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A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Cl...

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Autores principales: Walker, Romy, Mahmood, Khalid, Joo, Jihoon E., Clendenning, Mark, Georgeson, Peter, Como, Julia, Joseland, Sharelle, Preston, Susan G., Antill, Yoland, Austin, Rachel, Boussioutas, Alex, Bowman, Michelle, Burke, Jo, Campbell, Ainsley, Daneshvar, Simin, Edwards, Emma, Gleeson, Margaret, Goodwin, Annabel, Harris, Marion T., Henderson, Alex, Higgins, Megan, Hopper, John L., Hutchinson, Ryan A., Ip, Emilia, Isbister, Joanne, Kasem, Kais, Marfan, Helen, Milnes, Di, Ng, Annabelle, Nichols, Cassandra, O’Connell, Shona, Pachter, Nicholas, Pope, Bernard J., Poplawski, Nicola, Ragunathan, Abiramy, Smyth, Courtney, Spigelman, Allan, Storey, Kirsty, Susman, Rachel, Taylor, Jessica A., Warwick, Linda, Wilding, Mathilda, Williams, Rachel, Win, Aung K., Walsh, Michael D., Macrae, Finlay A., Jenkins, Mark A., Rosty, Christophe, Winship, Ingrid M., Buchanan, Daniel D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002795/
https://www.ncbi.nlm.nih.gov/pubmed/36909643
http://dx.doi.org/10.1101/2023.02.27.23285541
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author Walker, Romy
Mahmood, Khalid
Joo, Jihoon E.
Clendenning, Mark
Georgeson, Peter
Como, Julia
Joseland, Sharelle
Preston, Susan G.
Antill, Yoland
Austin, Rachel
Boussioutas, Alex
Bowman, Michelle
Burke, Jo
Campbell, Ainsley
Daneshvar, Simin
Edwards, Emma
Gleeson, Margaret
Goodwin, Annabel
Harris, Marion T.
Henderson, Alex
Higgins, Megan
Hopper, John L.
Hutchinson, Ryan A.
Ip, Emilia
Isbister, Joanne
Kasem, Kais
Marfan, Helen
Milnes, Di
Ng, Annabelle
Nichols, Cassandra
O’Connell, Shona
Pachter, Nicholas
Pope, Bernard J.
Poplawski, Nicola
Ragunathan, Abiramy
Smyth, Courtney
Spigelman, Allan
Storey, Kirsty
Susman, Rachel
Taylor, Jessica A.
Warwick, Linda
Wilding, Mathilda
Williams, Rachel
Win, Aung K.
Walsh, Michael D.
Macrae, Finlay A.
Jenkins, Mark A.
Rosty, Christophe
Winship, Ingrid M.
Buchanan, Daniel D.
author_facet Walker, Romy
Mahmood, Khalid
Joo, Jihoon E.
Clendenning, Mark
Georgeson, Peter
Como, Julia
Joseland, Sharelle
Preston, Susan G.
Antill, Yoland
Austin, Rachel
Boussioutas, Alex
Bowman, Michelle
Burke, Jo
Campbell, Ainsley
Daneshvar, Simin
Edwards, Emma
Gleeson, Margaret
Goodwin, Annabel
Harris, Marion T.
Henderson, Alex
Higgins, Megan
Hopper, John L.
Hutchinson, Ryan A.
Ip, Emilia
Isbister, Joanne
Kasem, Kais
Marfan, Helen
Milnes, Di
Ng, Annabelle
Nichols, Cassandra
O’Connell, Shona
Pachter, Nicholas
Pope, Bernard J.
Poplawski, Nicola
Ragunathan, Abiramy
Smyth, Courtney
Spigelman, Allan
Storey, Kirsty
Susman, Rachel
Taylor, Jessica A.
Warwick, Linda
Wilding, Mathilda
Williams, Rachel
Win, Aung K.
Walsh, Michael D.
Macrae, Finlay A.
Jenkins, Mark A.
Rosty, Christophe
Winship, Ingrid M.
Buchanan, Daniel D.
author_sort Walker, Romy
collection PubMed
description Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n=137; 80xCRCs, 33xECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.
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spelling pubmed-100027952023-03-11 A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome Walker, Romy Mahmood, Khalid Joo, Jihoon E. Clendenning, Mark Georgeson, Peter Como, Julia Joseland, Sharelle Preston, Susan G. Antill, Yoland Austin, Rachel Boussioutas, Alex Bowman, Michelle Burke, Jo Campbell, Ainsley Daneshvar, Simin Edwards, Emma Gleeson, Margaret Goodwin, Annabel Harris, Marion T. Henderson, Alex Higgins, Megan Hopper, John L. Hutchinson, Ryan A. Ip, Emilia Isbister, Joanne Kasem, Kais Marfan, Helen Milnes, Di Ng, Annabelle Nichols, Cassandra O’Connell, Shona Pachter, Nicholas Pope, Bernard J. Poplawski, Nicola Ragunathan, Abiramy Smyth, Courtney Spigelman, Allan Storey, Kirsty Susman, Rachel Taylor, Jessica A. Warwick, Linda Wilding, Mathilda Williams, Rachel Win, Aung K. Walsh, Michael D. Macrae, Finlay A. Jenkins, Mark A. Rosty, Christophe Winship, Ingrid M. Buchanan, Daniel D. medRxiv Article Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n=137; 80xCRCs, 33xECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations. Cold Spring Harbor Laboratory 2023-03-01 /pmc/articles/PMC10002795/ /pubmed/36909643 http://dx.doi.org/10.1101/2023.02.27.23285541 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Walker, Romy
Mahmood, Khalid
Joo, Jihoon E.
Clendenning, Mark
Georgeson, Peter
Como, Julia
Joseland, Sharelle
Preston, Susan G.
Antill, Yoland
Austin, Rachel
Boussioutas, Alex
Bowman, Michelle
Burke, Jo
Campbell, Ainsley
Daneshvar, Simin
Edwards, Emma
Gleeson, Margaret
Goodwin, Annabel
Harris, Marion T.
Henderson, Alex
Higgins, Megan
Hopper, John L.
Hutchinson, Ryan A.
Ip, Emilia
Isbister, Joanne
Kasem, Kais
Marfan, Helen
Milnes, Di
Ng, Annabelle
Nichols, Cassandra
O’Connell, Shona
Pachter, Nicholas
Pope, Bernard J.
Poplawski, Nicola
Ragunathan, Abiramy
Smyth, Courtney
Spigelman, Allan
Storey, Kirsty
Susman, Rachel
Taylor, Jessica A.
Warwick, Linda
Wilding, Mathilda
Williams, Rachel
Win, Aung K.
Walsh, Michael D.
Macrae, Finlay A.
Jenkins, Mark A.
Rosty, Christophe
Winship, Ingrid M.
Buchanan, Daniel D.
A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome
title A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome
title_full A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome
title_fullStr A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome
title_full_unstemmed A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome
title_short A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome
title_sort tumor focused approach to resolving the etiology of dna mismatch repair deficient tumors classified as suspected lynch syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002795/
https://www.ncbi.nlm.nih.gov/pubmed/36909643
http://dx.doi.org/10.1101/2023.02.27.23285541
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