MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: Reversion of a frameshifted coding microsatellite to its wild-type sequence Journal Article

   

Authors:	Shia, J.; Sanchez-Vega, F.; Cho, S.; Chen, J. F.; Chen, C. T.; Bhanot, U.; Urganci, N.; Firat, C.; Ntiamoah, P.; Isidro, R. A.; Srivastava, A.; Weiser, M. R.; Mandelker, D.; Vakiani, E.; Boland, C. R.; Garcia-Aguilar, J.; Stadler, Z. K.
Article Title:	MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: Reversion of a frameshifted coding microsatellite to its wild-type sequence
Abstract:	The discovery of “mismatch repair deficient (MMRd)-crypt foci” in non-neoplastic intestinal mucosa in Lynch syndrome (LS) has significantly enhanced our understanding of how tumors and tumor immunity form and evolve in LS. In this study, we report the frequent presence of “mismatch repair proficient (MMRp)-crypt foci” in both non-neoplastic and neoplastic intestinal mucosa in a patient with constitutional MMR deficiency (CMMRD), who carried a germline MSH6 pathogenic variant (c.3261dupC) in trans with an MSH6 likely pathogenic variant (c.3724_3726del) and whose tissues were otherwise deficient in MMR globally. The MMRp-crypts occurred at a rate of 1.1/100 crypts in non-neoplastic intestinal mucosa and were readily discernible in adenomas > 1 cm. Sequencing analysis revealed normalization of the MSH6c.3261dupC variant in MMRp-adenoma crypts, indicating reverse frameshifting of the exon 5 C8 microsatellite. Interestingly but not surprisingly, the MMRp-adenoma crypts remained microsatellite-instability-high (MSI-H), and shared oncogenic APC mutations with the background MMRd-adenoma. Contrasting with MSH6-CMMRD, no PMS2-CMMRD individuals (0/5) harbored MMRp-crypts. In conclusion, our study documents distinct MMRp-crypts in MSH6-CMMRD, a phenomenon in keeping with MSH6 being a frequent target of MSI-H due to its coding microsatellite and suggesting that MSH6-CMMRD can potentially serve as a unique model system to further our understanding of MSH6’s role in MSI-H tumor formation and evolution. Our findings also bear diagnostic implications; when using MMR immunohistochemistry as an ancillary tool in detecting CMMRD, awareness of these MMRp crypts can help avoid diagnostic pitfalls. © The Author(s), under exclusive licence to Springer Nature B.V. 2024.
Keywords:	immunohistochemistry; adolescent; adult; child; clinical article; human tissue; school child; middle aged; young adult; dna binding protein; exon; frameshift mutation; genetics; dna-binding proteins; case report; brain tumor; brain neoplasms; pathology; wild type; microsatellite dna; carcinogenesis; colorectal neoplasms; adenoma; colorectal tumor; mismatch repair; microsatellite instability; dna mismatch repair; gastrointestinal tract; endoscopic biopsy; intestine tumor; lynch syndrome; protein msh6; colorectal neoplasms, hereditary nonpolyposis; g-t mismatch-binding protein; polypectomy; apc protein; turcot syndrome; germ-line mutation; microsatellite repeats; hereditary nonpolyposis colorectal cancer; intestine mucosa; colorectal; neoplastic syndromes, hereditary; intestinal mucosa; crypt cell; germline mutation; msh6; aberrant crypt foci; humans; human; male; female; article; hereditary tumor syndrome; revertant; constitutional mismatch repair deficiency syndrome; cmmrd; coding microsatellite; crypt focus; intestinal adenoma; aberrant crypt focus
Journal Title:	Familial Cancer
Volume:	23
Issue:	4
ISSN:	1389-9600
Publisher:	Springer
Date Published:	2024-11-01
Start Page:	569
End Page:	577
Language:	English
DOI:	10.1007/s10689-024-00423-x
PUBMED:	39387980
PROVIDER:	scopus
PMCID:	PMC11723700
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85206358529&doi=10.1007%2fs10689-024-00423-x&partnerID=40&md5=1e8f6c0a2dc0d36ea7b01529e446b4ae
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding MSK author is Jinru Shia-- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/220696