Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer.
Colorectal cancer (CRC) has traditionally been classified into two groups: microsatellite stable/low-level instability (MSS/MSI-L) and high-level MSI (MSI-H) groups on the basis of multiple molecular and clinicopathologic criteria. Using methylated in tumor (MINT) markers 1, 2, 12, and 31, we stratified 77 primary CRCs into three groups: MINT++ (>2), MINT+ (1-2), and MINT- (0 markers methylated). The MSS/MSI-L/MINT++ group was indistinguishable from the MSI-H/MINT++ group with respect to methylation of p16(INK4a), p14(ARF), and RIZ1, and multiple morphological features. The only significant difference between MSI-H and non-MSI-H MINT++ cancers was the higher frequency of K-ras mutation (P < 0.004) and lower frequency of hMLH1 methylation (P < 0.001) in the latter. These data demonstrate that the separation of CRC into two nonoverlapping groups (MSI-H versus MSS/MSI-L) is a misleading oversimplification.
Whitehall
Vicki L J
VL
Conjoint Gastroenterology Laboratory, Clinical Research Centre, Royal Brisbane Hospital Research Foundation, Queensland 4029, Australia. vickiWh@qimr.edu.au
Wynter
Coral V A
CV
Walsh
Michael D
MD
Simms
Lisa A
LA
Purdie
David
D
Pandeya
Nirmala
N
Young
Joanne
J
Meltzer
Stephen J
SJ
Leggett
Barbara A
BA
Jass
Jeremy R
JR
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D011446:Prospective Studies; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000070957:MutL Protein Homolog 1