Mismatch repair deficient-crypts in non-neoplastic colonic mucosa in Lynch syndrome: Insights from an illustrative case Journal Article

  

Authors:	Shia, J.; Stadler, Z. K.; Weiser, M. R.; Vakiani, E.; Mendelsohn, R.; Markowitz, A. J.; Shike, M.; Boland, C. R.; Klimstra, D. S.
Article Title:	Mismatch repair deficient-crypts in non-neoplastic colonic mucosa in Lynch syndrome: Insights from an illustrative case
Abstract:	Mono-allelic germline mutations in DNA mismatch repair (MMR) genes lead to Lynch syndrome (LS). Questions remain as to the timing of the inactivation of the wild-type allele in LS-associated tumorigenesis. Speculation exists that it happens after the neoplasia has been initiated. However, a recent study reported the presence of MMR-deficiency in non-neoplastic colonic crypts in LS; thus the possibility can be raised that these crypts may be tumor precursors, and as such, biallelic loss of MMR may occur prior to neoplasia. Here we report a unique case that showed findings supporting both of the two seemingly conflicting notions. The patient was a 40-year-old female with LS, MSH2 type, who underwent a segmental colectomy for an adenocarcinoma. By immunohistochemistry, the carcinoma lost MSH2/MSH6. Interestingly, there was also complete loss of MSH2/MSH6 in a distinct focus of 20 colonic crypts that were morphologically non-neoplastic, thus supporting the possibility of biallelic loss of MMR before initiation of neoplasia. However, in a separate adenoma, MMR was preserved in neoplastic glands with low grade dysplasia and lost only in glands with high grade dysplasia, i.e., MMR loss after tumor initiation. These are relevant findings with regard to the timing of MMR deficiency in LS tumorigenesis, and bring forth the possibility that varied tumorigenic pathways may exist. Additionally, we observed that the MMR-deficient non-neoplastic crypts harbored increased intraepithelial CD8-positive T-lymphocytes similar to the patient’s carcinoma, providing a potential new venue for the study of the natural antitumor immune responses in LS individuals. © 2014, Springer Science+Business Media Dordrecht.
Keywords:	immunohistochemistry; adult; controlled study; human tissue; case report; adenocarcinoma; cd8+ t lymphocyte; tumor associated leukocyte; carcinogenesis; mismatch repair; microsatellite instability; colon resection; dysplasia; hereditary nonpolyposis colorectal cancer; intestine crypt; colon mucosa; tumor immunology; human; female; priority journal; article; mmr-deficient crypts; tumor-infiltrating-lymphocytes; adenoma–carcinoma sequence
Journal Title:	Familial Cancer
Volume:	14
Issue:	1
ISSN:	1389-9600
Publisher:	Springer
Date Published:	2015-03-01
Start Page:	61
End Page:	68
Language:	English
DOI:	10.1007/s10689-014-9751-2
PROVIDER:	scopus
PUBMED:	25173403
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84941618160&partnerID=40&md5=b349665894095113dc6aa65ea6c57a02
Notes:	Export Date: 2 October 2015 -- Source: Scopus

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