137 results found
Dominguez-Valentin M, Haupt S, Seppälä TT, et al., 2023, Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database, EClinicalMedicine, Vol: 58, Pages: 1-12, ISSN: 2589-5370
BACKGROUND: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. METHODS: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. FINDINGS: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. INTERPRETATION: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. FUNDING: We ackno
Moller P, Seppala T, Dowty JG, et al., 2022, Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium, Hereditary Cancer in Clinical Practice, Vol: 20, Pages: 1-11, ISSN: 1731-2302
ObjectiveTo compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants.MethodsCRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands.ResultsIn the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups.ConclusionsProspectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
Palles C, West HD, Chew E, et al., 2022, Germline MBD4 deficiency causes a multi-tumor predisposition syndrome, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 109, Pages: 953-960, ISSN: 0002-9297
Monahan KJ, Lincoln A, East JE, et al., 2020, Management strategies for the colonoscopic surveillance of people with Lynch syndrome during the COVID-19 pandemic, Gut, ISSN: 0017-5749
Burn J, Sheth H, Elliott F, et al., 2020, Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial, The Lancet, Vol: 395, Pages: 1855-1863, ISSN: 0140-6736
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). P
Monahan KJ, Bradshaw N, Dolwani S, et al., 2020, Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG), Gut, Vol: 69, Pages: 411-444, ISSN: 0017-5749
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.
Burn J, Alsina D, Hill J, et al., 2017, Response: A clinical consensus on improving the colonoscopic screening and surveillance of people with Lynch syndrome in England, British Medical Journal, Vol: 356, ISSN: 0959-8138
Monahan KJ, Alsina D, Bach S, et al., 2017, Urgent improvements needed to diagnose and manage Lynch syndrome, BMJ-BRITISH MEDICAL JOURNAL, Vol: 356, ISSN: 1756-1833
Movahedi M, Bishop DT, Macrae F, et al., 2015, Obesity, aspirin, and risk of colorectal cancer in carriers of hereditary colorectal cancer: a prospective investigation in the CAPP2 study, Journal of Clinical Oncology, Vol: 33, Pages: 3591-3597, ISSN: 0732-183X
PurposeIn 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 MethodsParticipants 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.ResultsDuring 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/m2 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).ConclusionObesity 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.
Cheng THT, Gorman M, Martin L, et al., 2015, Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 23, Pages: 260-263, ISSN: 1018-4813
Davis H, Irshad S, Bansal M, et al., 2015, Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche, Nature Medicine, Vol: 21, Pages: 62-70, ISSN: 1546-170X
Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.
Mesher D, Dove-Edwin I, Sasieni P, et al., 2014, A pooled analysis of the outcome of prospective colonoscopic surveillance for familial colorectal cancer, INTERNATIONAL JOURNAL OF CANCER, Vol: 134, Pages: 939-947, ISSN: 0020-7136
Saunders BP, Tsiamoulos ZP, Thomas H, et al., 2013, Rectal Endoscopic Submucosal Dissection Made Easy: A Solution to the Retraction Problem, GASTROENTEROLOGY, Vol: 145, Pages: 939-941, ISSN: 0016-5085
Vasen HFA, Blanco I, Aktan-Collan K, et al., 2013, Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts, GUT, Vol: 62, Pages: 812-823, ISSN: 0017-5749
Palles C, Cazier J-B, Howarth KM, et al., 2013, Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas, NATURE GENETICS, Vol: 45, Pages: 136-144, ISSN: 1061-4036
Mathers JC, Movahedi M, Macrae F, et al., 2012, Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial, LANCET ONCOLOGY, Vol: 13, Pages: 1242-1249, ISSN: 1470-2045
Nayagam S, Selvapatt N, Auguste JL, et al., 2012, QUALITY OF COLONOSCOPIC PROCEDURES AMONG INDEPENDENTLY PRACTISING GASTROENTEROLOGY TRAINEES IN A NW LONDON COHORT: ARE THEY REACHING NATIONAL STANDARDS?, GUT, Vol: 61, Pages: A59-A60, ISSN: 0017-5749
Jaeger E, Leedham S, Lewis A, et al., 2012, Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist <i>GREM1</i>, NATURE GENETICS, Vol: 44, Pages: 699-U127, ISSN: 1061-4036
Burn J, Gerdes A-M, Macrae F, et al., 2011, Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial, LANCET, Vol: 378, Pages: 2081-2087, ISSN: 0140-6736
Walker DG, Williams HRT, Kane SP, et al., 2011, Differences in Inflammatory Bowel Disease Phenotype between South Asians and Northern Europeans Living in North West London, UK, AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol: 106, Pages: 1281-1289, ISSN: 0002-9270
Houlston RS, Cheadle J, Dobbins SE, et al., 2010, Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33, NATURE GENETICS, Vol: 42, Pages: 973-U89, ISSN: 1061-4036
Beggs AD, Latchford AR, Vasen HFA, et al., 2010, Peutz-Jeghers syndrome: a systematic review and recommendations for management, GUT, Vol: 59, Pages: 975-986, ISSN: 0017-5749
Vasen HFA, Moeslein G, Alonso A, et al., 2010, Recommendations to improve identification of hereditary and familial colorectal cancer in Europe, FAMILIAL CANCER, Vol: 9, Pages: 109-115, ISSN: 1389-9600
Cairns SR, Scholefield JH, Steele RJ, et al., 2010, Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002), GUT, Vol: 59, Pages: 666-689, ISSN: 0017-5749
Williams HRT, Cox IJ, Walker DG, et al., 2009, Erratum: Characterization of inflammatory bowel disease with urinary metabolic profiling (American Journal of Gastroenterology (2009) 104 (1435-1444) DOI: 10.1038 / ajg.2009.175), American Journal of Gastroenterology, Vol: 104, ISSN: 0002-9270
Williams HRT, Cox IJ, Walker DG, et al., 2009, Characterization of Inflammatory Bowel Disease With Urinary Metabolic Profiling (vol 104, pg 1435, 2009), AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol: 104, Pages: 1894-1894, ISSN: 0002-9270
Williams HRT, Cox IJ, Walker DG, et al., 2009, Characterization of Inflammatory Bowel Disease With Urinary Metabolic Profiling, AMERICAN JOURNAL OF GASTROENTEROLOGY, Vol: 104, Pages: 1435-1444, ISSN: 0002-9270
Walker DG, Williams HRT, Padaruth S, et al., 2009, INFLAMMATORY BOWEL DISEASE IN CAUCASIAN AND UK SOUTH ASIAN PATIENTS: DIFFERENCE IN CLINICAL PHENOTYPE, Annual Meeting of the British-Society-of-Gastroenterology, Publisher: B M J PUBLISHING GROUP, Pages: A60-A60, ISSN: 0017-5749
Monahan KJ, Spain S, Thomas HJW, et al., 2009, AN ASSOCIATION STUDY OF A MITOCHONDRIAL TUMOUR SUPPRESSOR 1 COPY NUMBER POLYMORPHISM AND COLORECTAL CANCER, Annual Meeting of the British-Society-of-Gastroenterology, Publisher: B M J PUBLISHING GROUP, Pages: A88-A88, ISSN: 0017-5749
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.