Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome
PURPOSE: Lynch syndrome (LS)-associated colorectal cancer (CRC) is characterized by mismatch repair-deficiency (MMR-D) and/or microsatellite instability (MSI). However, with increasing utilization of germline testing, MMR-proficient (MMR-P) and/or microsatellite stable (MSS) CRC has also been observed. We sought to characterize MMR-P/MSS CRC among patients with LS.
METHODS: Patients with solid tumors with germline MMR pathogenic/likely pathogenic (P/LP) variants were identified on a prospective matched tumor-normal next-generation sequencing (NGS) protocol. CRCs were evaluated for MMR-D via immunohistochemical (IHC) staining and/or MSI via NGS. Clinical variables were correlated with MMR status using nonparametric tests.
RESULTS: Among 17,617 patients with solid tumors, 1.4% (n = 242) had LS. A total of 36% (86 of 242) of patients with LS had at least one CRC that underwent NGS profiling, amounting to 99 pooled CRCs assessed. A total of 10% (10 of 99) of CRCs were MMR-P, with 100% concordance between MSS status and retained MMR protein staining. A total of 89% (8 of 9) of patients in the MMR-P group had MSH6 or PMS2 variants, compared with 30% (23 of 77) in the MMR-D group (P = .001). A total of 46% (6 of 13) of PMS2+ patients had MMR-P CRC. The median age of onset was 58 and 43 years for MMR-P and MMR-D CRC, respectively (P = .07). Despite the later median age of onset, 40% (4 of 10) of MMR-P CRCs were diagnosed <50. A total of 60% (6 of 10) of MMR-P CRCs were metastatic compared with 13% (12 of 89) of MMR-D CRCs (P = .002). A total of 33% (3 of 9) of patients with MMR-P CRC did not meet LS testing criteria.
CONCLUSION: Patients with LS remained at risk for MMR-P CRC, which was more prevalent among patients with MSH6 and PMS2 variants. MMR-P CRC was later onset and more commonly metastatic compared with MMR-D CRC. Confirmation of tumor MMR/MSI status is critical for patient management and familial risk estimation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:7 |
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| Enthalten in: |
JCO precision oncology - 7(2023) vom: 22. Mai, Seite e2200675 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ranganathan, Megha [VerfasserIn] |
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| Links: |
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| Themen: |
EC 3.6.1.3 |
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| Anmerkungen: |
Date Completed 05.06.2023 Date Revised 02.07.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1200/PO.22.00675 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM357644727 |
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| 041 | |a eng | ||
| 100 | 1 | |a Ranganathan, Megha |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.06.2023 | ||
| 500 | |a Date Revised 02.07.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: Lynch syndrome (LS)-associated colorectal cancer (CRC) is characterized by mismatch repair-deficiency (MMR-D) and/or microsatellite instability (MSI). However, with increasing utilization of germline testing, MMR-proficient (MMR-P) and/or microsatellite stable (MSS) CRC has also been observed. We sought to characterize MMR-P/MSS CRC among patients with LS | ||
| 520 | |a METHODS: Patients with solid tumors with germline MMR pathogenic/likely pathogenic (P/LP) variants were identified on a prospective matched tumor-normal next-generation sequencing (NGS) protocol. CRCs were evaluated for MMR-D via immunohistochemical (IHC) staining and/or MSI via NGS. Clinical variables were correlated with MMR status using nonparametric tests | ||
| 520 | |a RESULTS: Among 17,617 patients with solid tumors, 1.4% (n = 242) had LS. A total of 36% (86 of 242) of patients with LS had at least one CRC that underwent NGS profiling, amounting to 99 pooled CRCs assessed. A total of 10% (10 of 99) of CRCs were MMR-P, with 100% concordance between MSS status and retained MMR protein staining. A total of 89% (8 of 9) of patients in the MMR-P group had MSH6 or PMS2 variants, compared with 30% (23 of 77) in the MMR-D group (P = .001). A total of 46% (6 of 13) of PMS2+ patients had MMR-P CRC. The median age of onset was 58 and 43 years for MMR-P and MMR-D CRC, respectively (P = .07). Despite the later median age of onset, 40% (4 of 10) of MMR-P CRCs were diagnosed <50. A total of 60% (6 of 10) of MMR-P CRCs were metastatic compared with 13% (12 of 89) of MMR-D CRCs (P = .002). A total of 33% (3 of 9) of patients with MMR-P CRC did not meet LS testing criteria | ||
| 520 | |a CONCLUSION: Patients with LS remained at risk for MMR-P CRC, which was more prevalent among patients with MSH6 and PMS2 variants. MMR-P CRC was later onset and more commonly metastatic compared with MMR-D CRC. Confirmation of tumor MMR/MSI status is critical for patient management and familial risk estimation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Mismatch Repair Endonuclease PMS2 |2 NLM | |
| 650 | 7 | |a EC 3.6.1.3 |2 NLM | |
| 700 | 1 | |a Sacca, Rosalba E |e verfasserin |4 aut | |
| 700 | 1 | |a Trottier, Magan |e verfasserin |4 aut | |
| 700 | 1 | |a Maio, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Kemel, Yelena |e verfasserin |4 aut | |
| 700 | 1 | |a Salo-Mullen, Erin |e verfasserin |4 aut | |
| 700 | 1 | |a Catchings, Amanda |e verfasserin |4 aut | |
| 700 | 1 | |a Kane, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chiyun |e verfasserin |4 aut | |
| 700 | 1 | |a Ravichandran, Vignesh |e verfasserin |4 aut | |
| 700 | 1 | |a Ptashkin, Ryan |e verfasserin |4 aut | |
| 700 | 1 | |a Mehta, Nikita |e verfasserin |4 aut | |
| 700 | 1 | |a Garcia-Aguilar, Julio |e verfasserin |4 aut | |
| 700 | 1 | |a Weiser, Martin R |e verfasserin |4 aut | |
| 700 | 1 | |a Donoghue, Mark T A |e verfasserin |4 aut | |
| 700 | 1 | |a Berger, Michael F |e verfasserin |4 aut | |
| 700 | 1 | |a Mandelker, Diana |e verfasserin |4 aut | |
| 700 | 1 | |a Walsh, Michael F |e verfasserin |4 aut | |
| 700 | 1 | |a Carlo, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ying L |e verfasserin |4 aut | |
| 700 | 1 | |a Cercek, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Yaeger, Rona |e verfasserin |4 aut | |
| 700 | 1 | |a Saltz, Leonard |e verfasserin |4 aut | |
| 700 | 1 | |a Segal, Neil H |e verfasserin |4 aut | |
| 700 | 1 | |a Mendelsohn, Robin B |e verfasserin |4 aut | |
| 700 | 1 | |a Markowitz, Arnold J |e verfasserin |4 aut | |
| 700 | 1 | |a Offit, Kenneth |e verfasserin |4 aut | |
| 700 | 1 | |a Shia, Jinru |e verfasserin |4 aut | |
| 700 | 1 | |a Stadler, Zsofia K |e verfasserin |4 aut | |
| 700 | 1 | |a Latham, Alicia |e verfasserin |4 aut | |
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