A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome
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Published:2023-04-26
Issue:1
Volume:21
Page:
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ISSN:1479-5876
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Container-title:Journal of Translational Medicine
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language:en
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Short-container-title:J Transl Med
Author:
Walker RomyORCID, 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.ORCID,
Abstract
AbstractRoutine 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; 80×CRCs, 33×ECs 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.
Funder
National Health and Medical Research Council Margaret and Irene Stewardson Fund NHMRC Investigator Grant Dame Kate Campbell Fellowship The University of Melbourne Research Scholarship Victorian Health and Medical Research Fellowship
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
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