title: Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer.
abstract: 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.
authors.affiliation: Conjoint Gastroenterology Laboratory, Clinical Research Centre, Royal Brisbane Hospital Research Foundation, Queensland 4029, Australia. vickiWh@qimr.edu.au
authors.forename: Vicki L J
authors.initials: VL
authors.lastname: Whitehall
authors.forename: Coral V A
authors.initials: CV
authors.lastname: Wynter
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Simms
authors.forename: David
authors.initials: D
authors.lastname: Purdie
authors.forename: Nirmala
authors.initials: N
authors.lastname: Pandeya
authors.forename: Joanne
authors.initials: J
authors.lastname: Young
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Leggett
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Jass
mesh_terms: 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
chemical_list: 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