Universal molecular screening does not effectively detect Lynch syndrome in clinical practice
Background: Lynch syndrome (LS) due to an inherited damaging mutation in mismatch repair (MMR) genes comprises 3% of all incident colorectal cancer (CRC). Molecular testing using immunohistochemistry (IHC) for MMR proteins is a recommended screening tool to identify LS in incident CRC. This study as...
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Format: | Article |
Language: | English |
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SAGE Publishing
2017-04-01
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Series: | Therapeutic Advances in Gastroenterology |
Online Access: | https://doi.org/10.1177/1756283X17690990 |
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author | Beatrice Brennan Christine T. Hemmings Ian Clark Desmond Yip Mitali Fadia Douglas R. Taupin |
author_facet | Beatrice Brennan Christine T. Hemmings Ian Clark Desmond Yip Mitali Fadia Douglas R. Taupin |
author_sort | Beatrice Brennan |
collection | DOAJ |
description | Background: Lynch syndrome (LS) due to an inherited damaging mutation in mismatch repair (MMR) genes comprises 3% of all incident colorectal cancer (CRC). Molecular testing using immunohistochemistry (IHC) for MMR proteins is a recommended screening tool to identify LS in incident CRC. This study assessed outcomes of population-based routine molecular screening for diagnosis of LS in a regional center. Methods: We conducted a prospective, consecutive case series study of universal IHC testing on cases of resected CRC from September 2004–December 2013. Referred cases with abnormal IHC results that attended a familial cancer clinic were assessed according to modified Bethesda criteria (until 2009) or molecular criteria (from 2009). Results: 1612 individuals underwent resection for CRC in the study period and had MMR testing by IHC. Of these, 274 cases (16.9%) exhibited loss of expression of MMR genes. The mean age at CRC diagnosis was 68.1 years (± standard deviation 12.7) and the mean age of those with an IHC abnormality was 71.6 (± 11.8). A total of 82 (29.9%) patients with an abnormal result were seen in a subspecialty familial cancer clinic. Patients aged under 50 ( p = 0.009) and those with loss of MSH6 staining ( p = 0.027) were more likely to be referred and to attend. After germ-line sequencing, 0.6% (10 of 82) were identified as having a clinically significant abnormality. A further eight probands with pathogenic germ-line mutations were identified from other referrals to the service over the same time period. Conclusions: While technically accurate, the yield of ‘universal’ IHC in detecting new Lynch probands is limited by real-world factors that reduce referrals and genetic testing. We propose an alternative approach for universal, incident case detection of Lynch syndrome with ‘one-stop’ MMR testing and sequencing. |
first_indexed | 2024-12-23T06:10:05Z |
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id | doaj.art-4e80cc76a90f44fb8af334ff5eabdca1 |
institution | Directory Open Access Journal |
issn | 1756-283X 1756-2848 |
language | English |
last_indexed | 2024-12-23T06:10:05Z |
publishDate | 2017-04-01 |
publisher | SAGE Publishing |
record_format | Article |
series | Therapeutic Advances in Gastroenterology |
spelling | doaj.art-4e80cc76a90f44fb8af334ff5eabdca12022-12-21T17:57:28ZengSAGE PublishingTherapeutic Advances in Gastroenterology1756-283X1756-28482017-04-011010.1177/1756283X17690990Universal molecular screening does not effectively detect Lynch syndrome in clinical practiceBeatrice BrennanChristine T. HemmingsIan ClarkDesmond YipMitali FadiaDouglas R. TaupinBackground: Lynch syndrome (LS) due to an inherited damaging mutation in mismatch repair (MMR) genes comprises 3% of all incident colorectal cancer (CRC). Molecular testing using immunohistochemistry (IHC) for MMR proteins is a recommended screening tool to identify LS in incident CRC. This study assessed outcomes of population-based routine molecular screening for diagnosis of LS in a regional center. Methods: We conducted a prospective, consecutive case series study of universal IHC testing on cases of resected CRC from September 2004–December 2013. Referred cases with abnormal IHC results that attended a familial cancer clinic were assessed according to modified Bethesda criteria (until 2009) or molecular criteria (from 2009). Results: 1612 individuals underwent resection for CRC in the study period and had MMR testing by IHC. Of these, 274 cases (16.9%) exhibited loss of expression of MMR genes. The mean age at CRC diagnosis was 68.1 years (± standard deviation 12.7) and the mean age of those with an IHC abnormality was 71.6 (± 11.8). A total of 82 (29.9%) patients with an abnormal result were seen in a subspecialty familial cancer clinic. Patients aged under 50 ( p = 0.009) and those with loss of MSH6 staining ( p = 0.027) were more likely to be referred and to attend. After germ-line sequencing, 0.6% (10 of 82) were identified as having a clinically significant abnormality. A further eight probands with pathogenic germ-line mutations were identified from other referrals to the service over the same time period. Conclusions: While technically accurate, the yield of ‘universal’ IHC in detecting new Lynch probands is limited by real-world factors that reduce referrals and genetic testing. We propose an alternative approach for universal, incident case detection of Lynch syndrome with ‘one-stop’ MMR testing and sequencing.https://doi.org/10.1177/1756283X17690990 |
spellingShingle | Beatrice Brennan Christine T. Hemmings Ian Clark Desmond Yip Mitali Fadia Douglas R. Taupin Universal molecular screening does not effectively detect Lynch syndrome in clinical practice Therapeutic Advances in Gastroenterology |
title | Universal molecular screening does not effectively detect Lynch syndrome in clinical practice |
title_full | Universal molecular screening does not effectively detect Lynch syndrome in clinical practice |
title_fullStr | Universal molecular screening does not effectively detect Lynch syndrome in clinical practice |
title_full_unstemmed | Universal molecular screening does not effectively detect Lynch syndrome in clinical practice |
title_short | Universal molecular screening does not effectively detect Lynch syndrome in clinical practice |
title_sort | universal molecular screening does not effectively detect lynch syndrome in clinical practice |
url | https://doi.org/10.1177/1756283X17690990 |
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