Urgent improvements needed to diagnose and manage Lynch syndrome. Por Monahan, K, Alsina, D, Bach, S, Buchanan, J, Burn, J, Clark, S, Dawson, P, De Souza, B, Din, F, Dolwani, S, Dunlop, M, East, J, Evans, D, Fearnhead, N, Frayling, I, Glynne-Jones, R, Hill, J, Houlston, R, Hull, M, Lalloo, F, Latchford, A, Lishman, S, Quirke, P, Rees, C, Rutter, M, Sasieni, P, Senapati, A, Speake, D, Thomas, H, Tomlinson, I

“...Lynch syndrome is currently under-recognised, underdiagnosed, and undermanaged, so opportunities to reduce cancer mortality are often missed. ...”

Novel MLH1 duplication identified in Colombian families with Lynch syndrome. Por Alonso-Espinaco, V, Giráldez, MD, Trujillo, C, van der Klift, H, Muñoz, J, Balaguer, F, Ocaña, T, Madrigal, I, Jones, A, Echeverry, M, Velez, A, Tomlinson, I, Milà, M, Wijnen, J, Carvajal-Carmona, L, Castells, A, Castellví-Bel, S

“... PURPOSE: Lynch syndrome accounts for 2-4% of all colorectal cancer, and is mainly caused by germline mutations in the DNA mismatch repair genes. ...”

Novel MLH1 duplication identified in Colombian families with Lynch syndrome Por Alonso-Espinaco, V, Giráldez, MD, Trujillo, C, Van Der Klift, H, Muñoz, J, Balaguer, F, Ocaña, T, Madrigal, I, Jones, A, Echeverry, M, Velez, A, Tomlinson, I, Milà, M, Wijnen, J, Carvajal-Carmona, L, Castells, A, Castellví-Bel, S

“...Purpose: Lynch syndrome accounts for 2-4% of all colorectal cancer, and is mainly caused by germline mutations in the DNA mismatch repair genes. ...”

The English National Lynch Syndrome transformation project: an NHS Genomic Medicine Service Alliance (GMSA) programme Por Monahan, KJ, Ryan, N, Monje-Garcia, L, Armstrong, R, Church, DN, Cook, J, Elghobashy, A, Lalloo, F, Lane, S, McDermott, FD, Miles, T, Hardy, SA, Tyson, A, Wang, VYW, Kim, A, Gelinas, S, Faravelli, F, Elmslie, F, Shaw, AC

“...Objective: In England, through the Genomic Medicine Service Alliances (GMSAs), a national transformation project aims to embed robust pathways to deliver universal Lynch syndrome (LS) testing for patients with colorectal and endometrial cancers. ...”

Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome. Por Wijnen, J, Brohet, R, van Eijk, R, Jagmohan-Changur, S, Middeldorp, A, Tops, C, van Puijenbroek, M, Ausems, MG, Gómez García, E, Hes, F, Hoogerbrugge, N, Menko, F, van Os, T, Sijmons, R, Verhoef, S, Wagner, A, Nagengast, F, Kleibeuker, J, Devilee, P, Morreau, H, Goldgar, D, Tomlinson, I, Houlston, R, van Wezel, T, Vasen, H

“...To assess whether these influence CRC risk in the Lynch syndrome, we genotyped these variants in a large series of proven mutation carriers. ...”

CD31-positive microvessel density within adenomas of Lynch Syndrome patients is similar compared to adenomas of non-Lynch patients Por Vleugels, J, Van Neerven, S, Van Leerdam, M, Wanders, L, De Wit, M, Carvalho, B, Delis-Van Diemen, P, Kallenberg, F, Vermeulen, L, Beliën, J, East, J, Meijer, G, Dekker, E

“...<p><strong>Background and study aims</strong> Microsatellite instability accelerates colorectal cancer development in patients with Lynch syndrome (LS). Previous research showed that virtual chromoendoscopy increases detection of adenomas during colonoscopy surveillance of patients with LS. ...”

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Por Thompson, B, Spurdle, AB, Plazzer, J, Greenblatt, MS, Akagi, K, Al-Mulla, F, Bapat, B, Bernstein, I, Capellá, G, den Dunnen, J, du Sart, D, Fabre, A, Farrell, M, Farrington, S, Frayling, I, Frebourg, T, Goldgar, D, Heinen, C, Holinski-Feder, E, Kohonen-Corish, M, Robinson, K, Leung, S, Martins, A, Moller, P, Morak, M

“...The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. ...”

Cerebral primitive neuroectodermal tumor in an adult with a heterozygous MSH2 mutation. Por Jeans, A, Frayling, I, Jasani, B, Side, L, Blesing, C, Ansorge, O

“...INVESTIGATIONS: Immunohistochemical analysis for DNA mismatch repair proteins, germline mutation analysis of MSH2. DIAGNOSIS: Lynch syndrome with a heterozygous germline mutation in MSH2. ...”

Features of patients with hereditary mixed polyposis syndrome caused by duplication of GREM1 and implications for screening and surveillance Por Lieberman, S, Walsh, T, Schechter, M, Adar, T, Goldin, E, Beeri, R, Sharon, N, Baris, H, Ben Avi, L, Half, E, Lerer, I, Shirts, B, Pritchard, C, Tomlinson, I, King, M, Levy-Lahad, E, Peretz, T, Goldberg, Y

“...One family met diagnostic criteria for Lynch syndrome. Expansion of the hereditary mixed polyposis syndrome phenotype can inform surveillance strategies for carriers of GREM1 duplications....”

Lay perspectives on receiving different types of genomic secondary findings: a qualitative vignette study Por Vornanen, M, Aktan-Collan, K, Hallowell, N, Kontinnen, H, Haukkala, A

“...Participants received a hypothetical letter revealing a SF predisposing to a severe but actionable disease—cardiovascular disease (familial hypercholesterolemia, long QT syndrome) or cancer (Lynch syndrome, Li–Fraumeni syndrome). Participants (N = 29) wrote down their initial reactions, and discussed (N = 23) these in focus groups. ...”

The Mendelian colorectal cancer syndromes Por Tomlinson, I

“...Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1). Lynch syndrome (MSH2, MLH1, MSH6, PMS2), by contrast, is associated primarily with cancer risk. ...”

“I would like to discuss it further with an expert”: a focus group study of Finnish adults’ perspectives on genetic secondary findings Por Vornanen, M, Aktan-Collan, K, Hallowell, N, Konttinen, H, Kääriäinen, H, Haukkala, A

“...In this qualitative study which included four focus group discussions (N = 23) we used four vignette letters, each reporting a genetic SF predisposing to a different disease: familial hypercholesterolemia, long QT syndrome, Lynch syndrome, and Li-Fraumeni syndrome. Transcribed focus group discussions were analyzed using inductive thematic analysis. ...”

Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions Por Fahed, Akl C, Wang, Minxian, Homburger, Julian R, Patel, Aniruddh P, Bick, Alexander G, Neben, Cynthia L, Lai, Carmen, Brockman, Deanna, Philippakis, Anthony, Ellinor, Patrick T, Cassa, Christopher A, Lebo, Matthew, Ng, Kenney, Lander, Eric S, Zhou, Alicia Y, Kathiresan, Sekar, Khera, Amit V

“...Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions — familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background — the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. ...”
Obter o texto integral

Aspirin in the chemoprevention of colorectal neoplasia: an overview. Por Chan, A, Arber, N, Burn, J, Chia, W, Elwood, P, Hull, M, Logan, R, Rothwell, P, Schrör, K, Baron, J

“...Aspirin has also been shown to be beneficial in a clinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirin for at least two years, there was a 50% or more reduction in the risk of CRC commencing five years after randomization and after aspirin had been discontinued. ...”

Colorectal cancer stratification in the routine clinical pathway: A district general hospital experience Por Wedden, S, Miller, K, Frayling, I, Thomas, T, Chefani, A, Miller, K, Hamblin, A, Taylor, J, D'Arrigo, C

“...We have shown that MMR IHC combined with BRAFV600E IHC is practical and easy to perform in a small district general hospital, has full concordance with DNA-based tests and satisfies the latest NICE requirements for the identification of potential Lynch syndrome patients. We provide a framework for the interpretation and presentation of test results. ...”

Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)... Por Monahan, KJ, Bradshaw, N, Dolwani, S, Desouza, B, Dunlop, MG, East, JE, Ilyas, M, Kaur, A, Lalloo, F, Latchford, A, Rutter, MD, Tomlinson, I, Thomas, HJW, Hill, J, Hereditary CRC Guidelines Edelphi Consensus Group

“...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. ...”

Polygenic risk scores for complex diseases: where are we now? Por Loh, Marie, Chambers, John Campbell

“...Indeed, recent findings have pointed to how polygenic background could also increase the accuracy of risk estimation for individuals with monogenic risk variant in conditions such as familial hypercholesterolaemia, hereditary breast and ovarian cancer, and Lynch syndrome....”
Obter o texto integral

Practical guidance for mismatch repair-deficiency testing in endometrial cancer Por Stelloo, E, Jansen, A, Osse, E, Nout, R, Creutzberg, C, Church, D, Morreau, H, Smit, V, van Wezel, T, Bosse, T

“...<strong>Background:</strong> Mismatch repair (MMR)-deficiency analysis is increasingly recommended for all endometrial cancers, as it identifies Lynch syndrome-patients, and is emerging as a prognostic classifier to guide adjuvant treatment. ...”

Germline variant testing in serrated polyposis syndrome Por Murphy, A, Solomons, J, Risby, P, Gabriel, J, Bedenham, T, Johnson, M, Atkinson, N, Bailey, AA, Bird-Lieberman, E, Leedham, SJ, East, JE, Biswas, S

“...The majority were tested for a hereditary colorectal cancer panel including MUTYH, APC, PTEN, SMAD4, BMPR1A, STK11, NTLH1, POLD1, POLE, GREM1 (40-kb duplication), PMS2, and Lynch syndrome mismatch repair genes.<br><br> <strong>Results</strong> One hundred and seventy-three patients were diagnosed with SPS based on World Health Organization 2019 criteria between February 2010 and December 2020. ...”

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion. Por Sengupta, N, Yau, C, Sakthianandeswaren, A, Mouradov, D, Gibbs, P, Suraweera, N, Cazier, J, Polanco-Echeverry, G, Ghosh, A, Thaha, M, Ahmed, S, Feakins, R, Propper, D, Dorudi, S, Sieber, O, Silver, A, Lai, C

“...RESULTS: Age of onset of BAN CRC was significantly lower than for CAU patients (p=3.0 x 10-5) and this difference was not due to Lynch syndrome or the polyposis syndromes. KRAS mutations in BAN microsatellite stable (MSS) CRCs were comparatively rare (5.4%) compared to CAU MSS CRCs (25%; p=0.04), which correlates with the high percentage of mucinous histotype observed (31%) in the BAN samples. ...”