FERNANDO PÉREZ SANZ¹, María de Carmen Turpín Sevilla², JOSE GARCIA SOLANO³, Patricia Sebastián León⁴, ANTONIO JAVIER TRUJILLO SANTOS⁵, Pablo Carbonell Meseguer⁶, Eduardo Estrada⁷, Anne Tuomisto⁸, Irene Herruzo⁹, Lochlan Fennell¹⁰, Markus Mäkinen⁸, Edith Rodríguez Braun³, Vicky Whitehall¹⁰, Ana Conesa Cegarra¹¹, Pablo Conesa³

(1) PLATAFORMA DE INFORMÁTICA BIOMÉDICA Y BIOINFORMÁTICA, IMIB-Arrixaca, España
(2) Universidad Francisco de Vitoria, 28223, España (Comunidad de Madrid)
(3) PATOLOGÍA MOLECULAR Y FARMACOGENÉTICA, IMIB-Arrixaca, España
(4) Centro de Investigación Príncipe Felipe, España (Comunidad Valenciana)
(5) TROMBOEMBOLISMO VENOSO, IMIB-Arrixaca, España
(6) INVESTIGACIÓN EN PEDIATRÍA, IMIB-Arrixaca, España
(7) Department of Social Psychology and Methodology, Universidad Autónoma de Madrid, España (Comunidad de Madrid)
(8) Universidad de Oulu, Finlandia
(9) Universidad Francisco de Vitoria, España (Comunidad de Madrid)
(10) QIMR Berghofer Medical Research Institute, Australia
(11) Microbiology and Cell Sciences Department, Institute for Food and Agricultural Sciences, Genetics Institute, University of Florida, Estados Unidos

The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets, despite the fact that çCRC is diagnosed based on histological grounds.

Using the Illumina´s 450k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinoma (SAC), 32 conventional carcinoma (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI-H), and, additionally, 35 normal adjacent mucosa. Scores reflecting the overall methylation at 250bp, 1kb and 2kb from transcription starting site (TSS) were studied and according to their occurrence in CpG island, shores, shelves and open sea genomic regions. KRAS, BRAF, MSI and CIMP status were reported in all this cases.

SAC has an intermediate methylation pattern between CC and hmMSI-H for the three genome locations. In addition, the shift from promoter hypermethylation to genomic hypomethylation occurs at a small sequence between 250bp and 1Kb from the gene TSS, and an asymmetric distribution of methylation was observed between both sides of the CpG islands (N vs. S shores).

These findings show that different histological subtypes of CRC have a particular global methylation pattern depending on sequence distance to TSS and highlight the so far underestimated importance of CpGs aberrantly hypomethylated in the clinical phenotype of CRCs.