Effectiveness of each Bethesda marker in defining microsatellite instability when screening for Lynch syndrome.
OBJECTIVE
A panel of five markers (two mononuclotide markers and three dinucleotide markers; the so-called Bethesda markers) has been proposed to define MSI status. However reducing these 5 markers into one or two markers have been suggested to be sufficient for detection of the MLH1- or MSH2-mutated Lynch syndrome. We attempted to examine the effectiveness of each Bethesda marker for the determination of MSI status clinically relevant to Lynch syndrome.


METHODS
We compared the MSI status obtained using each or a combination of two Bethesda markers to those obtained using all five Bethesda markers in 1,531 non-selected colorectal cancer patients.


RESULTS
At least one mononucleotide marker was unstable in 94% of the MSI-H tumors defined by the Bethesda markers (126 of 134). After sequencing MLH1 and MSH2 genes from 31 of 86 patients eligible for the genetic test, 18 germline mutations were detected. Seventeen of these mutations were from high MSI tumors, and 1 was from a MSS tumor defined by 5 Bethesda markers. A combination of two mononucleotide markers was able to identify all 17 mutation-positive individuals with MSI-H tumors defined by the five Bethesda markers.


CONCLUSIONS
Instability in two mononucleotide markers, BAT26 and BAT25, was most effective markers at defining MSI status. Sensitivity is only slightly impaired by using two mononucleotide markers instead of five markers.
Sinn
Dong Hyun
DH
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Chang
Dong Kyung
DK
Kim
Young-Ho
YH
Rhee
Poong-Lyul
PL
Kim
Jae J
JJ
Kim
Dae Shick
DS
Park
Cheol Keun
CK
Kim
Jong Won
JW
Yun
Seong Hyeon
SH
Lee
Woo-Yong
WY
Chun
Ho-Kyung
HK
Rhee
Jong Chul
JC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000230:Adenocarcinoma / Q000208:ethnology / Q000235:genetics*; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics; D018900:Dinucleotide Repeats / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D005820:Genetic Testing; D006801:Humans; D007723:Korea; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011237:Predictive Value of Tests
D048868:Adaptor Proteins, Signal Transducing; C516892:BAT26 microsatellite DNA; D014408:Biomarkers, Tumor; D005819:Genetic Markers; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein