title: Neoadjuvant therapy in microsatellite-stable colorectal carcinoma induces concomitant loss of MSH6 and Ki-67 expression.
abstract: Universal screening using immunohistochemistry for DNA mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2) is advocated by major professional medical organizations to identify Lynch syndrome-associated colorectal carcinoma. Loss of MSH6 expression independent of MSH2 expression has been reported in microsatellite-stable (MSS) colorectal carcinoma after neoadjuvant therapy. The mechanism remains unclear. We studied the immunohistochemical expression of MSH2, MSH6, and Ki-67 in MSS colorectal carcinoma with (n=50) or without (n=64) preoperative neoadjuvant therapy and Lynch syndrome-associated colorectal carcinoma with confirmed MSH6 germline mutation (n=3). Twelve of 50 MSS colorectal carcinoma postneoadjuvant resections demonstrated reduced MSH6 expression, with loss of expression ranging from 20% to 100% of tumor cells. Eight of 64 MSS colorectal carcinomas without neoadjuvant therapy also exhibited reduced MSH6 expression but to a lesser degree (10%-50% of tumor cells with loss of expression). In both subgroups, concomitant loss of MSH6 and Ki-67 expressions was demonstrated in the same tumor areas in consecutive tissue sections. However, 3 cases of Lynch syndrome-associated colorectal carcinoma due to germline MSH6 mutation revealed complete loss of MSH6 expression with discordant positive Ki-67 staining in the tumor cells. The MSH2-independent, Ki-67-related expression of MSH6 in colorectal carcinoma helps to explain the heterogeneous MSH6 staining in MSS colorectal carcinoma with or without neoadjuvant therapy.
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213. Electronic address: kuans@upmc.edu.
authors.forename: Shih-Fan
authors.initials: SF
authors.lastname: Kuan
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.
authors.forename: Randall
authors.initials: R
authors.lastname: Brand
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.
authors.forename: Beth
authors.initials: B
authors.lastname: Dudley
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.
authors.forename: Reetesh K
authors.initials: RK
authors.lastname: Pai
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001706:Biopsy; D059186:Chemoradiotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000032:analysis / Q000235:genetics; D020360:Neoadjuvant Therapy; D016896:Treatment Outcome
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D019394:Ki-67 Antigen; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: Colorectal carcinoma; DNA mismatch-repair protein; Immunohistochemistry; Ki-67; MSH6; Microsatellite instability; Neoadjuvant therapy