gene expression; large intestine; sessile serrated adenoma/polyp; epigenomics; molecular diagnosis
Parker Hannah, OrjuelaStephany, Martinho OliveiraAndreia, CereattiFabrizio, SauterMatthias, HeinrichHenriette, TanziGiulia, WeberAchim, KomminothPaul, VavrickaStephan, AlbaneseLuca, BuffoliFederico, RobinsonMark, MarraGiancarlo (2018), The proto CpG island methylator phenotype of sessile serrated adenomas/polyps, in Epigenetics
, 13(10-11), 1088-1105.
Uzozie A., Selevsek N., Wahlander A., Nanni P., Grossmann J., Weber A., Buffoli F., Marra G. (2017), Targeted Proteomics for Multiplexed Verification of Markers of Colorectal Tumorigenesis., in Molecular and Cellular Proteomics
, 16(3), 407-427.
Maglietta A., Maglietta R., Staiano T., Bertoni R., Ancona N., Marra G.* (* equal contribution), Resta L.* (* equal contribution) (2016), The immune landscapes of polypoid and nonpolypoid precancerous colorectal lesions., in PLOS ONE
, 11(7), 1-18.
Erzinger MM., Bovet C., Hecht KM., Senger S., Winiker P., Sobotzki N., Cristea S., Beerenwinkel N., Shay JW., Marra G., Wollscheid B., Sturla S. (2016), Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A, in PLOS ONE
, 11(3):e0150219(11(3):e015), 1/17-17/17.
Fischer D. et al., Metabolic alterations during colorectal cancer development - a combined analysis of the metabolome and transcriptome., in manuscript in preparation
, 0(0), 0-0.
Uzozie A. et al., Selected reaction monitoring for the verification of markers of colorectal tumorigenesis., in Molecular and Cellular Proteomics
, 0(00), 0-0.
Transcriptomic and methylomic data
||Marra, Giancarlo; Robinson, Mark
|Persistent Identifier (PID)
||E-MTAB-6952; E-MTAB-6951; E-MTAB-6949.
Transcriptomic and methylomic data from RNA and DNA extracted from human colorectal tissues.
Prevention of colorectal cancer has been greatly facilitated by the introduction of colonoscopy, which allows direct inspection of the gut’s epithelial lining and removal of any precancerous lesions that might be present. Ongoing advances in endoscopic technology, technique, and operator training have markedly reduced the incidence of colon cancers-at least in the distal colon. The more limited success achieved in the prevention of proximal colon cancers has been attributed in part to the higher prevalence in this portion of the large bowel of “flat” precancerous lesions, which develop laterally rather than protruding into the gut lumen like classical colon polyps. These lesions are not only more difficult to identify and excise during endoscopy: they are also more likely to be erroneously dismissed by pathologists as lesions with no malignant potential, and the patients harboring them followed with a relatively relaxed schedule of colonoscopic surveillance. The error can have grave consequences because flat lesions of this kind are typical of the recently recognized serrated pathway to colorectal cancer, and the subtype known as sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of a subset of proximal colon cancers characterized by the CpG-island methylator phenotype (CIMP) and defective DNA mismatch repair (MMR). CIMP is an epigenetic disorder of unknown origin, which can inactivate the transcription of tumor suppressors and other key genes by causing cytosine methylation in promoter CpG islands. Silencing of the MMR gene MLH1-a major CIMP target- occurs during the adenoma-carcinoma transition and leads to a typical DNA mutator phenotype. CIMP-positive / MMR-deficient colon cancers are sporadic (i.e., not inherited) and more common in older individuals, women in particular. They represent ~10% of all colorectal cancers and roughly one out of four of those in the proximal colon.If SSA/Ps are indeed the precursors of these cancers, proximal-colon SSA/Ps probably have features that facilitate this specific line of progression and distinguish them from their counterparts in the distal colon. The project described in this application is designed to test the hypothesis that the difference between proximal- and distal-colon SSA/Ps lies in their levels of CpG-island methylation. To this end, preinvasive colon lesions with sessile and nonpolypoid morphologies (typical of SSA/Ps) endoscopically removed from 200 women will be subjected to targeted multiplex bisulfite DNA sequencing to detect epigenetic and genetic alterations at 48 genomic loci, including 46 that have recently been identified by the PI’s group as likely targets of the “proto-CIMP” suspected to characterize proximal SSA/Ps. The results will be refined in light of the results of high-throughput assessment of cytosine methylation and gene expression studies conducted with lesional DNA and RNA from selected proximal- and distal-colon SSA/Ps. This two-pronged approach should allow us to identify and validate a small number of methylated promoters and genes with altered expression, whose combined, multiplexed analysis might be developed into a simple molecular assay for pinpointing precancerous proximal-colon lesions that are the actual precursors of CIMP positive / MMR-deficient cancers. Molecular-based identification of lesions of this type removed during colonoscopy will allow clinicians to prescribe more rational, cost-effective endoscopic surveillance. In addition, our genome-wide analysis of these precancerous lesions-in the absence of the “noise” caused by the myriad cancer-associated genetic alterations that occur later (MMR deficiency in particular)-should provide potential clues to the underlying causes of CIMP in colon tumorigenesis.