01, 95% CI = -0.9; -0.1), and in duodenal lesions (P = 0.04, 95 CI % = -0.9; -0.1) after treatment. No treatment effects were found on the COX mRNA expression, or in the plasma PGE(2) levels. Dietary AA/EPA ratio was inversely associated with all the indicators of EFA status (all P < 0.01). These findings suggest that the effects of COX chemoprevention should be further investigated in FAP and that dietary needs should be included in the treatment of FAP.

Widespread but not localized neoplasia in inflammatory bowel disease worsens the prognosis of colorectal cancer.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC). Recently, new phenotypes of CRC in IBD have been suggested. Studies of the prognosis of CRC in IBD have shown conflicting results. The aim of the study was to analyze factors for prognosis in CRC-IBD, including the impact of the new phenotypes. METHODS: By using the nationwide, population-based Cancer Registry of Norway, we compared survival of a CRC-IBD cohort with CRC in the background population (all-CRC), adjusting for the topographical distribution of dysplasia at cancer diagnosis (widespread versus localized neoplasia in IBD) and other factors. We also analyzed prognostic factors within CRC-IBD. RESULTS: The mean age at CRC diagnosis was 43 years in widespread, 52 years in localized neoplasia IBD, and 70 years in all-CRC (P < 0.05). Adjusted for cofactors, prognosis of CRC-IBD was poorer compared to all-CRC (mortality rate ratio [MRR] 3.71, 95% confidence interval [CI]: 2.54-5.42, P < 0.001). Prognosis of widespread neoplasia IBD was poorer compared to all-CRC (MRR 4.27, 95% CI: 2.83-6.44, P < 0.001) and compared to localized neoplasia IBD (MRR 3.58, 95% CI: 0.87-14.72, P = 0.076). Survival was not significantly different between localized neoplasia IBD and all-CRC (P = 0.132). CONCLUSIONS: The results demonstrate lower age and poorer survival of CRC in IBD compared to CRC in the background population. The unfavorable effect of IBD on prognosis of CRC was pronounced in widespread neoplasia IBD. The diagnosis of this phenotype seems to be an important prognostic sign in patients with CRC in IBD.

APC mutation spectrum of Norwegian familial adenomatous polyposis families: high ratio of novel mutations.

INTRODUCTION: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease caused by mutations in the adenomatous polyposis coli (APC) gene. Massive formation of colorectal adenomas, of which some will inevitably develop into adenocarcinomas, is the hallmark of the disease. Characterization of causative APC mutations allows presymptomatic diagnosis, close follow-up and prophylactic intervention in families. To date more than 900 different germline mutations have been characterized worldwide demonstrating allelic heterogeneity. PURPOSE: The germline mutation spectrum of APC identified in 69 apparently unrelated Norwegian FAP families are presented and discussed with reference to clinical phenotype and novel mutation rate. METHODS: Different methods have been used over the years. However, all mutations were confirmed detectable by an implemented denaturing high-performance liquid chromatography screening approach. Multiplex ligation-dependent probe amplification analysis was employed for potential gross rearrangements. RESULTS: Fifty-three distinctive mutations were detected, of which 22 have been detected in Norway exclusively. Except for two major deletion mutations encompassing the entire APC, all mutations resulted in premature truncation of translation caused by non-sense (31%) or change in reading frame (69%). CONCLUSION: A high ratio of novel APC mutations continues to contribute to APC mutation heterogeneity causing FAP. This is the first comprehensive report of APC germline mutation spectrum in Norway.

Two distinct groups of colorectal cancer in inflammatory bowel disease.

BACKGROUND: The histological variability in colitis-associated colorectal cancer (CRC in inflammatory bowel disease [IBD]) and the association to clinical factors is unknown. METHODS: In population-based material including 67 patients with CRC in IBD, histopathology of the cancers and tissue samples from different colorectal localizations were reevaluated, and relationships to clinical factors analyzed. RESULTS: Forty-three of 60 patients (75%) showed dysplasia in the colorectum apart from the cancer, while 17 (25%) had no dysplasia at cancer diagnosis. Mean age at onset of IBD was 22 years in patients with and 34 years in patients without dysplasia (P = 0.01). The mean duration of colitis-CRC interval was 21 years in patients with and 16 years in patients without dysplasia (P = 0.02). The latter group included all patients with a colitis-CRC interval <10 years. Active inflammation was more likely to occur in patients with dysplasia (odds ratio [OR] 4.2). The 2 groups were not discriminated by gender, family history of CRC or IBD, diagnosis of PSC, medical treatment, active symptoms, or histological features like type of cancer and differentiation. In multiple logistic regression analysis the age at onset of IBD was the strongest predictive variable for dysplasia at cancer diagnosis (P = 0.025). CONCLUSIONS: Widespread neoplasia occurs in the majority of cases with CRC in IBD and is associated with early onset of IBD. Localized neoplasia occurs in about a quarter of the patients and shows an association with late-onset IBD. The 2 groups probably represent different pathogenetic entities of neoplasia in IBD. This might have consequences for surveillance strategies.

Relationship between clinical parameters and the colitis-colorectal cancer interval in a cohort of patients with colorectal cancer in inflammatory bowel disease.

OBJECTIVE: Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC), but more knowledge is needed about the possible relationship between clinical parameters and the time to development of cancer in IBD. The aim of the study was to determine the variability of the colitis-CRC interval and to analyze the association with clinical variables in an attempt to gain information on predictive factors of time to cancer within a relatively large cohort of CRC patients. MATERIAL AND METHODS: Patients diagnosed with IBD prior to 1 May 2005 at three university hospitals in Oslo were matched against the CRC files at the Cancer Registry of Norway. Only histological re-confirmed IBD and adenocarcinoma of the colorectum were included. RESULTS: Sixty-one patients with CRC in ulcerative colitis and 6 in Crohn's disease, including 13 CRC in primary sclerosing cholangitis (PSC), covering a follow-up of 1625 patient years,were identified. The median time from diagnosis of IBD to CRC was 17 years. Seven of 58 patients (12%) developed CRC within 10 years from onset of IBD symptoms and 14/67 (21%) within 10 years after the diagnosis of IBD. The colitis-CRC interval decreased by a factor of 0.154 (p = 0.018) when age at onset of IBD increased by one year. Mean age at onset of IBD was 30 years in patients with Dukes' stage C or D compared with 20 years in Dukes' stage A or B patients (p = 0.017). The colitis-CRC interval decreased by a factor of 0.138 (p = 0.003) when the percentage of the colitis-CRC interval with active symptoms increased by 1%. Patients with PSC were significantly younger at onset of IBD symptoms (PSC: 19 years versus no PSC:29 years, p = 0.04), but the colitis-CRC interval was similar to IBD without PSC (17 years versus 20 years, p = 0.236). Mean duration of the colitis-CRC interval was not related to family history or drug consumption prior to CRC. CONCLUSIONS: In the present cohort, for whom the median time from diagnosis of IBD to CRC was 17 years, 21% of the cancers developed before 10 years of disease, which is before colonoscopic screening is usually recommended. High age at onset of IBD may be related to a more aggressive development of CRC in IBD and early inclusion in screening programs might be considered for this group of patients. Symptom activity but not the diagnosis of PSC, family history of CRC or IBD or drug treatment seems to have an effect on the colitis-CRC interval.

Familial adenomatous polyposis patients have high levels of arachidonic acid and docosahexaenoic acid and low levels of linoleic acid and alpha-linolenic acid in serum phospholipids.

Familial adenomatous polyposis (FAP) provides a model of APC inactivation as an early genetic event for the approximately 85% of colorectal cancers that develop from polyps. Abnormal fatty acid composition of tissues and serum phospholipids has been linked to cancer risk. Our aim was to describe the composition of fatty acids in serum phospholipids in 38 colectomized FAP patients as compared to 160 healthy subjects. Mean fatty acid intakes were similar between the groups. Colectomy was done on average 16 years prior to inclusion, and 18% were diagnosed with colorectal cancer at colectomy. The levels (weight %) of linoleic and alpha-linolenic acid were higher among the reference subjects (difference: 3.96, 95% confidence interval (CI) = 2.87, 5.04, and difference: 0.06, 95% CI = 0.04, 0.08, respectively), and the levels of arachidonic and docosahexaenoic acid were lower (difference: -3.70, 95% CI = -4.35, -3.06, and difference: -5.26, 95% CI = -6.25, -4.28, respectively) as compared to the FAP patients (all p < or = 0.0001). The abnormal fatty acid composition was not related to time since colectomy, intestinal reconstruction or history of colorectal cancer for any of the fatty acids assessed. Compositional differences in the fatty acid profile of serum phospholipids have not been described before in FAP patients. Further studies are needed to confirm these findings and assess clinical significances of a possible distorted fatty acid metabolism, including a potentially different dietary need of essential fatty acids. The relevance of these findings for APC induced cancers remains unclear.