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1.
Cancer Prev Res (Phila) ; 15(9): 623-634, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35878732

ABSTRACT

ABSTRACT: The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33-0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non-colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32-0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non-colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62-1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non-colorectal cancer cancers for patients with LS. PREVENTION RELEVANCE: Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers. See related Spotlight, p. 557.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Colorectal Neoplasms , Aspirin/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/prevention & control , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Follow-Up Studies , Humans , Incidence , Resistant Starch
3.
Lancet ; 395(10240): 1855-1863, 2020 06 13.
Article in English | MEDLINE | ID: mdl-32534647

ABSTRACT

BACKGROUND: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population. METHODS: In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990. FINDINGS: Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43-0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39-0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34-0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31-0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43-0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously. INTERPRETATION: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. FUNDING: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Aspirin/therapeutic use , Colorectal Neoplasms, Hereditary Nonpolyposis/prevention & control , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Aspirin/adverse effects , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Double-Blind Method , Follow-Up Studies , Heterozygote , Humans , Intention to Treat Analysis , Life Tables , Medication Adherence , Proportional Hazards Models
4.
Gut ; 69(3): 411-444, 2020 03.
Article in English | MEDLINE | ID: mdl-31780574

ABSTRACT

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.


Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapy , Population Surveillance , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/prevention & control , Adenomatous Polyposis Coli/therapy , Colonoscopy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/prevention & control , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/prevention & control , Colorectal Neoplasms, Hereditary Nonpolyposis/therapy , DNA Glycosylases/genetics , Family Health , Humans , Intestinal Polyposis/congenital , Intestinal Polyposis/genetics , Intestinal Polyposis/therapy , Ireland , Life Style , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/therapy , Peutz-Jeghers Syndrome/genetics , Peutz-Jeghers Syndrome/therapy , Referral and Consultation/standards , Risk Factors , United Kingdom
5.
J Clin Oncol ; 33(31): 3591-7, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26282643

ABSTRACT

PURPOSE: In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This prospective study investigated the association between body mass index and cancer risk in patients with Lynch syndrome (LS). PATIENTS AND METHODS: Participants with LS were recruited to the CAPP2 study, in which they were randomly assigned to receive aspirin 600 mg per day or aspirin placebo, plus resistant starch 30 g per day or starch placebo (2 × 2 factorial design). Mean intervention period was 25.0 months, and mean follow-up was 55.7 months. RESULTS: During follow-up, 55 of 937 participants developed CRC. For obese participants, CRC risk was 2.41× (95% CI, 1.22 to 4.85) greater than for underweight and normal-weight participants (reference group), and CRC risk increased by 7% for each 1-kg/m(2) increase in body mass index. The risk of all LS-related cancers in obese people was 1.77× (95% CI, 1.06 to 2.96; P = .03) greater than for the reference group. In subgroup analysis, obesity was associated with 3.72× (95% CI, 1.41 to 9.81) greater CRC risk in patients with LS with MLH1 mutation, but no excess risk was observed in those with MSH2 or MSH6 mutation (P = .5). The obesity-related excess CRC risk was confined to those randomly assigned to the aspirin placebo group (adjusted hazard ratio, 2.75; 95% CI, 1.12 to 6.79; P = .03). CONCLUSION: Obesity is associated with substantially increased CRC risk in patients with LS, but this risk is abrogated in those taking aspirin. Such patients are likely to benefit from obesity prevention and/or regular aspirin.


Subject(s)
Aspirin/therapeutic use , Body Mass Index , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms/complications , Colorectal Neoplasms/prevention & control , Obesity/complications , Adaptor Proteins, Signal Transducing/genetics , Adiposity , Adult , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Body Weight , Colorectal Neoplasms/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA-Binding Proteins/genetics , Female , Follow-Up Studies , Heterozygote , Humans , Incidence , Male , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein/genetics , Mutation , Nuclear Proteins/genetics , Prospective Studies , Risk Factors
6.
Gut ; 62(6): 812-23, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23408351

ABSTRACT

Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/therapy , Adult , Aged , Colonoscopy/standards , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Female , Humans , Male , Middle Aged , Neoplasms/diagnosis , Neoplasms/etiology , Neoplasms/genetics , Neoplasms/therapy , Public Health Surveillance , Risk Factors , Young Adult
7.
Nat Genet ; 45(2): 136-44, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23263490

ABSTRACT

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.


Subject(s)
Adenoma/genetics , Colorectal Neoplasms/genetics , DNA Mismatch Repair/genetics , DNA Polymerase III/genetics , DNA Polymerase II/genetics , DNA Replication/genetics , Models, Molecular , Exodeoxyribonucleases/genetics , Genetic Linkage , Genome-Wide Association Study , Germ-Line Mutation/genetics , Humans , Microsatellite Repeats/genetics , Pedigree , Poly-ADP-Ribose Binding Proteins , Schizosaccharomyces/genetics , Sequence Analysis, DNA
8.
Lancet Oncol ; 13(12): 1242-9, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23140761

ABSTRACT

BACKGROUND: Observational studies report that higher intake of dietary fibre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of colorectal cancer, but no randomised trials with prevention of colorectal cancer as a primary endpoint have been done. We assessed the effect of resistant starch on the incidence of colorectal cancer. METHODS: In the CAPP2 study, individuals with Lynch syndrome were randomly assigned in a two-by-two factorial design to receive 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was done with a block size of 16. Post-intervention, patients entered into double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint for this analysis was development of colorectal cancer in participants randomly assigned to resistant starch or resistant-starch placebo with both intention-to-treat and per-protocol analyses. This study is registered, ISRCTN 59521990. FINDINGS: 463 patients were randomly assigned to receive resistant starch and 455 to receive resistant-starch placebo. At a median follow-up 52·7 months (IQR 28·9-78·4), 53 participants developed 61 primary colorectal cancers (27 of 463 participants randomly assigned to resistant starch, 26 of 455 participants assigned to resistant-starch placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 1·40 (95% CI 0·78-2·56; p=0·26) and Poisson regression accounting for multiple primary events gave an incidence rate ratio (IRR) of 1·15 (95% CI 0·66-2·00; p=0·61). For those completing 2 years of intervention, per-protocol analysis yielded a HR of 1·09 (0·55-2·19, p=0·80) and an IRR of 0·98 (0·51-1·88, p=0·95). No information on adverse events was gathered during post-intervention follow-up. INTERPRETATION: Resistant starch had no detectable effect on cancer development in carriers of hereditary colorectal cancer. Dietary supplementation with resistant starch does not emulate the apparently protective effect of diets rich in dietary fibre against colorectal cancer. FUNDING: European Union, Cancer Research UK, Bayer Corporation, National Starch and Chemical Co, UK Medical Research Council, Newcastle Hospitals Trustees, Cancer Council of Victoria Australia, THRIPP South Africa, The Finnish Cancer Foundation, SIAK Switzerland, and Bayer Pharma.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/prevention & control , Dietary Carbohydrates/therapeutic use , Dietary Fiber/administration & dosage , Heterozygote , Starch/therapeutic use , Adult , Aged , Colorectal Neoplasms/prevention & control , Double-Blind Method , Female , Germ-Line Mutation , Humans , Male , Middle Aged , Young Adult
9.
Lancet ; 378(9809): 2081-7, 2011 Dec 17.
Article in English | MEDLINE | ID: mdl-22036019

ABSTRACT

BACKGROUND: Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. METHODS: In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. RESULTS: 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35-1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32-0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19-0·86, p=0·02) and an IRR of 0·37 (0·18-0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. INTERPRETATION: 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. FUNDING: European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Aspirin/therapeutic use , Colorectal Neoplasms, Hereditary Nonpolyposis/prevention & control , Heterozygote , Adenoma/prevention & control , Chemoprevention , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Dietary Carbohydrates/therapeutic use , Double-Blind Method , Humans , Starch/therapeutic use
10.
Am J Gastroenterol ; 106(7): 1281-9, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21577243

ABSTRACT

OBJECTIVES: The incidence and prevalence of inflammatory bowel disease (IBD) is increasing throughout Asia. Since the 1950s, there has been substantial migration from South Asia (India, Pakistan, and Bangladesh) to the United Kingdom. The aim of this study was to define the clinical phenotype of IBD in UK South Asians living in North West London, and to compare the results with a white Northern European IBD cohort. METHODS: The phenotypic details of 367 South Asian IBD patients (273 ulcerative colitis (UC) and 94 Crohn's disease (CD)), undergoing active follow-up in five North West London hospitals, were compared with those of 403 consecutively collected white Northern European IBD patients (188 UC and 215 CD). RESULTS: The phenotype of IBD differed significantly between the two populations. 63.0% of South Asian UC patients had extensive colitis compared with 42.5% of the Northern European cohort (P < 0.0001). Proctitis was uncommon in South Asian UC patients (9.9 vs. 26.1% in Northern European patients, P<0.0001). In the South Asian CD cohort, disease location was predominantly colonic (46.8%). CD behavior differed significantly between the groups, with less penetrating disease compared with Northern Europeans (P=0.01) and a reduced need for surgery (P=0.003). CONCLUSIONS: The phenotype of IBD in South Asians living in North West London is significantly different from that of a white Northern European IBD cohort. Knowledge of ethnic variations in disease phenotype may help to identify key genetic, environmental, and behavioral factors contributing to the development of IBD.


Subject(s)
Asian People , Colitis, Ulcerative/ethnology , Crohn Disease/ethnology , Phenotype , White People , Adolescent , Adult , Bangladesh/ethnology , Colectomy , Colitis, Ulcerative/complications , Colitis, Ulcerative/pathology , Colitis, Ulcerative/surgery , Colon/pathology , Crohn Disease/complications , Crohn Disease/pathology , Crohn Disease/surgery , Environment , Female , Humans , Ileum/pathology , India/ethnology , London/epidemiology , Male , Pakistan/ethnology , Prevalence , Proctitis/ethnology , Time Factors , Young Adult
11.
Nat Genet ; 42(11): 973-7, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20972440

ABSTRACT

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10⁻¹° and rs6687758, OR = 1.09, P = 2.27 × 10⁻9, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10⁻8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10⁻¹° and rs7136702, OR = 1.06, P = 4.02 × 10⁻8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10⁻¹°). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.


Subject(s)
Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 13/genetics , Chromosomes, Human, Pair 1/genetics , Chromosomes, Human, Pair 3/genetics , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Chromosome Mapping/methods , Female , Genome-Wide Association Study/methods , Genotype , Humans , Male , Meta-Analysis as Topic , Odds Ratio , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide , Risk Assessment
12.
Gut ; 59(5): 666-89, 2010 May.
Article in English | MEDLINE | ID: mdl-20427401

ABSTRACT

The British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) commissioned this update of the 2002 guidance. The aim, as before, is to provide guidance on the appropriateness, method and frequency of screening for people at moderate and high risk from colorectal cancer. This guidance provides some new recommendations for those with inflammatory bowel disease and for those at moderate risk resulting from a family history of colorectal cancer. In other areas guidance is relatively unchanged, but the recent literature was reviewed and is included where appropriate.


Subject(s)
Colorectal Neoplasms/diagnosis , Early Detection of Cancer/methods , Acromegaly/complications , Adenoma/diagnosis , Anastomosis, Surgical/adverse effects , Colon, Sigmoid/surgery , Colonoscopy/methods , Colonoscopy/standards , Colorectal Neoplasms/etiology , Colorectal Neoplasms/surgery , Early Detection of Cancer/standards , Evidence-Based Medicine/methods , Humans , Inflammatory Bowel Diseases/complications , Neoplastic Syndromes, Hereditary/diagnosis , Population Surveillance/methods , State Medicine/standards , Ureter/surgery
13.
Am J Gastroenterol ; 104(6): 1435-44, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19491857

ABSTRACT

OBJECTIVES: Distinguishing between the inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC) is important for both management and prognostic reasons. Discrimination using noninvasive techniques could be an adjunct to conventional diagnostics. Differences have been shown between the intestinal microbiota of CD and UC patients and controls; the gut bacteria influence specific urinary metabolites that are quantifiable using proton high-resolution nuclear magnetic resonance (NMR) spectroscopy. This study tested the hypothesis that such metabolites differ between IBD and control cohorts, and that using multivariate pattern-recognition analysis, the cohorts could be distinguished by urine NMR spectroscopy. METHODS: NMR spectra were acquired from urine samples of 206 Caucasian subjects (86 CD patients, 60 UC patients, and 60 healthy controls). Longitudinal samples were collected from 75 individuals. NMR resonances specific for metabolites influenced by the gut microbes were studied, including hippurate, formate, and 4-cresol sulfate. Multivariate analysis of all urinary metabolites involved principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA). RESULTS: Hippurate levels were lowest in CD patients and differed significantly between the three cohorts (P<0.0001). Formate levels were higher and 4-cresol sulfate levels lower in CD patients than in UC patients or controls (P=0.0005 and P=0.0002, respectively). PCA revealed clustering of the groups; PLS-DA modeling was able to distinguish the cohorts. These results were independent of medication and diet and were reproducible in the longitudinal cohort. CONCLUSIONS: Specific urinary metabolites related to gut microbial metabolism differ between CD patients, UC patients, and controls. The emerging technique of urinary metabolic profiling with multivariate analysis was able to distinguish these cohorts.


Subject(s)
Colitis, Ulcerative/urine , Cresols/urine , Crohn Disease/urine , Formates/urine , Hippurates/urine , Sulfuric Acid Esters/urine , Adolescent , Adult , Aged , Biomarkers/urine , Female , Humans , Inflammatory Bowel Diseases/urine , Magnetic Resonance Spectroscopy , Male , Middle Aged , Prognosis , Young Adult
14.
N Engl J Med ; 359(24): 2567-78, 2008 Dec 11.
Article in English | MEDLINE | ID: mdl-19073976

ABSTRACT

BACKGROUND: Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. METHODS: In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. RESULTS: Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. CONCLUSIONS: The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.)


Subject(s)
Adenoma/prevention & control , Aspirin/therapeutic use , Carcinoma/prevention & control , Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy , Colorectal Neoplasms/prevention & control , Starch/therapeutic use , Adenoma/epidemiology , Adult , Aged , Aspirin/administration & dosage , Aspirin/adverse effects , Carcinoma/epidemiology , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mismatch Repair/genetics , Drug Therapy, Combination , Female , Humans , Incidence , Male , Middle Aged , Proportional Hazards Models , Risk , Starch/adverse effects , Treatment Failure
15.
Fam Cancer ; 6(1): 13-9, 2007.
Article in English | MEDLINE | ID: mdl-16937234

ABSTRACT

This study assessed current practice and methods for improvement in the management of families with hereditary non-polyposis colorectal cancer (HNPCC). HNPCC families registered at five London Genetics Centres and a specialised Colorectal family cancer clinic (CFCC) were identified. Ascertainment of management and outcome details were obtained by scrutiny of patient records and by correspondence with General practitioners (GPs). Two hundred and three families with HNPCC were identified. 79.5% (403/507) of at-risk relatives ascertained were contacted by the genetics centres, and 80.2% (65/81) by the CFCC (P = 1.0). 54.8% (211/385) of probands and relatives within genetics centres' catchment areas were advised to undertake a surveillance programme, compared with 82.1% (64/78) of those cared for by the CFCC (P < 4.2 x 10(-6)). Adherence to surveillance guidelines was 76.6% (49/64) in individuals cared for by the only centre that undertook responsibility for surveillance follow-up (CFCC) and 41.7% (88/211) for the genetics centres, which did not assume responsibility (P < 8.9 x 10(-7)) (using two sided P-values for P (O > or = E/O < or = E)). 15.3% of GPs were unaware their patient had been recommended a surveillance programme, 65% did not know who was responsible for ensuring surveillance follow-up. A questionnaire to fifteen UK genetics centres demonstrated that the majority (86.7%) did not assume responsibility for surveillance follow-up. Since surveillance adherence is clearly better where centres assume responsibility for follow-up, it is recommended that regional or national registers of HNPCC families be developed and maintained to ensure effective management.


Subject(s)
Colonoscopy/methods , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/prevention & control , Precancerous Conditions/diagnosis , Precancerous Conditions/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms, Hereditary Nonpolyposis/mortality , Family Characteristics , Female , Follow-Up Studies , Genetic Predisposition to Disease , Genetic Testing , Humans , London/epidemiology , Male , Mass Screening , Middle Aged , Molecular Diagnostic Techniques , Pedigree , Population Surveillance/methods , Registries
16.
Gastroenterology ; 130(7): 1995-2000, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16762622

ABSTRACT

BACKGROUND & AIMS: Lynch syndrome is an autosomal dominant predisposition to colorectal cancer caused by mutations in DNA mismatch repair genes; colorectal cancer risk is high. Few studies have addressed colorectal cancer risk in individuals from dominant families without mismatch repair deficiency. We sought to establish whether these individuals are also at increased risk by examining the incidence of advanced neoplasia during surveillance. METHODS: In this prospective cohort study, BAT26 testing of tumors was carried out at 2 tertiary centers on 125 individuals from 97 families (with a dominant colorectal cancer history) to classify families as Lynch syndrome (microsatellite unstable) or non-Lynch syndrome (microsatellite stable). Colonoscopy results in 288 at-risk family members were compared. RESULTS: Twenty-nine families were classified as Lynch syndrome and 68 as non-Lynch syndrome. Seven hundred seventy-six colonoscopies were undertaken. High-risk adenomas occurred in 7 of 91 (7.7%) Lynch syndrome individuals and 15 of 197 (7.6%) non-Lynch syndrome individuals, adjusted relative risk 1.15 (95% CI: 0.6-2.3). Cancer was observed only in Lynch syndrome individuals (4/91; 4.4%), Fisher exact test, P = .010. Multiple adenomas were only seen in non-Lynch syndrome individuals (13/197; 6.6%), Fisher exact text, P = .06. CONCLUSIONS: Individuals with an autosomal dominant family history of colorectal cancer with and without evidence of Lynch syndrome are at equal risk of high-risk adenomas during surveillance, but colorectal cancer was only seen in Lynch syndrome. Therefore non-Lynch syndrome individuals do require colonoscopic surveillance, but the interval could be lengthened because risk of (interval) cancer is low. Lynch syndrome individuals require short surveillance intervals as is the recommended practice.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Genetic Predisposition to Disease/epidemiology , MutS Homolog 2 Protein/genetics , Age Distribution , Base Pair Mismatch , Cohort Studies , Colonoscopy/methods , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Genetic Testing , Humans , Incidence , Male , Pedigree , Prognosis , Prospective Studies , Reference Values , Risk Assessment , Sex Distribution
17.
BMJ ; 331(7524): 1047, 2005 Nov 05.
Article in English | MEDLINE | ID: mdl-16243849

ABSTRACT

OBJECTIVE: To determine to what extent individuals with various family histories of colorectal cancer (from one to three or more affected first degree relatives) benefit from colonoscopic surveillance. DESIGN: Prospective, observational study of high risk families, followed up over 16 years. SETTING: Tertiary referral family cancer clinic in London. PARTICIPANTS: 1678 individuals from families registered with the clinic. Individuals were classified according to the strength of their family history: hereditary non-polyposis colorectal cancer (if they fulfilled the Amsterdam criteria), and one, two, or three affected first degree relatives (moderate risk). INTERVENTIONS: Colonoscopy was initially offered at five year intervals or three year intervals if an adenoma was detected. MAIN OUTCOME MEASURES: The incidence of adenomas with high risk pathological features or cancer. This was analysed by age, the extent of the family history, and findings on previous colonoscopies. The cohort was flagged for cancer and death. Incidence of colorectal cancer and mortality during over 15,000 person years of follow-up were compared with those expected in the absence of surveillance. RESULTS: High risk adenomas and cancer were most common in families with hereditary non-polyposis colorectal cancer (on initial colonoscopy 5.7% and 0.9%, respectively). In the families with moderate risk, these findings were particularly uncommon under age 45 (1.1% and 0%) and on follow-up colonoscopy if advanced neoplasia was absent initially (1.7% and 0.1%). The incidence of colorectal cancer was substantially lower-80% in families with moderate risk (P = 0.00004), and 43% in families with hereditary non-polyposis colorectal cancer (P = 0.06)-than the expected incidence in the absence of surveillance when the family history was taken into account. CONCLUSIONS: Colonoscopic surveillance reduces the risk of colorectal cancer in people with a strong family history. This study confirms that members of families with hereditary non-polyposis colorectal cancer require surveillance with short intervals. Individuals with a lesser family history may not require surveillance under age 45, and if advanced neoplasia is absent on initial colonoscopy, surveillance intervals may be lengthened. This would reduce the demand for colonoscopic surveillance.


Subject(s)
Colonoscopy/methods , Colorectal Neoplasms, Hereditary Nonpolyposis/prevention & control , Adult , Aged , Colorectal Neoplasms, Hereditary Nonpolyposis/mortality , Follow-Up Studies , Humans , Incidence , London/epidemiology , Middle Aged , Pedigree , Prospective Studies , Risk Factors
18.
Cancer Epidemiol Biomarkers Prev ; 14(6): 1460-3, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15941956

ABSTRACT

Whereas a recent study reported an increased risk of colorectal cancer associated with any HFE germ line mutation (C282Y or H63D), other investigators have concluded there is no increased risk, or that any increase is dependent on polymorphisms in HFE-interacting genes such as the transferrin receptor (TFR). We have established the frequency of HFE mutations in colorectal cancer patients (n = 327) with a family history of the disease and randomly selected controls (n = 322); this design increases greatly the study's power. Genotyping for the TRF S142G polymorphism was also conducted on a large proportion of the study group. Using PCR, restriction enzyme mapping, sequencing followed by data analysis with Fisher's exact test and logistic regression, we show that the presence of any HFE mutation (Y282 or D63) was not associated with colorectal cancer risk (P = 0.57). In contrast, individuals compound heterozygous for both mutations (15 cases versus 5 controls) had thrice the odds of developing colorectal cancer (odds ratio, 3.03; 95% confidence interval, 1.06-8.61) compared with those with a single mutation. This finding did not quite reach statistical significance after allowing for multiple post hoc testing (P(observed) = 0.038 versus P = 0.025, with Bonferonni correction). Overall, our data indicate that individuals with a single HFE mutation, C282Y or H63D, are unlikely predisposed to develop colorectal cancer. However, risk of colorectal cancer might be increased by compound heterozygosity for the HFE mutations in the small number of subjects studied. TFR gene polymorphism was not an independent risk factor and did not modify the disease risk associated with HFE mutation.


Subject(s)
Colorectal Neoplasms/etiology , Colorectal Neoplasms/genetics , Germ-Line Mutation , Histocompatibility Antigens Class I/genetics , Membrane Proteins/genetics , Polymorphism, Genetic , Adult , Aged , Case-Control Studies , Female , Genotype , Hemochromatosis Protein , Heterozygote , Humans , Male , Middle Aged , Odds Ratio , Polymerase Chain Reaction , Risk Factors
19.
Cancer Res ; 63(22): 7595-9, 2003 Nov 15.
Article in English | MEDLINE | ID: mdl-14633673

ABSTRACT

Colorectal carcinomas develop according to particular genetic pathways, including the chromosomal instability (CIN+), microsatellite instability (MSI+) and MSI- CIN- routes. We have determined the genetic pathway in patients with MYH-associated polyposis (MAP), a syndrome of colorectal adenomas and cancer that results from defective base excision repair (BER). As in previous studies, MAP tumors showed a high frequency of G>T mutations in APC, in accordance with defective BER. We found that K-ras mutations were common in MAP tumors, all of the changes comprising conversion of the first guanine residue of codon 12 to thymidine (G12C, GGT>TGT). We found no BRAF mutations at the codon 599 hotspot or elsewhere in exon 14. Almost all of the MAP cancers were near-diploid (CIN-), and none was MSI+. A few p53 mutations were found, but these were not predominantly G>T changes. p53 overexpression was, however, frequent. No SMAD4 or TGFBIIR mutations were found. MAP tumors appear to follow a distinct genetic pathway, with some features of both the CIN and MSI pathways. BER deficiency is rarely accompanied by CIN or MSI. The spectrum of somatic mutations in MAP tumors reflects both selection and hypermutation to which certain guanine residues are particularly prone.


Subject(s)
Adenoma/genetics , Adenomatous Polyposis Coli/genetics , Colorectal Neoplasms/genetics , DNA Glycosylases/genetics , N-Glycosyl Hydrolases/genetics , Adenoma/enzymology , Adenomatous Polyposis Coli/enzymology , Adult , Aged , Colorectal Neoplasms/enzymology , DNA Repair , Genes, ras/genetics , Humans , Middle Aged , Mutation
20.
Cancer Lett ; 200(2): 149-52, 2003 Oct 28.
Article in English | MEDLINE | ID: mdl-14568168

ABSTRACT

Aneuploidy is a characteristic of a subset of colorectal tumours. CHEK2 (also known as CHK2) is one of the cell cycle checkpoint genes coding for a family of proteins that sense damage in eukaryotic cells. Germline variation in CHEK2 has recently been shown to confer cancer susceptibility. Heterozygous mutations have been identified in patients with TP53-negative Li-Fraumeni syndrome. Furthermore, the CHEK2 1100delC variant carried by 1% of the population has been shown to act as a low penetrance allele for both breast and prostate cancers. To further our knowledge about the contribution of CHEK2 1100delC to cancer incidence we have analysed a series of 149 patients with multiple colorectal adenomas some of whom developed colorectal cancer. The CHEK2 1100delC allele was not over-represented in cases suggesting that this variant is not associated with an increased risk of colorectal disease.


Subject(s)
Adenoma/genetics , Carcinoma/genetics , Colorectal Neoplasms/genetics , Neoplasms, Multiple Primary/genetics , Protein Kinases/genetics , Protein Serine-Threonine Kinases , Aged , Checkpoint Kinase 2 , Female , Genes, Tumor Suppressor , Genes, cdc , Genetic Predisposition to Disease , Genetic Variation , Humans , Male , Middle Aged , Mutation
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