Synapse - Prevalence and clinical implications of mismatch repair-proficient colorectal cancer in patients with Lynch syndrome

Prevalence and clinical implications of mismatch repair-proficient colorectal cancer in patients with Lynch syndrome Journal Article

Authors:	Ranganathan, M.; Sacca, R. E.; Trottier, M.; Maio, A.; Kemel, Y.; Salo-Mullen, E.; Catchings, A.; Kane, S.; Wang, C.; Ravichandran, V.; Ptashkin, R.; Mehta, N.; Garcia-Aguilar, J.; Weiser, M. R.; Donoghue, M. T. A.; Berger, M. F.; Mandelker, D.; Walsh, M. F.; Carlo, M.; Liu, Y. L.; Cercek, A.; Yaeger, R.; Saltz, L.; Segal, N. H.; Mendelsohn, R. B.; Markowitz, A. J.; Offit, K.; Shia, J.; Stadler, Z. K.; Latham, A.
Article Title:	Prevalence and clinical implications of mismatch repair-proficient colorectal cancer in patients with Lynch syndrome
Abstract:	PURPOSELynch 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. METHODSPatients 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. RESULTSAmong 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. CONCLUSIONPatients 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.
Keywords:	chemotherapy; statistics; guidelines; colon; mutations; association; feasibility; microsatellite-instability; epcam; interval cancers
Journal Title:	JCO Precision Oncology
Volume:	7
ISSN:	2473-4284
Publisher:	American Society of Clinical Oncology
Date Published:	2023-09-01
Start Page:	e2200675
Language:	English
ACCESSION:	WOS:001197689200044
DOI:	10.1200/po.22.00675
PROVIDER:	wos
PMCID:	PMC10309569
PUBMED:	37262391
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Alicia Latham -- Source: Wos