Secondary mutation in a coding mononucleotide tract in MSH6 causes loss of immunoexpression of MSH6 in colorectal carcinomas with MLH1/PMS2 deficiency.
Immunohistochemical staining for DNA mismatch repair proteins may be affected by various biological and technical factors. Staining variations that could potentially lead to erroneous interpretations have been recognized. A recently recognized staining variation is the significant reduction of staining for MSH6 in some colorectal carcinomas. The frequency and specific characteristics of this aberrant MSH6 staining pattern, however, have not been well analyzed. In this study of 420 colorectal carcinoma samples obtained from patients fulfilling the Revised Bethesda Guidelines, we detected 9 tumors (2%) showing extremely limited staining for MSH6 with positive staining present in <5% of the tumor cells. Our analyses showed that these tumors belonged to two distinct categories: (1) MLH1 and/or PMS2 protein-deficient carcinomas (n=5, including 1 with a pathogenic mutation in PMS2); and (2) MLH1, PMS2 and MSH2 normal but with chemotherapy or chemoradiation therapy before surgery (n=4). To test our hypothesis that somatic mutation in the coding region microsatellite of the MSH6 gene might be a potential underlying mechanism for such limited MSH6 staining, we evaluated frameshift mutation in a (C)(8) tract in exon 5 of the MSH6 gene in seven tumors that had sufficient DNA for analysis, and detected mutation in four; all four tumors belonged to the MLH1/PMS2-deficient group. In conclusion, our data outline the main scenarios where significant reduction of MSH6 staining is more likely to occur in colorectal carcinoma, and suggest that somatic mutations of the coding region microsatellites of the MSH6 gene is an underlying mechanism for this staining phenomenon in MLH1/PMS2-deficient carcinomas.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Shiaj@Mskcc.org
Jinru
J
Shia
Liying
L
Zhang
Moshe
M
Shike
Min
M
Guo
Zsofia
Z
Stadler
Xiaoling
X
Xiong
Laura H
LH
Tang
Efsevia
E
Vakiani
Nora
N
Katabi
Hangjun
H
Wang
Ruben
R
Bacares
Jeanine
J
Ruggeri
C Richard
CR
Boland
Marc
M
Ladanyi
David S
DS
Klimstra
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000172:deficiency*; D000251:Adenosine Triphosphatases / Q000032:analysis / Q000172:deficiency*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000032:analysis / Q000172:deficiency*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000032:analysis / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes