Getting rid of the PMS2 pseudogenes: mission impossible?
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Adenosine Triphosphatases↗
Biomedical subjects
Jan H Kleibeuker
Publications and source records attributed to Jan H Kleibeuker.
Prognostic significance of tumor necrosis factor-related apoptosis-inducing ligand and its receptors in adjuvantly treated stage III colon cancer patients.
PURPOSE: In preclinical models, there is synergism between chemotherapy and recombinant human tumor necrosis factor (TNF) -related apoptosis-inducing ligand (TRAIL) on apoptosis induction in tumor cells. Therefore, the prognostic relevance was analyzed of the expression of TRAIL and its death receptors DR4 and DR5 on disease-free survival and overall survival in stage III colon cancer patients treated with adjuvant chemotherapy. METHODS: Tissue microarrays were constructed of primary tumor tissue from 376 stage III colon cancer patients treated in a randomized adjuvant chemotherapy study (fluorouracil/levamisole v fluorouracil/levamisole/leucovorin) and stained immunohistochemically for TRAIL, DR4, and DR5. Log-rank tests and Cox proportional hazard analysis, with adjustment for treatment arm, sex, age, N stage, microsatellite instability status, and p53 mutation status, were performed. RESULTS: The majority of tumors showed high expression of TRAIL (83%), DR4 (92%), and DR5 (87%). Median follow-up was 43 months. High DR4 expression was associated with worse disease-free survival (odds ratio [OR] = 2.19; 95% CI, 1.06 to 4.53; P = .03), worse overall survival (OR = 2.22; 95% CI,1.03 to 4.81; P = .04) and shorter time to recurrence (P = .02) compared with those with low DR4 expression. TRAIL or DR5 expression had no prognostic value. CONCLUSION: High DR4 expression is associated with worse disease-free and overall survival in stage III adjuvant-treated colon cancer patients. Evaluation of DR4 expression in stage III colon cancer patients may identify a subset requiring more aggressive adjuvant treatment.
Adult↗
TRAIL induces apoptosis in human colorectal adenoma cell lines and human colorectal adenomas.
PURPOSE: Recombinant human (rh) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential new anticancer drug which can induce apoptosis in colorectal cancer cell lines. The aim of this study was to investigate whether it is possible to induce apoptosis in human adenoma cell lines and human adenomas using rhTRAIL. EXPERIMENTAL DESIGN: Two human adenoma cell lines were exposed to 0.1 microg/mL of rhTRAIL for 5 hours. Apoptosis and caspase activation in cell lines were evaluated using immunocytochemistry, fluorimetric caspase assays, and Western blotting. Short-term explant cultures were established from freshly removed human adenomas (n = 38) and biopsies of normal colon epithelium (n = 15), and these were incubated for 5 hours in the presence or absence of 1 microg/mL of rhTRAIL. Apoptosis was determined in paraffin-embedded tissue using morphologic criteria and cleaved caspase-3 staining. RESULTS: In the adenoma cell lines, rhTRAIL induced up to 55% apoptosis. This coincided with caspase-8 and caspase-3 activation and could be inhibited by a pan-caspase inhibitor. rhTRAIL induced caspase-dependent apoptosis in adenomas with high-grade dysplasia (n = 21) compared with the paired untreated counterparts (apoptotic index, 34 +/- 5% versus 17 +/- 2%, mean +/- SE; P = 0.002), but not in adenomas with low-grade dysplasia (n = 17) or in normal colon epithelium (n = 15). CONCLUSIONS: Colorectal adenoma cell lines and adenomas with high-grade dysplasia are sensitive to rhTRAIL-induced apoptosis, whereas normal colon epithelium is not. This suggests the potential application of rhTRAIL in the treatment of adenomas with high-grade dysplasia.
Adenoma↗
MUTYH and the mismatch repair system: partners in crime?
Biallelic germline mutations of MUTYH-a gene encoding a base excision repair protein-are associated with an increased susceptibility of colorectal cancer. Whether monoallelic MUTYH mutations also increase cancer risk is not yet clear, although there is some evidence suggesting a slight increase of risk. As the MUTYH protein interacts with the mismatch repair (MMR) system, we hypothesised that the combination of a monoallelic MUTYH mutation with an MMR gene mutation increases cancer risk. We therefore investigated the prevalence of monoallelic MUTYH mutations in carriers of a germline MMR mutation: 40 carriers of a truncating mutation (group I) and 36 of a missense mutation (group II). These patients had been diagnosed with either colorectal or endometrial cancer. We compared their MUTYH mutation frequencies with those observed in a group of 134 Dutch colorectal and endometrial cancer patients without an MMR gene mutation (0.7%) and those reported for Caucasian controls (1.5%). In group I one monoallelic MUTYH mutation was found (2.5%). In group II five monoallelic germline MUTYH mutations were found (14%), four of them in MSH6 missense mutation carriers (20%). Of all patients with an MMR gene mutation, only those with a missense mutation showed a significantly higher frequency of (monoallelic) MUTYH mutations than the Dutch cancer patients without MMR gene mutations (P = 0.002) and the published controls (P = 0.001). These results warrant further study to test the hypothesis of mutations in MMR genes (in particular MSH6) and MUTYH acting together to increase cancer risk.
Adaptor Proteins, Signal Transducing↗
Anastomotic biliary strictures after liver transplantation: causes and consequences.
We retrospectively studied the prevalence, presentation, results of treatment, and graft and patient survival of grafts developing an anastomotic biliary stricture (AS) in 531 adult liver transplantations performed between 1979 and 2003. Clinical and laboratory information was obtained from the hospital files, and radiological studies were re-evaluated. Twenty-one possible risk factors for the development of AS (variables of donor, recipient, surgical procedure, and postoperative course) were analyzed in a univariate and stepwise multivariate model. Forty-seven grafts showed an anastomotic stricture: 42 in duct-to-duct anastomoses, and 5 in hepaticojejunal Roux-en-Y anastomoses. The cumulative risk of AS after 1, 5, and 10 years was 6.6%, 10.6%, and 12.3% respectively. Postoperative bile leakage (P = 0.001), a female donor/male recipient combination (P = 0.010), and the era of transplantation (P = 0.006) were independent risk factors for the development of an AS. In 47% of cases, additional (radiologically minor) nonanastomotic strictures were diagnosed. All patients were successfully treated by 1 or more treatment modalities. As primary treatment, endoscopic retrograde cholangiopancreaticography (ERCP) was successful in 24 of 36 (67%) cases and percutaneous transhepatic cholangiodrainage in 4 of 11 (36%). In the end 15 patients (32%) were operated, all with long-term success. AS presenting more than 6 months after transplantation needed more episodes of stenting by ERCP, and more stents per episode compared to those presenting within 6 months and recurred more often. Graft and patient survival were not impaired by AS.
Adolescent↗
Decrease in mortality in Lynch syndrome families because of surveillance.
BACKGROUND & AIMS: Lynch syndrome family members have a high risk of developing colorectal (CRC), endometrial (EC), and other cancers. A large-scale surveillance program was introduced in The Netherlands in the late 1980s. The aims of the study were to evaluate the effectiveness of this program by assessing mortality because of CRC and EC before and after 1990 and to compare mortality because of all cancers (except CRC/EC) with mortality in the general population. METHODS: Family members with at least 50% probability of being a carrier were selected for the study. The standardized mortality ratio (SMR) because of cancer and the absolute excess risk of death (AER) were calculated. RESULTS: In the total cohort (N = 2788), 445 subjects had died because of cancer. The 3 most frequent causes of cancer-related deaths were CRC (50.3%), EC (6.7%), and brain tumors (6.7%). A significant decrease (70%) in SMR for CRC over time was observed (P < .001); the SMR for EC showed no decreasing trend over time. A significantly increased SMR was found for cancer of the small bowel (SMR = 18.3), brain (SMR = 9.1), kidney/ureter (SMR = 5.9), ovarium (SMR = 2.3), pancreas (SMR = 2.2), and stomach (SMR = 2.1). The AER was significantly increased for brain tumors only. CONCLUSIONS: Since the introduction of surveillance, the mortality because of CRC has decreased. Except for brain tumors, we did not find a significantly increased AER for tumors other than CRC/EC.
Adult↗
Inflammatory bowel disease after liver transplantation: a role for cytomegalovirus infection.
OBJECTIVE: Despite the use of immunosuppressive drugs, recurrent and de novo inflammatory bowel disease (IBD) can develop after orthotopic liver transplantation (OLT). Cytomegalovirus (CMV) infection has been suggested to play a role in the pathogenesis of IBD. The aim of this study was to investigate the role of CMV infection in the development of IBD after OLT. MATERIAL AND METHODS: All 84 patients who underwent transplantation for primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) in our center between May 1987 and June 2002 and who survived the first year after transplantation were included in the study. Diagnosis of active CMV infection was made using the pp65-antigenemia assay. RESULTS: Thirty-one of the 84 patients (37%) had IBD prior to OLT. Eighteen patients (21%) experienced IBD after OLT, either as flare-up (n=12) or de novo (n=6), at a median of 1.4 years (range 0.3 to 6.3) after OLT. Forty-eight percent of all patients experienced CMV infection after OLT, at a median of 27 days (range 8 to 193). CMV infection was primary in half the patients. At 1, 3, and 5 years after OLT, active IBD-free survival without CMV infection was 91, 88, and 88%, respectively. With CMV infection these figures were 93, 82, and 67%. De novo IBD was seen only in those who had experienced a CMV infection (p=0.02). CONCLUSIONS: In patients transplanted for end-stage PSC or AIH, active IBD, especially de novo IBD, occurred more often in patients who experienced CMV infection in the postoperative period. This finding supports a pathogenic role for CMV in the development of IBD.
Adolescent↗
Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease.
OBJECTIVE: The multidrug resistance (MDR1) gene encodes for P-glycoprotein, a drug efflux pump. Mice deficient for the MDR1a gene spontaneously develop colitis. In humans, a polymorphism in exon 26 (C3435T) is associated with reduced expression levels and function of MDR1. Currently there are controversial data on the association between MDR1 and inflammatory bowel disease (IBD). The purpose of this study was to examine the involvement of this gene in IBD in a large population of Dutch patients with IBD and family-based controls. MATERIAL AND METHODS: A total of 781 IBD cases and 315 controls were investigated. CD phenotypes were determined according to the Vienna Classification. Individuals were genotyped for six single nucleotide polymorphisms (SNPs) close to and in the MDR1 locus. This included the C3435T variant and six microsatellite markers close to and in the MDR1 locus. Single locus association analysis, haplotype association analysis and haplotype sharing statistic (HSS) were used to search for differences between patients and controls. RESULTS: No association was observed for any of the SNPs with IBD as a group, or for ulcerative colitis, Crohn's disease and Crohn's disease phenotypes, either by single locus or haplotype association analysis or by HSS. CONCLUSIONS: No association was observed between the MDR1 gene and IBD. This suggests that it is unlikely that MDR1 plays a role in IBD susceptibility.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Clinical outcome of Crohn's disease according to the Vienna classification: disease location is a useful predictor of disease course.
OBJECTIVES: Crohn's disease (CD) is a complex genetic disease with multiple clinical patterns. Clinical classifications may help to identify subgroups of patients that have a distinct pattern of disease, and they are also a prerequisite for the conduction of genetic and therapeutic studies. The aim of this study was to determine the usefulness of the Vienna classification in patient care and clinical studies. METHODS: The clinical data of patients were carefully reviewed retrospectively. The behaviour and location of the disease were determined according to the Vienna classification and additional clinical characteristics including surgical data, vitamin B12 status and medication were also assessed. RESULTS: Data according to the Vienna classification of 292 CD cases were available. The mean age at diagnosis was 31.4 years. The operation rate was higher in patients with ileocolonic localization (P<0.05) and stricturing and penetrating disease behaviour (P<0.001). The incidence of vitamin B12 deficiency was 41.9% in cases with ileal involvement and 20.7% in cases with disease confined to the colon. In 187 cases (64.0%) an operation was performed because of CD-related complications, in a majority (126, 67.4%) this took place within 5 years after diagnosis. Intolerance of azathioprine occurred in 36 cases (22.0%). CONCLUSIONS: Ileocolonic disease localization is associated with a complicated course of disease. Vitamin B12 deficiency occurs frequently, also in patients with disease apparently confined to the colon. We propose that location parameters can be used for the prediction of disease course in clinical settings and in interventional studies.
Adolescent↗
BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes.
Recently, it was shown that the oncogenic activation of BRAF, a member of the RAS/RAF family of kinases, by the V600E mutation is characteristic for sporadic colon tumors with microsatellite instability. Further, it was shown to associate with the silencing of the mismatch repair (MMR) gene MLH1 by hypermethylation. Moreover, BRAF mutations proved to be absent in tumors from hereditary nonpolyposis colorectal cancer syndrome (HNPCC) families with germline mutations in the MMR genes MLH1 and MSH2. These data suggest that the oncogenic activation of BRAF is involved only in sporadic colorectal tumorigenesis. In order to further support this hypothesis, we have extended the analysis of the BRAF gene to a different subset of HNPCC families without germline mutations in MLH1 and MSH2. BRAF-V600E mutations were analysed by automatic sequencing in 38 tumors from HNPCC families with germline mutations in the MSH6 gene and also in HNPCC (suspected) families that do not have mutations in the MMR genes MLH1, MSH2 and MSH6. All patients belong to different families. No mutations were detected in 14 tumors from HNPCC patients with germline mutations in MSH6. Further, no mutations of BRAF were found in tumors from 23 MMR-negative families, from which 13 fulfilled the Amsterdam criteria (HNPCC) and 10 were suspected for HNPCC as they were positive for the Bethesda criteria. Overall, our data reinforce the concept that BRAF is not involved in the colorectal tumorigenesis of HNPCC. The detection of a positive BRAF-V600E mutation in a colorectal cancer suggests a sporadic origin of the disease and the absence of germline alterations of MLH1, MSH2 and also of MSH6. These findings have a potential impact in the genetic testing for HNPCC diagnostics and suggest a potential use of BRAF as exclusion criteria for HNPCC or as a molecular marker of sporadic cancer.
Amino Acid Substitution↗
Colorectal cancer and the CHEK2 1100delC mutation.
The CHEK2 1100delC mutation was recently identified as a low-penetrance breast cancer susceptibility allele. The mutation occurred more frequently in families with clustering of breast and colorectal cancers (CRCs) than in families with clustering of breast cancer only. Hence, the 1100delC mutation could also be a low-penetrance CRC susceptibility allele. To test this hypothesis, we examined the mutation in 629 unselected CRC cases, 230 controls, and 105 selected CRCs diagnosed in patients before age 50. The mutation was observed in 1.6% of unselected patients and in 0.3% of controls (Not significant (NS)). After stratifying unselected patients according to defined genetic risk (on the basis of age at diagnosis and family history of colorectal and endometrial cancer), the highest frequency was observed in high-risk patients (12.5%), followed by moderate-risk patients (3.3%), and was lowest in low-risk patients (1.0%, P(trend) 0.014). In selected patients, 1.6% carried the mutation (NS). Subgroup analyses for tumor localization, gender, and age at diagnosis did not reveal an association with the 1100delC genotype. In addition, a pooled analysis, combining data of one published study in unselected CRC cases and our study, also did not reveal an association. In conclusion, the frequency of the 1100delC genotype was neither significantly increased in unselected CRC patients nor in selected CRC patients diagnosed before age 50. However, after stratifying unselected CRC patients according to defined genetic risk, a significant trend of increasing frequency was observed. Together, the results are consistent with a low-penetrance effect (OR 1.5-2.0) of the CHEK2 1100delC on CRC risk. Large case-control studies are required to clarify the exact role of the CHEK2 1100delC mutation in CRC.
Checkpoint Kinase 2↗
The human leukocyte antigen region and colorectal cancer risk.
PURPOSE: Recently, we found a certain haplotype in the human leukocyte antigen Class III subregion to be associated with breast cancer. Epidemiologic studies have shown that breast cancer and colorectal cancer have several risk factors in common. In view of these studies and because polymorphisms located in the human leukocyte antigen III region have been found to be associated with colorectal cancer, we wondered whether the same region also is involved in colorectal cancer susceptibility. METHODS: The human leukocyte antigen region was genotyped with 14 microsatellite markers in germline DNA from 643 colorectal cancer patients and 841 family-based controls. Association analyses and the Haplotype Sharing Statistic were used to search for differences between patients and controls. Subgroup analyses were performed for gender, age at diagnosis, and localization of the tumor. RESULTS: The Haplotype Sharing Statistic analysis revealed neither a difference in mean haplotype sharing between all patients and controls, nor in any of the subgroups. The single allele, genotype, and two-locus association analyses for all patients and for the different subgroups did not show an association with colorectal cancer for the 14 microsatellite markers. Also, no association was observed between the tumor necrosis factor-beta polymorphism and colorectal cancer. CONCLUSIONS: No association was observed between commonly occurring haplotypes and alleles in the human leukocyte antigen region and colorectal cancer risk.
Adult↗
Economic evaluation of a randomized trial comparing Helicobacter pylori test-and-treat and prompt endoscopy strategies for managing dyspepsia in a primary-care setting.
BACKGROUND: In western European countries, most dyspeptic patients are initially managed by their general practitioners (GPs), who use a range of strategies to manage dyspepsia. We performed an economic analysis of a Helicobacter pylori test-and-treat strategy versus a prompt endoscopy approach in a primary care setting. METHODS: Data were used from the Strategy: Endoscopy versus Serology (SENSE) study, performed in The Netherlands from 1998 to 2001. Patients were randomized to a prompt endoscopy (n = 105) or test-and-treat (n = 118) group. Follow-up lasted 1 year. Adverse events were not recorded in the SENSE study. Health care costs were based on the total amount of dyspepsia-related drugs used, the number of dyspepsia-related GP visits, the number of diagnostic tests, and the number of dyspepsia-related referrals to specialists. The use of medical resources was calculated as standardized costs for 1999, recorded as euros. (On December 31, 1999, 1.00 Euro = 1.00 US dollar.) Quality of life was measured at inclusion and 1 year later, using the RAND-36 questionnaire. To calculate quality-adjusted life-years (QALYs), we transformed the individual scores of the RAND-36 into 1 overall score, the Health Utilities Index Mark 2, which introduced a limitation to the study. An incremental cost-effectiveness ratio (ICER) was calculated. The 95% confidence limits were calculated using a parametric bootstrap method with angular transformation. All cost data were analyzed from a third-party payer perspective. RESULTS: The total costs per patient were 511 Euros, with 0.037 QALY gained per patient, in the test-and-treat group, and 748 Euros, with 0.032 QALY gained per patient, in the endoscopy group (between groups, P < 0.001 and P = NS, respectively). The point estimate of the ICER indicated that the test-and-treat strategy yielded cost savings and QALYs gained. Parametric bootstrap confidence limits indicated cost savings per QALY gained in 75.7% of the bootstrap simulations. CONCLUSION: This analysis of data from the SENSE1026 study suggests that the H pylori test-and-treat strategy was more cost-effective than prompt endoscopy in the initial management of dyspepsia in general practice, from the perspective of a third-party payer.
Adult↗
Expression of tumour necrosis factor-related apoptosis-inducing ligand death receptors in sporadic and hereditary colorectal tumours: potential targets for apoptosis induction.
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and antibodies against TRAIL receptors death receptor 4 (DR4) and death receptor 5 (DR5) are under investigation for cancer therapy. To study the potential application of these agents, the expression of DR4 and DR5 were studied immunohistochemically in colorectal adenomas and carcinomas from patients with sporadic disease (n=74 and 56, respectively), familial adenomatous polyposis (FAP, n=41 and 4, respectively) and hereditary non-polyposis colorectal cancer (HNPCC, n=50 and 21, respectively). BAX, which is frequently mutated in tumours with high-frequency microsatellite instability (MSI-H) may play a role in sensitivity to TRAIL. Therefore, MSI-H carcinomas (n=42, of which 27 sporadic and 15 HNPCC) were analysed for apoptotic activity, assessed by M30 immunoreactivity, and BAX mutations. Most adenomas from all three patient groups expressed DR4 and DR5. Most carcinomas expressed DR4, except for six cases, all with mucinous histology. All carcinomas, including mucinous carcinomas, showed DR5 expression. BAX mutations were found in 6/42 MSI-H cancers with similar apoptotic indices and expression of DR4, DR5 and TRAIL in BAX mutant and wild-type cases. Since most sporadic and hereditary colorectal neoplasms express DR4 and DR5, targeting of these receptors may be a potential prevention or treatment strategy.
Adult↗
No increased susceptibility to breast cancer from combined CHEK2 1100delC genotype and the HLA class III region risk factors.
CHEK2 is low-penetrance breast cancer susceptibility gene. The 1100delC mutation may interact with variants/mutations in other breast cancer susceptibility loci. We identified a risk haplotype in the HLA class III region in breast cancer patients [de Jong MM, Nolte IM, de Vries EGE, et al. The HLA class III subregion is responsible for an increased breast cancer risk. Hum Mol Genet 2003, 12, 2311-2319] and tested whether it interacted with 1100delC mutation. The CHEK2 1100delC mutation was analysed in the same series of patients and controls as in the HLA breast cancer study. In 962 unselected breast cancer patients, the 1100delC mutation was observed in 2.9% and in 367 controls in 1.4% (NS). The highest 1100delC frequency occurred in high-risk (4.4%), followed by moderate-risk (3.8%), and lowest in low genetic risk patients (2.4%, P(trend) 0.029). In HLA risk haplotype carriers no increased breast cancer risk was observed in the presence of 1100delC mutation. Patients more often had one than both genetic risk factors. The 1100delC mutation and the HLA risk haplotype confer increased breast cancer risks, but an interactive effect on breast cancer between both factors is unlikely. In contrast, the effect of 1100delC mutation on breast cancer risk was limited to individuals without HLA risk haplotype, suggesting a mutual excluding effect between these risk factors.
Adult↗
Association between Toll-like receptor 4 and inflammatory bowel disease.
BACKGROUND: The human Toll-like receptor 4 (TLR4) participates in the innate response. Recently, the TLR4 variant Asp299Gly has been described to affect the response of this receptor to lipopolysaccharide. As such, there is a potentially important role of TLR4 in the pathogenesis of inflammatory bowel disease (IBD). We studied the involvement of TLR4 in IBD in a large population of Dutch patients with IBD and in family-based controls. METHODS: In 781 IBD cases and 315 controls, genotyping was performed forAsp299Gly and Thr399Ile variants and for 4 microsatellite markers flanking TLR4. Association analysis and the were applied. In addition, interaction of TLR4 with the caspase recruitment domain containing protein 15 gene (CARD15) was studied in patients with Crohn's disease (CD). RESULTS: The haplotype sharing statistic showed association at microsatellite marker D9S1864 with IBD (P = 0.0019), and in particular with CD (P = 0.0025) and at TLR406 with ulcerative colitis (UC; P = 0.027). No association was found for Asp299Gly and Thr399Ile. However, the frequencies of both variant allele carriers were higher among CD cases with a disease onset > or = 40 years than among controls. No evidence for interaction between TLR4 and CARD15 was found. CONCLUSIONS: Haplotype analysis shows that TLR4 is associated with both CD and UC. The Asp299Gly and Thr399Ile variants do not show an association with CD, UC, or IBD as a group, indicating that these polymorphisms are likely not the causal ones. We propose that the 2 polymorphisms are in linkage with (the) disease susceptibility variant(s) located elsewhere on TLR4.
Adolescent↗
Prevalence of prednisolone (non)compliance in adult liver transplant recipients.
Limited evidence is available concerning (non)compliance with the immunosuppressive regimen in adult liver transplant recipients. In our study we prospectively assessed prednisolone (non)compliance in 108 adult liver transplant recipients using electronic event monitoring (EEM) in an outpatient setting. The EEM is a pill bottle fitted with a cap containing a microelectronic circuit that registers date and time of bottle openings and closings. Median taking compliance was 100% (range 60-105%), median dosing compliance was 99% (range 58-100%); median timing compliance (TIC) was 94% (42-100%). A drug holiday (DH) of > or =48 h was found in 39% of the patients of > or =72 h in 16% of the patients. Using EEM in liver transplant recipients, we found an overall high level of compliance for prednisolone, except that TIC was low in about one third of the patients. Age below 40 years was found a significant risk factor for decreased TIC and for DHs of > or =48 h.
Adult↗
Prevalence of adenomas among young individuals at average risk for colorectal cancer.
OBJECTIVES: We evaluated the prevalence and characteristics of adenomas in a young population not genetically predisposed for the development of colorectal cancer (CRC). METHODS: The databases of the Dutch Hereditary Colorectal Cancer Registry were used. The study population included patients (n = 444) who had regular endoscopy until mutation analysis revealed they did not carry the (Adenomatous Polyposis Coli (APC)/Mismatch Repair) gene defect identified in their family. RESULTS: At first colonoscopy (n = 342; 50% males, mean age 37 yr) a total of 19 adenomas (10 males, mean age 50 yr, range 24-91 yr) and two CRCs (2 males, age 49 and 72 yr) were identified, and at first sigmoidoscopy (n = 102; 53% males, mean age 29 yr) three adenomas (2 males, age 8, 40, and 41 yr) were found. A second colonoscopy was performed in 14 patients with, and in 162 patients without an adenoma. Three of 14 patients (21%) developed a new adenoma (all >50 yr) and 8 of 162 (5%) patients developed their first adenoma during follow-up. In the colonoscopy group, the cumulative proportion of patients free of adenomas at age 50 yr was 86%. Of all adenomas diagnosed during colonoscopy (n = 49), 65% were located distal from the flexura lienalis. Of the adenomas detected during all endoscopies (n = 53), 9.8% were > or =7 mm, 7.5% showed high-grade dysplasia, and 7.5% showed tubulovillous features. CONCLUSIONS: On the basis of our findings during colonoscopy we conclude that the risk of developing adenomas/CRC in young individuals without genetic risk factors is low. Adenoma surveillance programs should focus on young individuals with a positive family (or personal) history for adenomas/CRC, or on individuals >50 yr.
Adenoma↗