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Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome
BACKGROUND AND AIMS: Tumor immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins is often used to guide germline genetic testing and variant classification for patients with suspected Lynch syndrome. This analysis examined the spectrum of germline findings in a cohort of individua...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9923021/ https://www.ncbi.nlm.nih.gov/pubmed/36793599 http://dx.doi.org/10.3389/fonc.2023.1069467 |
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author | Pan, Shujuan Cox, Hannah Willmott, Jamie Mundt, Erin Gorringe, Heidi Landon, Michelle Bowles, Karla R. Coffee, Bradford Roa, Benjamin B. Mancini-DiNardo, Debora |
author_facet | Pan, Shujuan Cox, Hannah Willmott, Jamie Mundt, Erin Gorringe, Heidi Landon, Michelle Bowles, Karla R. Coffee, Bradford Roa, Benjamin B. Mancini-DiNardo, Debora |
author_sort | Pan, Shujuan |
collection | PubMed |
description | BACKGROUND AND AIMS: Tumor immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins is often used to guide germline genetic testing and variant classification for patients with suspected Lynch syndrome. This analysis examined the spectrum of germline findings in a cohort of individuals showing abnormal tumor IHC. METHODS: We assessed individuals with reported abnormal IHC findings and referred for testing with a six-gene syndrome-specific panel (n=703). Pathogenic variants (PVs) and variants of uncertain significance (VUS) in MMR genes were designated expected/unexpected relative to IHC results. RESULTS: The PV positive rate was 23.2% (163/703; 95% confidence interval [CI], 20.1%-26.5%); 8.0% (13/163; 95% CI, 4.3%-13.3%) of PV carriers had a PV in an unexpected MMR gene. Overall, 121 individuals carried VUS in MMR genes expected to be mutated based on IHC results. Based on independent evidence, in 47.1% (57/121; 95% CI, 38.0%-56.4%) of these individuals the VUSs were later reclassified as benign and in 14.0% (17/121; 95% CI, 8.4%-21.5%) of these individuals the VUSs were reclassified as pathogenic. CONCLUSIONS: Among patients with abnormal IHC findings, IHC-guided single-gene genetic testing may miss 8% of individuals with Lynch syndrome. In addition, in patients with VUS identified in MMR genes predicted to be mutated by IHC, extreme caution must be taken when the IHC results are considered in variant classification. |
format | Online Article Text |
id | pubmed-9923021 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99230212023-02-14 Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome Pan, Shujuan Cox, Hannah Willmott, Jamie Mundt, Erin Gorringe, Heidi Landon, Michelle Bowles, Karla R. Coffee, Bradford Roa, Benjamin B. Mancini-DiNardo, Debora Front Oncol Oncology BACKGROUND AND AIMS: Tumor immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins is often used to guide germline genetic testing and variant classification for patients with suspected Lynch syndrome. This analysis examined the spectrum of germline findings in a cohort of individuals showing abnormal tumor IHC. METHODS: We assessed individuals with reported abnormal IHC findings and referred for testing with a six-gene syndrome-specific panel (n=703). Pathogenic variants (PVs) and variants of uncertain significance (VUS) in MMR genes were designated expected/unexpected relative to IHC results. RESULTS: The PV positive rate was 23.2% (163/703; 95% confidence interval [CI], 20.1%-26.5%); 8.0% (13/163; 95% CI, 4.3%-13.3%) of PV carriers had a PV in an unexpected MMR gene. Overall, 121 individuals carried VUS in MMR genes expected to be mutated based on IHC results. Based on independent evidence, in 47.1% (57/121; 95% CI, 38.0%-56.4%) of these individuals the VUSs were later reclassified as benign and in 14.0% (17/121; 95% CI, 8.4%-21.5%) of these individuals the VUSs were reclassified as pathogenic. CONCLUSIONS: Among patients with abnormal IHC findings, IHC-guided single-gene genetic testing may miss 8% of individuals with Lynch syndrome. In addition, in patients with VUS identified in MMR genes predicted to be mutated by IHC, extreme caution must be taken when the IHC results are considered in variant classification. Frontiers Media S.A. 2023-01-30 /pmc/articles/PMC9923021/ /pubmed/36793599 http://dx.doi.org/10.3389/fonc.2023.1069467 Text en Copyright © 2023 Pan, Cox, Willmott, Mundt, Gorringe, Landon, Bowles, Coffee, Roa and Mancini-DiNardo https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Pan, Shujuan Cox, Hannah Willmott, Jamie Mundt, Erin Gorringe, Heidi Landon, Michelle Bowles, Karla R. Coffee, Bradford Roa, Benjamin B. Mancini-DiNardo, Debora Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome |
title | Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome |
title_full | Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome |
title_fullStr | Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome |
title_full_unstemmed | Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome |
title_short | Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome |
title_sort | discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected lynch syndrome |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9923021/ https://www.ncbi.nlm.nih.gov/pubmed/36793599 http://dx.doi.org/10.3389/fonc.2023.1069467 |
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