A gene expression signature of genetic instability in colon cancer.
Genetic instability plays a central role in the development and progression of human cancer. Two major classes of genetic instability, microsatellite instability (MSI) and chromosome instability (microsatellite stable; MSS), are best understood in the context of colon cancer, where MSI tumors represent approximately 15% of cases, and compared with MSS tumors, more often arise in the proximal colon and display favorable clinical outcome. To further explore molecular differences, we profiled gene expression in a set of 18 colon cancer cell lines using cDNA microarrays representing approximately 21,000 different genes. Supervised analysis identified a robust expression signature distinguishing MSI and MSS samples. As few as eight genes predicted with high accuracy the underlying genetic instability in the original and in three independent sample sets, comprising 13 colon cancer cell lines, 61 colorectal tumors, and 87 gastric tumors. Notably, the MSI signature was retained despite genetically correcting the underlying instability, suggesting the signature reflects a legacy of the tumor having arisen from MSI, rather than sensing the ongoing state of MSI. Our findings support a model in which MSI and MSS preferentially target different genes and pathways in cancer. Further, among the MSI signature genes, our findings implicate a role of elevated metallothionein expression in the clinical behavior of MSI cancers.
Giacomini
Craig P
CP
Department of Pathology, Stanford University, Stanford, CA 94305-5176, USA.
Leung
Suet Yi
SY
Chen
Xin
X
Yuen
Siu Tsan
ST
Kim
Young H
YH
Bair
Eric
E
Pollack
Jonathan R
JR
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D003110:Colonic Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D042822:Genomic Instability; D045325:HCT116 Cells; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1