Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/138387
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome |
Author: | Walker, R. Mahmood, K. Joo, J.E. Clendenning, M. Georgeson, P. Como, J. Joseland, S. Preston, S.G. Antill, Y. Austin, R. Boussioutas, A. Bowman, M. Burke, J. Campbell, A. Daneshvar, S. Edwards, E. Gleeson, M. Goodwin, A. Harris, M.T. Henderson, A. et al. |
Citation: | Journal of Translational Medicine, 2023; 21(1):282-1-282-15 |
Publisher: | BioMed Central |
Issue Date: | 2023 |
ISSN: | 1479-5876 1479-5876 |
Statement of Responsibility: | Romy Walker ... Nicola Poplawski ... et al. and for the Family Cancer Clinics of Australia |
Abstract: | 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; 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. |
Keywords: | Family Cancer Clinics of Australia Suspected Lynch syndrome; DNA mismatch repair deficiency; Colorectal cancer; Endometrial cancer; Sebaceous skin tumor; Lynch syndrome; MLH1 methylation; Muir-Torre syndrome |
Description: | Published online 26 April 2023 |
Rights: | © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons. org/licenses/ by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
DOI: | 10.1186/s12967-023-04143-1 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/GNT1125269 http://purl.org/au-research/grants/nhmrc/1194896 http://purl.org/au-research/grants/nhmrc/1195099 http://purl.org/au-research/grants/nhmrc/1194392 |
Published version: | http://dx.doi.org/10.1186/s12967-023-04143-1 |
Appears in Collections: | Paediatrics publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
hdl_138387.pdf | Published version | 2.32 MB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.