20 results on '"Clendenning, Mark"'
Search Results
2. Mismatch repair gene pathogenic germline variants in a population-based cohort of breast cancer
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Nguyen-Dumont, Tu, Steen, Jason A., Winship, Ingrid, Park, Daniel J., Pope, Bernard J., Hammet, Fleur, Mahmoodi, Maryam, Tsimiklis, Helen, Theys, Derrick, Clendenning, Mark, Giles, Graham G., Hopper, John L., and Southey, Melissa C.
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- 2020
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3. Identifying primary and secondary MLH1 epimutation carriers displaying low-level constitutional MLH1 methylation using droplet digital PCR and genome-wide DNA methylation profiling of colorectal cancers
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Joo, Jihoon E., Mahmood, Khalid, Walker, Romy, Georgeson, Peter, Candiloro, Ida, Clendenning, Mark, Como, Julia, Joseland, Sharelle, Preston, Susan, Graversen, Lise, Wilding, Mathilda, Field, Michael, Lemon, Michelle, Wakeling, Janette, Marfan, Helen, Susman, Rachel, Isbister, Joanne, Edwards, Emma, Bowman, Michelle, Kirk, Judy, Ip, Emilia, McKay, Lynne, Antill, Yoland, Hopper, John L., Boussioutas, Alex, Macrae, Finlay A., Dobrovic, Alexander, Jenkins, Mark A., Rosty, Christophe, Winship, Ingrid M., and Buchanan, Daniel D.
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Genome wide DNA methylation ,MLH1 epimutation ,Lynch syndrome ,MLH1 methylation ,MMR deficiency ,Colorectal cancer - Abstract
Background: MLH1 epimutation is characterised by constitutional monoallelic MLH1 promoter hypermethylation, which can cause colorectal cancer (CRC). Tumour molecular profiles of MLH1 epimutation CRCs were used to classify germline MLH1 promoter variants of uncertain significance and MLH1 methylated early-onset CRCs (EOCRCs). Genome-wide DNA methylation and somatic mutational profiles of tumours from two germline MLH1: c.-11C > T and one MLH1: c.-[28A > G; 7C > T] carriers and three MLH1 methylated EOCRCs (< 45 years) were compared with 38 reference CRCs. Methylation-sensitive droplet digital PCR (ddPCR) was used to detect mosaic MLH1 methylation in blood, normal mucosa and buccal DNA. Results: Genome-wide methylation-based Consensus Clustering identified four clusters where the tumour methylation profiles of germline MLH1: c.-11C > T carriers and MLH1 methylated EOCRCs clustered with the constitutional MLH1 epimutation CRCs but not with the sporadic MLH1 methylated CRCs. Furthermore, monoallelic MLH1 methylation and APC promoter hypermethylation in tumour were observed in both MLH1 epimutation and germline MLH1: c.-11C > T carriers and MLH1 methylated EOCRCs. Mosaic constitutional MLH1 methylation in MLH1: c.-11C > T carriers and 1 of 3 MLH1 methylated EOCRCs was identified by methylation-sensitive ddPCR. Conclusions: Mosaic MLH1 epimutation underlies the CRC aetiology in MLH1: c.-11C > T germline carriers and a subset of MLH1 methylated EOCRCs. Tumour profiling and ultra-sensitive ddPCR methylation testing can be used to identify mosaic MLH1 epimutation carriers.
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- 2023
4. DNA Mismatch Repair Gene Variant Classification: Evaluating the Utility of Somatic Mutations and Mismatch Repair Deficient Colonic Crypts and Endometrial Glands.
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Walker, Romy, Mahmood, Khalid, Como, Julia, Clendenning, Mark, Joo, Jihoon E., Georgeson, Peter, Joseland, Sharelle, Preston, Susan G., Pope, Bernard J., Chan, James M., Austin, Rachel, Bojadzieva, Jasmina, Campbell, Ainsley, Edwards, Emma, Gleeson, Margaret, Goodwin, Annabel, Harris, Marion T., Ip, Emilia, Kirk, Judy, and Mansour, Julia
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INTESTINAL mucosa physiology ,ENDOMETRIUM physiology ,DNA ,GENETIC mutation ,IMMUNOHISTOCHEMISTRY ,HEREDITARY nonpolyposis colorectal cancer ,GENETIC testing ,GENES ,RESEARCH funding - Abstract
Simple Summary: Lynch syndrome is caused by germline pathogenic variants in the DNA mismatch repair (MMR) genes predisposing carriers to colorectal and endometrial cancer. Genetic testing for Lynch syndrome, in the form of multigene panel testing, frequently identifies variants of uncertain clinical significance (VUS). These VUS have limited clinical actionability and create uncertainty for patients and clinicians regarding their risk of cancer. In this study, we tested carriers of germline VUS for features consistent with Lynch syndrome, namely (1) tumor microsatellite instability/MMR-deficiency, (2) the presence of a somatic second hit in the MMR gene harboring the VUS by tumor sequencing and (3) the presence of MMR-deficiency in normal colonic mucosa crypts or normal endometrial glands. Our findings showed that microsatellite instability/MMR-deficiency status and somatic second hits were consistent with MMR variant classifications as determined by the ACMG/InSiGHT framework. In addition to this, the presence of MMR-deficient crypts/glands were consistent with pathogenic variant classification. Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. Lynch syndrome specific tumor features were evaluated for their ability to support the ACMG/InSiGHT framework in classifying variants of uncertain clinical significance (VUS) in the MMR genes. Twenty-eight CRC or EC tumors from 25 VUS carriers (6xMLH1, 9xMSH2, 6xMSH6, 4xPMS2), underwent targeted tumor sequencing for the presence of microsatellite instability/MMR-deficiency (MSI-H/dMMR) status and identification of a somatic MMR mutation (second hit). Immunohistochemical testing for the presence of dMMR crypts/glands in normal tissue was also performed. The ACMG/InSiGHT framework reclassified 7/25 (28%) VUS to likely pathogenic (LP), three (12%) to benign/likely benign, and 15 (60%) VUS remained unchanged. For the seven re-classified LP variants comprising nine tumors, tumor sequencing confirmed MSI-H/dMMR (8/9, 88.9%) and a second hit (7/9, 77.8%). Of these LP reclassified variants where normal tissue was available, the presence of a dMMR crypt/gland was found in 2/4 (50%). Furthermore, a dMMR endometrial gland in a carrier of an MSH2 exon 1-6 duplication provides further support for an upgrade of this VUS to LP. Our study confirmed that identifying these Lynch syndrome features can improve MMR variant classification, enabling optimal clinical care. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas
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Clendenning, Mark, Huang, Alvin, Jayasekara, Harindra, Lorans, Marie, Preston, Susan, O’Callaghan, Neil, Pope, Bernard J., Macrae, Finlay A., Winship, Ingrid M., Milne, Roger L., Giles, Graham G., English, Dallas R., Hopper, John L., Win, Aung K., Jenkins, Mark A., Southey, Melissa C., Rosty, Christophe, Buchanan, Daniel D., and On behalf of investigators from the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort
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- 2017
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6. RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers
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Fennell, Lochlan J., Clendenning, Mark, McKeone, Diane M., Jamieson, Saara H., Balachandran, Samanthy, Borowsky, Jennifer, Liu, John, Kawamata, Futoshi, Bond, Catherine E., Rosty, Christophe, Burge, Matthew E., Buchanan, Daniel D., Leggett, Barbara A., and Whitehall, Vicki L. J.
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- 2017
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7. Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene
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Win, Aung Ko, Reece, Jeanette C., Buchanan, Daniel D., Clendenning, Mark, Young, Joanne P., Cleary, Sean P., Kim, Hyeja, Cotterchio, Michelle, Dowty, James G., MacInnis, Robert J., Tucker, Katherine M., Winship, Ingrid M., Macrae, Finlay A., Burnett, Terrilea, Le Marchand, Loïc, Casey, Graham, Haile, Robert W., Newcomb, Polly A., Thibodeau, Stephen N., Lindor, Noralane M., Hopper, John L., Gallinger, Steven, and Jenkins, Mark A.
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- 2015
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8. High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry
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Rosty, Christophe, Walsh, Michael D., Lindor, Noralane M., Thibodeau, Stephen N., Mundt, Erin, Gallinger, Steven, Aronson, Melyssa, Pollett, Aaron, Baron, John A., Pearson, Sally, Clendenning, Mark, Walters, Rhiannon J., Nagler, Belinda N., Crawford, William J., Young, Joanne P., Winship, Ingrid, Win, Aung Ko, Hopper, John L., Jenkins, Mark A., and Buchanan, Daniel D.
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- 2014
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9. Detection of large scale 3′ deletions in the PMS2 gene amongst Colon-CFR participants: have we been missing anything?
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Clendenning, Mark, Walsh, Michael D., Gelpi, Judith Balmana, Thibodeau, Stephen N., Lindor, Noralane, Potter, John D., Newcomb, Polly, LeMarchand, Loic, Haile, Robert, Gallinger, Steve, Hopper, John L., Jenkins, Mark A., Rosty, Christophe, Young, Joanne P., Buchanan, Daniel D., and Colorectal Cancer Family Registry
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- 2013
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10. Mutation deep within an intron of MSH2 causes Lynch syndrome
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Clendenning, Mark, Buchanan, Daniel D., Walsh, Michael D., Nagler, Belinda, Rosty, Christophe, Thompson, Bryony, Spurdle, Amanda B., Hopper, John L., Jenkins, Mark A., and Young, Joanne P.
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- 2011
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11. Epitope-positive truncating MLH1 mutation and loss of PMS2: implications for IHC-directed genetic testing for lynch syndrome
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Zighelboim, Israel, Powell, Matthew A., Babb, Sheri A., Whelan, Alison J., Schmidt, Amy P., Clendenning, Mark, Senter, Leigha, Thibodeau, Stephen N., de la Chapelle, Albert, and Goodfellow, Paul J.
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- 2009
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12. Analysis of families with Lynch syndrome complicated by advanced serrated neoplasia: the importance of pathology review and pedigree analysis
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Walsh, Michael D., Buchanan, Daniel D., Walters, Rhiannon, Roberts, Aedan, Arnold, Sven, McKeone, Diane, Clendenning, Mark, Ruszkiewicz, Andrew R., Jenkins, Mark A., Hopper, John L., Goldblatt, Jack, George, Jillian, Suthers, Graeme K., Phillips, Kerry, Young, Graeme P., Macrae, Finlay, Drini, Musa, Woods, Michael O., Parry, Susan, Jass, Jeremy R., and Young, Joanne P.
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- 2009
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13. Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas.
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Clendenning, Mark, Huang, Alvin, Jayasekara, Harindra, Lorans, Marie, Preston, Susan, O’Callaghan, Neil, Pope, Bernard J., Macrae, Finlay A., Winship, Ingrid M., Milne, Roger L., Giles, Graham G., English, Dallas R., Hopper, John L., Win, Aung K., Jenkins, Mark A., Southey, Melissa C., Rosty, Christophe, Buchanan, Daniel D., and On behalf of investigators from the Melbourne Collaborative Cohort Study and the Australasian Colorectal Cancer Family Registry Cohort
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In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin ( B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival by B2M mutation status were estimated using Cox regression, adjusting for age at CRC diagnosis, sex, AJCC stage and grade. B2M mutations occurred in 30 (20.8%) of the 144 MMR-deficient CRCs (29% of the MLH1-methylated, 17% of the Lynch syndrome and 9% of the suspected Lynch CRCs). No B2M mutations were identified in the 63 adenomas tested. B2M mutations differed by site, stage, grade and lymphocytic infiltration although none reached statistical significance (p > 0.05). The HR for overall survival for B2M mutated CRC was 0.65 (95% CI 0.29-1.48) compared with B2M wild-type. We observed differences in B2M mutation status in MMR-deficient CRC by tumour subtypes, site, stage, grade, immune infiltrate and for overall survival that warrant further investigation in larger studies before B2M mutation status can be considered to have clinical utility. [ABSTRACT FROM AUTHOR]
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- 2018
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14. RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers.
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Fennell, Lochlan J., Clendenning, Mark, McKeone, Diane M., Jamieson, Saara H., Balachandran, Samanthy, Borowsky, Jennifer, Liu, John, Kawamata, Futoshi, Bond, Catherine E., Rosty, Christophe, Burge, Matthew E., Buchanan, Daniel D., Leggett, Barbara A., and Whitehall, Vicki L. J.
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The WNT signaling pathway is commonly altered during colorectal cancer development. The E3 ubiquitin ligase, RNF43, negatively regulates the WNT signal through increased ubiquitination and subsequent degradation of the Frizzled receptor. RNF43 has recently been reported to harbor frequent truncating frameshift mutations in sporadic microsatellite unstable (MSI) colorectal cancers. This study assesses the relative frequency of RNF43 mutations in hereditary colorectal cancers arising in the setting of Lynch syndrome. The entire coding region of RNF43 was Sanger sequenced in 24 colorectal cancers from 23 patients who either (i) carried a germline mutation in one of the DNA mismatch repair genes ( MLH1, MSH6, MSH2, PMS2), or (ii) showed immunohistochemical loss of expression of one or more of the DNA mismatch repair proteins, was BRAF wild type at V600E, were under 60 years of age at diagnosis, and demonstrated no promoter region methylation for MLH1 in tumor DNA. A validation cohort of 44 colorectal cancers from mismatch repair germline mutation carriers from the Australasian Colorectal Cancer Family Registry (ACCFR) were sequenced for the most common truncating mutation hotspots (X117 and X659). RNF43 mutations were found in 9 of 24 (37.5%) Lynch syndrome colorectal cancers. The majority of mutations were frameshift deletions in the G659 G7 repeat tract (29%); 2 cancers (2/24, 8%) from the one patient harbored frameshift mutations at codon R117 (C6 repeat tract) within exon 3. In the ACCFR validation cohort, RNF43 hotspot mutations were identified in 19/44 (43.2%) of samples, which was not significantly different to the initial series. The proportion of mutant RNF43 in Lynch syndrome related colorectal cancers is significantly lower than the previously reported mutation rate found in sporadic MSI colorectal cancers. These findings identify further genetic differences between sporadic and hereditary colorectal cancers. This may be because Lynch Syndrome cancers commonly arise in colorectal adenomas already bearing the APC mutation, whereas sporadic microsatellite unstable colorectal cancers arise from serrated polyps typically lacking APC mutation, decreasing the selection pressure on other WNT signaling related loci in Lynch syndrome. [ABSTRACT FROM AUTHOR]
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- 2018
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15. Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts.
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Buchanan, Daniel D, Clendenning, Mark, Rosty, Christophe, Eriksen, Stine V, Walsh, Michael D, Walters, Rhiannon J, Thibodeau, Stephen N, Stewart, Jenna, Preston, Susan, Win, Aung Ko, Flander, Louisa, Ait Ouakrim, Driss, Macrae, Finlay A, Boussioutas, Alex, Winship, Ingrid M, Giles, Graham G, Hopper, John L, Southey, Melissa C, English, Dallas, and Jenkins, Mark A
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HEREDITARY nonpolyposis colorectal cancer , *COLON cancer , *GENETIC disorders , *LYNCH syndrome II , *IMMUNOHISTOCHEMISTRY , *MICROSATELLITE repeats - Abstract
Background and Aim Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches. Methods Colorectal cancers from 813 patients diagnosed with CRC < 60 years of age from the Australasian Colorectal Cancer Family Registry (ACCFR) and from 826 patients from the Melbourne Collaborative Cohort Study (MCCS) were tested for MMR protein expression using immunohistochemistry, microsatellite instability (MSI), BRAFV600E somatic mutation, and for MLH1 methylation. MMR gene mutation testing (Sanger sequencing and Multiplex Ligation Dependent Probe Amplification) was performed on germline DNA of patients with MMR-deficient tumors and a subset of MMR-proficient CRCs. Results Of the 813 ACCFR probands, 90 probands demonstrated tumor MMR deficiency (11.1%), and 42 had a MMR gene germline mutation (5.2%). For the MCCS, MMR deficiency was identified in the tumors of 103 probands (12.5%) and seven had a germline mutation (0.8%). All the mutation carriers were diagnosed prior to 70 years of age. Probands with a MMR-deficient CRC without MLH1 methylation and a gene mutation were considered Lynch-like and comprised 41.1% and 25.2% of the MMR-deficient CRCs for the ACCFR and MCCS, respectively. Conclusions Identification of MMR gene mutation carriers in Australian CRC-affected patients is optimized by immunohistochemistry screening of CRC diagnosed before 70 years of age. A significant proportion of MMR-deficient CRCs will have unknown etiology (Lynch-like) proving problematic for clinical management. [ABSTRACT FROM AUTHOR]
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- 2017
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16. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database
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Thompson, Bryony A, Spurdle, Amanda B, Plazzer, John-Paul, Greenblatt, Marc S, Akagi, Kiwamu, Al-Mulla, Fahd, Bapat, Bharati, Bernstein, Inge, Capellá, Gabriel, den Dunnen, Johan T, du Sart, Desiree, Fabre, Aurelie, Farrell, Michael P, Farrington, Susan M, Frayling, Ian M, Frebourg, Thierry, Goldgar, David E, Heinen, Christopher D, Holinski-Feder, Elke, Kohonen-Corish, Maija, Robinson, Kristina Lagerstedt, Leung, Suet Yi, Martins, Alexandra, Moller, Pal, Morak, Monika, Nystrom, Minna, Peltomaki, Paivi, Pineda, Marta, Qi, Ming, Ramesar, Rajkumar, Rasmussen, Lene Juel, Royer-Pokora, Brigitte, Scott, Rodney J, Sijmons, Rolf, Tavtigian, Sean V, Tops, Carli M, Weber, Thomas, Wijnen, Juul, Woods, Michael O, Macrae, Finlay, Genuardi, Maurizio, Castillejo, Adela, Sexton, Adrienne, Chan, Anthony K W, Viel, Alessandra, Blanco, Amie, French, Amy, Laner, Andreas, Wagner, Anja, van den Ouweland, Ans, Mensenkamp, Arjen, Payá, Artemio, Betz, Beate, Redeker, Bert, Smith, Betsy, Espenschied, Carin, Cummings, Carole, Engel, Christoph, Fornes, Claudia, Valenzuela, Cristian, Alenda, Cristina, Buchanan, Daniel, Barana, Daniela, Konstantinova, Darina, Cairns, Dianne, Glaser, Elizabeth, Silva, Felipe, Lalloo, Fiona, Crucianelli, Francesca, Hogervorst, Frans, Casey, Graham, Tomlinson, Ian, Blanco, Ignacio, Villar, Isabel López, Garcia-Planells, Javier, Bigler, Jeanette, Shia, Jinru, Martinez-Lopez, Joaquin, Gille, Johan J P, Hopper, John, Potter, John, Soto, José Luis, Kantelinen, Jukka, Ellis, Kate, Mann, Kirsty, Varesco, Liliana, Zhang, Liying, Le Marchand, Loic, Marafie, Makia J, Nordling, Margareta, Tibiletti, Maria Grazia, Kahan, Mariano Ariel, Ligtenberg, Marjolijn, Clendenning, Mark, Jenkins, Mark, Speevak, Marsha, Digweed, Martin, Kloor, Matthias, Hitchins, Megan, Myers, Megan, Aronson, Melyssa, Valentin, Mev Dominguez, Kutsche, Michael, Parsons, Michael, Walsh, Michael, Kansikas, Minttu, Zahary, Mohd Nizam, Pedroni, Monica, Heider, Nao, Poplawski, Nicola, Rahner, Nils, Lindor, Noralane M, Sala, Paola, Nan, Peng, Propping, Peter, Newcomb, Polly, Sarin, Rajiv, Haile, Robert, Hofstra, Robert, Ward, Robyn, Tricarico, Rossella, Bacares, Ruben, Young, Sean, Chialina, Sergio, Kovalenko, Serguei, Gunawardena, Shanaka R, Moreno, Sira, Ho, Siu Lun, Yuen, Siu Tsan, Thibodeau, Stephen N, Gallinger, Steve, Burnett, Terrilea, Teitsch, Therese, Chan, Tsun Leung, Smyrk, Tom, Cranston, Treena, Psofaki, Vasiliki, Steinke-Lange, Verena, Barbera, Victor-Manuel, Universitat de Barcelona, Queensland Institute of Medical Research, sans affiliation, HNPCC-register, Hvidovre Hospital, University of Copenhagen = Københavns Universitet (KU), Programa de Diagnòstic Molecular de Càncer Hereditari, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals, Hospitalet de Llobregat, Human Genetics, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute of Medical Genetics, University Hospital of Wales, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), International Agency for Cancer Research (IACR), University Hospital of the Ludwig-Maximilians University, University Hospital of the Ludwig-Maximilian-University Munich, Medizinische Klinik â€' Innenstadt, Lehrstuhl für Endokrinologie/Diabetologie, Department of Biosciences, School of Materials and Metallurgy, Northeastern University [Boston], Department of Science, Discipline of Medical Genetic, Faculty of Health, The Hunter Medical Research Institute, University of Newcastle, Department of Oncological Sciences, University of Utah-Huntsman Cancer Institute, Department of Earth and Environmental Sciences [Rochester], University of Rochester [USA], Department of Clinical Genetics and GROM, School for Oncology and Developmental Biology, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Medical Genetics Unit, Department of Clinical Physiopathology, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Other Research, Neurology, Ethical, Legal, Social Issues in Genetics (ELSI), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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medicine.medical_specialty ,InSiGHT locus-specific database ,MICROSATELLITE INSTABILITY ,[SDV]Life Sciences [q-bio] ,MEDLINE ,MISSENSE SUBSTITUTIONS ,Locus (genetics) ,MSH6 GERMLINE MUTATIONS ,Biology ,computer.software_genre ,Settore MED/03 - GENETICA MEDICA ,DNA Mismatch Repair ,LYNCH-SYNDROME ,Article ,Multidisciplinary approach ,Càncer colorectal ,Databases, Genetic ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,SEQUENCE VARIANTS ,Genetics ,medicine ,PMS2 ,Malalties hereditàries ,Humans ,ComputingMilieux_MISCELLANEOUS ,Gastrointestinal Neoplasms ,Tumors ,Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] ,Database ,Classification ,Disease Management ,Genetic Variation ,UNKNOWN CLINICAL-SIGNIFICANCE ,COLON-CANCER ,NONPOLYPOSIS COLORECTAL-CANCER ,HUMAN GENOME VARIATION ,medicine.disease ,Colorectal cancer ,Lynch syndrome ,3. Good health ,MSH6 ,TUMOR CHARACTERISTICS ,MSH2 ,Medical genetics ,computer ,Genetic diseases - Abstract
Contains fulltext : 138857.pdf (Publisher’s version ) (Closed access) The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. 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. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.
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- 2014
17. Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome.
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Chau, Rowena, Ghazaleh, Seyedeh, Dashti, Ouakrim, Driss Ait, Buchanan, Daniel D., Clendenning, Mark, Rosty, Christophe, Winship, Ingrid M., Young, Joanne P., Giles, Graham G., Macrae, Finlay A., Boussioutas, Alex, Parry, Susan, Figueiredo, Jane C., Levine, A. Joan, Ahnen, Dennis J., Casey, Graham, Haile, Robert W., Gallinger, Steven, and Marchand, Loïc Le
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CANCER risk factors ,HEREDITARY nonpolyposis colorectal cancer ,FOLIC acid in human nutrition ,CALCIUM supplements ,DNA repair ,GENETIC mutation ,CALCIUM ,DIETARY supplements ,DNA ,FOLIC acid ,RESEARCH funding ,VITAMINS ,ACQUISITION of data ,PROPORTIONAL hazards models ,GENETIC carriers - Abstract
Background: People with a DNA mismatch repair (MMR) gene mutation have a substantially elevated risk of colorectal cancer (CRC) but the modifiers of this risk are not well established. We investigated the association between dietary supplement intake and CRC risk for carriers.Methods: This study included 1966 (56% female) carriers of an MMR gene mutation (719 MLH1, 931 MSH2, 211 MSH6 and 105 PMS2) who were recruited from the USA, Canada, Australia and New Zealand into the Colon Cancer Family Registry between 1997 and 2012. Information on lifestyle factors including supplement intake was collected at the time of recruitment. Using Cox proportional hazards regression weighted to correct for ascertainment bias, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between self-reported multivitamin, calcium and folic acid supplement intake and CRC risk.Results: Of 744 carriers with CRC, 18%, 6% and 5% reported intake of multivitamin, calcium and folic acid supplements for at least 1 month, respectively, compared with 27%, 11% and 10% of 1222 carriers without CRC. After adjusting for identified confounding variables, a decreased CRC risk was associated with multivitam inintake for at least 3 years (HR 0.47, 95% CI 0.32-0.69) and calcium intake for at least 3 years(HR 0.42, 95% CI 0.23-0.74), compared with never users. There was no evidence of an association between folic acid supplement intake and CRC risk (P = 0.82).Conclusion: Intake of multivitamin and calcium supplements might be associated with a decreased risk of CRC for MMR gene mutation carriers. [ABSTRACT FROM AUTHOR]- Published
- 2016
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18. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome).
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Daniel, Buchanan D., Rosty, Christophe, Clendenning, Mark, Amanda, Spurdle B., and Aung, Ko Win
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COLON cancer diagnosis ,GENETICS of colon cancer ,COLON tumors ,GERM cells ,DNA repair ,PROTEIN expression ,GENETIC testing ,GENETICS - Abstract
Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these "Lynch-like" or "suspected Lynch syndrome" cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic inactivation. Determining the underlying cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely to reshape the current triaging schemes used to identify germline MMR gene mutations in cancer-affected individuals and their relatives. [ABSTRACT FROM AUTHOR]
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- 2014
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19. Cancer Risks for MLH 1 and MSH 2 Mutation Carriers.
- Author
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Dowty, James G., Win, Aung K., Buchanan, Daniel D., Lindor, Noralane M., Macrae, Finlay A., Clendenning, Mark, Antill, Yoland C., Thibodeau, Stephen N., Casey, Graham, Gallinger, Steve, Marchand, Loic Le, Newcomb, Polly A., Haile, Robert W., Young, Graeme P., James, Paul A., Giles, Graham G., Gunawardena, Shanaka R., Leggett, Barbara A., Gattas, Michael, and Boussioutas, Alex
- Abstract
ABSTRACT We studied 17,576 members of 166 MLH 1 and 224 MSH 2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer ( CRC), endometrial cancer ( EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH 1 and MSH 2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed ( P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH 2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH 1 and MSH 2 mutation carriers are the most precise currently available. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
20. Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome.
- Author
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Georgeson, Peter, Walsh, Michael D., Clendenning, Mark, Daneshvar, Simin, Pope, Bernard J., Mahmood, Khalid, Joo, Jihoon E., Jayasekara, Harindra, Jenkins, Mark A., Winship, Ingrid M., and Buchanan, Daniel D.
- Subjects
HEREDITARY nonpolyposis colorectal cancer ,CIRCULATING tumor DNA ,MICROSATELLITE repeats ,SOMATIC mutation ,TUMORS ,ULTRAVIOLET radiation ,SKIN - Abstract
Background: Muir‐Torre syndrome is defined by the development of sebaceous skin lesions in individuals who carry a germline mismatch repair (MMR) gene mutation. Loss of expression of MMR proteins is frequently observed in sebaceous skin lesions, but MMR‐deficiency alone is not diagnostic for carrying a germline MMR gene mutation. Methods: Whole exome sequencing was performed on three MMR‐deficient sebaceous lesions from individuals with MSH2 gene mutations (Lynch syndrome) and three MMR‐proficient sebaceous lesions from individuals without Lynch syndrome with the aim of characterizing the tumor mutational signatures, somatic mutation burden, and microsatellite instability status. Thirty predefined somatic mutational signatures were calculated for each lesion. Results: Signature 1 was ubiquitous across the six lesions tested. Signatures 6 and 15, associated with defective DNA MMR, were significantly more prevalent in the MMR‐deficient lesions from the MSH2 carriers compared with the MMR‐proficient non‐Lynch sebaceous lesions (mean ± SD=41.0 ± 8.2% vs. 2.3 ± 4.0%, p = 0.0018). Tumor mutation burden was, on average, significantly higher in the MMR‐deficient lesions compared with the MMR‐proficient lesions (23.3 ± 11.4 vs. 1.8 ± 0.8 mutations/Mb, p = 0.03). All four sebaceous lesions observed in sun exposed areas of the body demonstrated signature 7 related to ultraviolet light exposure. Conclusion: Tumor mutational signatures 6 and 15 and somatic mutation burden were effective in differentiating Lynch‐related from non‐Lynch sebaceous lesions. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
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