@article{1d96703ff1a64cc19b4b1e684208c335,
title = "Integrative Genome-Scale DNA Methylation Analysis of a Large and Unselected Cohort Reveals 5 Distinct Subtypes of Colorectal Adenocarcinomas",
abstract = "Background \& Aims: Colorectal cancer is an epigenetically heterogeneous disease, however, the extent and spectrum of the CpG island methylator phenotype (CIMP) is not clear. Methods: Genome-scale methylation and transcript expression were measured by DNA Methylation and RNA expression microarray in 216 unselected colorectal cancers, and findings were validated using The Cancer Genome Atlas 450K and RNA sequencing data. Mutations in epigenetic regulators were assessed using CIMP-subtyped Cancer Genome Atlas exomes. Results: CIMP-high cancers dichotomized into CIMP-H1 and CIMP-H2 based on methylation profile. KRAS mutation was associated significantly with CIMP-H2 cancers, but not CIMP-H1 cancers. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CIMP-negative subgroup to 75 years in the CIMP-H1 subgroup (P < .0001). CIMP-H1 predominantly comprised consensus molecular subtype 1 cancers (70\%) whereas consensus molecular subtype 3 was over-represented in the CIMP-H2 subgroup (55\%). Polycomb Repressive Complex-2 (PRC2)-marked loci were subjected to significant gene body methylation in CIMP cancers (P < 1.6 × 10-78). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster–specific mutations were observed in chromatin remodeling genes, such as in the SWItch/Sucrose Non-Fermentable and Chromodomain Helicase DNA-Binding gene families. Conclusions: There are 5 clinically and molecularly distinct subgroups of colorectal cancer. We show a striking association between CIMP and age, sex, and tumor location, and identify a role for gene body methylation in the progression of serrated neoplasia. These data support our recent findings that CIMP is uncommon in young patients and that BRAF mutant polyps in young patients may have limited potential for malignant progression.",
keywords = "BRAF, CIMP, Colorectal Cancer, DNA Methylation, Epigenetics, KRAS",
author = "Lochlan Fennell and Troy Dumenil and L. Wockner and Gunter Hartel and K. Nones and Catherine Bond and Jennifer Borowsky and C. Liu and D. McKeone and Lisa Bowdler and G. Montgomery and Kerenaftali Klein and Isabell Hoffmann and Patch, \{Ann Marie\} and Stephen Kazakoff and Pearson, \{John V\} and Nicola Waddell and Pratyaksha Wirapati and Paul Lochhead and Yu Imamura and S. Ogino and R. Shao and Sabine Tejpar and Barbara Leggett and V. Whitehall",
note = "Funding Information: Funding This work was supported through funding from the National Health and Medical Research Council (1050455 and 1063105), the US National Institutes of Health (R01 CA151933 and R35 CA197735), and Pathology Queensland. Also supported by a Senior Research Fellowship from the Gastroenterological Society of Australia (V.W.); and by a Research Training Program Living Scholarship from the Australia Government and a Top-Up award from QIMR Berghofer and Australian Rotary Health (L.F.). Author contributions Lochlan Fennell performed bioinformatic and statistical analyses on the data, was involved in the conceptualization aspects of the study, and prepared the manuscript; Troy Dumenil performed molecular and bioinformatic analyses and revised the manuscript for content; Gunter Hartel was involved in the statistical and bioinformatic analysis of the data; Katia Nones was involved in the bioinformatic analysis of methylation data and revised the manuscript for content; Catherine Bond performed molecular analyses and revised the manuscript for content; Diane McKeone was involved in molecular analyses; Lisa Bowdler processed the microarrays; Grant Montgomery processed the microarrays; Leesa Wockner was involved in bioinformatic analyses; Kerenaftali Klein was involved in bioinformatic analyses; Ann-Marie Patch was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; Stephen Kazakoff was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; John Pearson was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; Nicola Waddell was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; Pratyaksha Wirapati performed consensus molecular subtype analysis; Paul Lochhead performed Long Interspersed Nuclear Element-1 methylation assays and analysis; Yu Imamura performed Long Interspersed Nuclear Element-1 methylation assays and analysis; Shuji Ogino performed Long Interspersed Nuclear Element-1 methylation assays and analysis and provided supervision for this aspect of the study; Renfu Shao supervised the study and was involved in the conceptualization aspects of the study; Sabine Tejpar performed Consensus Molecular Subtype analysis and provided supervision for this aspect of the study; Barbara Leggett supervised the study, was involved in conceptualization aspects of the study, revised the manuscript for content, and secured funding for the study; Cheng Liu performed molecular analyses and revised the manuscript for content; Jennifer Borowsky performed molecular analyses and revised the manuscript for content; Isabell Hoffmann performed bioinformatic analysis and revised the manuscript for content; and Vicki Whitehall conceptualized the study, performed statistical analyses, revised the manuscript for content, secured funding for the study, and provided overarching supervision of the study. Funding This work was supported through funding from the National Health and Medical Research Council (1050455 and 1063105), the US National Institutes of Health (R01 CA151933 and R35 CA197735), and Pathology Queensland. Also supported by a Senior Research Fellowship from the Gastroenterological Society of Australia (V.W.); and by a Research Training Program Living Scholarship from the Australia Government and a Top-Up award from QIMR Berghofer and Australian Rotary Health (L.F.). The authors are thankful for the insightful comments offered by the reviewers and for their contribution in greatly improving the manuscript. The microarray data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-8148 (expression) and E-MTAB-7036 (methylation). Author contributions Lochlan Fennell performed bioinformatic and statistical analyses on the data, was involved in the conceptualization aspects of the study, and prepared the manuscript; Troy Dumenil performed molecular and bioinformatic analyses and revised the manuscript for content; Gunter Hartel was involved in the statistical and bioinformatic analysis of the data; Katia Nones was involved in the bioinformatic analysis of methylation data and revised the manuscript for content; Catherine Bond performed molecular analyses and revised the manuscript for content; Diane McKeone was involved in molecular analyses; Lisa Bowdler processed the microarrays; Grant Montgomery processed the microarrays; Leesa Wockner was involved in bioinformatic analyses; Kerenaftali Klein was involved in bioinformatic analyses; Ann-Marie Patch was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; Stephen Kazakoff was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; John Pearson was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; Nicola Waddell was involved in bioinformatic analyses of The Cancer Genome Atlas exome data; Pratyaksha Wirapati performed consensus molecular subtype analysis; Paul Lochhead performed Long Interspersed Nuclear Element-1 methylation assays and analysis; Yu Imamura performed Long Interspersed Nuclear Element-1 methylation assays and analysis; Shuji Ogino performed Long Interspersed Nuclear Element-1 methylation assays and analysis and provided supervision for this aspect of the study; Renfu Shao supervised the study and was involved in the conceptualization aspects of the study; Sabine Tejpar performed Consensus Molecular Subtype analysis and provided supervision for this aspect of the study; Barbara Leggett supervised the study, was involved in conceptualization aspects of the study, revised the manuscript for content, and secured funding for the study; Cheng Liu performed molecular analyses and revised the manuscript for content; Jennifer Borowsky performed molecular analyses and revised the manuscript for content; Isabell Hoffmann performed bioinformatic analysis and revised the manuscript for content; and Vicki Whitehall conceptualized the study, performed statistical analyses, revised the manuscript for content, secured funding for the study, and provided overarching supervision of the study. Funding This work was supported through funding from the National Health and Medical Research Council (1050455 and 1063105), the US National Institutes of Health (R01 CA151933 and R35 CA197735), and Pathology Queensland. Also supported by a Senior Research Fellowship from the Gastroenterological Society of Australia (V.W.); and by a Research Training Program Living Scholarship from the Australia Government and a Top-Up award from QIMR Berghofer and Australian Rotary Health (L.F.). Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = jan,
doi = "10.1016/j.jcmgh.2019.04.002",
language = "English",
volume = "8",
pages = "269--290",
journal = "Cellular and Molecular Gastroenterology and Hepatology",
issn = "2352-345X",
publisher = "Elsevier",
number = "2",
}
