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.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA, Shiaj@mskcc.org.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.forename: Zsofia K
authors.initials: ZK
authors.lastname: Stadler
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.forename: Robin
authors.initials: R
authors.lastname: Mendelsohn
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Markowitz
authors.forename: Moshe
authors.initials: M
authors.lastname: Shike
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein