The impact of microsatellite instability on the molecular phenotype of colorectal tumors.
Frequent microsatellite instability MSI (MSI-H) occurring in human tumors is characterized by defective DNA mismatch repair and unique clinical features. However, infrequent MSI (MSI-L) has not been attributable to any other defined molecular pathway, and its existence as a biologically distinct category has been challenged. Moreover, the global molecular phenotypes (GMPs) underlying MSI-H, MSI-L, or microsatellite-stable (MSS) tumors have never been evaluated. To evaluate the impact of MSI status on GMP and to determine the importance of MSI relative to other molecular and clinical features, cDNA microarray-derived data from 41 colon cancers were interpreted using principal components analysis. The clinically relevant principal component with the greatest impact on GMP was component 3, which distinguished MSI-H from non-MSI-H (i.e., MSI-L and microsatellite stable) tumors and was designated the MSI-H separator. Notably, MSI-L cancers were also clearly distinguished from non-MSI-L tumors by another principle component, component 10 (the "MSI-L separator"). This second finding validates the existence of MSI-L tumors as a distinct molecular phenotypic category. Thus, both components 3 and 10 reflected different aspects of MSI and helped to establish principal components analysis as a useful tool to identify and characterize distinct biological features of human malignancy.
Mori
Yuriko
Y
Department of Medicine, Division of Gastroenterology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
Selaru
Florin M
FM
Sato
Fumiaki
F
Yin
Jing
J
Simms
Lisa A
LA
Xu
Yan
Y
Olaru
Andreea
A
Deacu
Elena
E
Wang
Suna
S
Taylor
Jennifer M
JM
Young
Joanne
J
Leggett
Barbara
B
Jass
Jeremy R
JR
Abraham
John M
JM
Shibata
David
D
Meltzer
Stephen J
SJ
D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D015203:Reproducibility of Results