Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer.
OBJECTIVE
Hereditary nonpolyposis colorectal cancer (HNPCC) may be caused by mutations in mismatch repair (MMR) genes. The aim of this study was to validate immunohistochemistry and family history as prescreening tools to predict germline mutations in MLH1, MSH2, and MSH6.


METHODS
Pedigrees from 250 families were extended, cancer diagnoses were verified, and families were classified according to the Amsterdam and the Bethesda criteria. Tumor specimens were examined with immunohistochemistry for the presence of MLH1, MSH2, and MSH6 proteins. Mutation analyses were performed in blood samples from the same patients.


RESULTS
Blood samples from affected index persons in 181 families and tumor specimens from 127 of the affected index persons were obtained. Thirty tumors lacked one or more gene products. Sensitivity of immunohistochemistry to detect mutation carriers was 100%, specificity was 82%, and positive predictive value was 85%. Sensitivities, specificities, and positive predictive values for the Amsterdam criteria were 82%, 8%, and 45%, respectively, and for the Bethesda criteria were 100%, 0%, and 48%, respectively. Distribution of mutations was MLH1 = 4, MSH2 = 11, and MSH6 = 4.


CONCLUSIONS
Wide clinical criteria to select HNPCC kindreds, followed by immunohistochemistry of tumor material from one affected person in each family, had high sensitivity and specificity to predict MMR mutations.
Stormorken
Astrid T
AT
Section of Genetic Counselling, Department of Cancer Genetics, The Norwegian Radium Hospital, N-0310 Oslo, Norway.
Bowitz-Lothe
Inger Marie
IM
Norèn
Tove
T
Kure
Elin
E
Aase
Steinar
S
Wijnen
Juul
J
Apold
Jaran
J
Heimdal
Ketil
K
Møller
Pål
P
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis; D009687:Nuclear Proteins / Q000032:analysis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D012680:Sensitivity and Specificity
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein