CpG Island Methylation in Serrated and Conventional CRC Precursor Neoplasms: How Individual Marker Genes and Panels Relate to Histology and Oncogene Mutation Status
S Yang, H Xu, H Huang, B Burke, SK Duhon, S Cerda, MJ O'Brien. Boston University School of Medicine, Boston, MA
Background: Epigenetic silencing of suppressor and mutator genes by CpG island methylation (CIM) has been studied mainly in advanced colorectal cancer (CRC). Here we investigate the relationship of CIM to histology and oncogene status in CRC precursor polyps.
Design: DNA samples from 50 polyps, 10 BRAF mut sessile serrated adenomas, 30 dysplastic serrated polyps (SA-14 KRAS mut and 16 BRAF mut) and 10 KRAS mut conventional adenomas(CoA) were assayed by MS-PCR for the following 15 CIM markers: p16, hMLH1, MGMT, MINT1, MINT2, SOCS1, Neurog1, RUNX3, IGF2, CACNA11G, SFRPS, RASSF2A, Reprimo, 30ST2 and HPP1. These included the canonical panel (Cn), that proposed by Weisenberger et al.(Wr) and methylation markers linked to KRAS mut by Nagasaka et al.(Na). Groups were compared using Fisher Exact and U-Mann Whitney tests as appropriate.
Results: All 15 markers showed higher (11) or equivalent (4) positive frequency rate among BRAF vs KRAS mutated categories; the mean BRAF/KRAS marker positivity ratio was 2.75, 1.5 and 1.37 respectively. The specificity of individual genes for either group was low. All 3 panels showed significant differences in positive marker frequency rate for BRAF mut compared to KRAS mut precursors (Wr: p <0.0001; Na: p=.001; Cn: p =.014) and for KRAS mut SA compared to KRAS mut CoA (Wr: p=.07; Na: p =.02; Cn: p=.02).
Fig 1 Legend: Box-plots comparing the distribution of marker positivity frequency among KRAS mut versus BRAF mut CRC precursors using 3 separate panels, from left to right Wr, Na and Cn.
Conclusions: A series of gene methylation markers comprising 3 distinct panels indicated, with varying precision, that BRAF mut vs KRAS mut and serrated vs non-serrated histology in CRC precursor neoplasms were associated with higher levels of CpG island methylation.
Tuesday, March 10, 2009 1:30 PM
Platform Session: Section B, Tuesday Afternoon