The CIMP Phenotype in BRAF Mutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort

Winnie C Fernando; Mariska S Miranda; Daniel L Worthley; Kazutomo Togashi; Dianne J Watters; Barbara A Leggett; Kevin J Spring

doi:10.1155/2014/374926

The CIMP Phenotype in BRAF Mutant Serrated Polyps from a Prospective Colonoscopy Patient Cohort

Gastroenterol Res Pract. 2014:2014:374926. doi: 10.1155/2014/374926. Epub 2014 Apr 10.

Authors

Winnie C Fernando¹, Mariska S Miranda², Daniel L Worthley³, Kazutomo Togashi⁴, Dianne J Watters⁵, Barbara A Leggett⁶, Kevin J Spring⁷

Affiliations

¹ Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia ; School of Biomolecular and Physical Sciences, Griffith University, Brisbane, QLD 4111, Australia.
² Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia ; The School of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia.
³ Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia.
⁴ Department of Coloproctology, Aizu Medical Center, Fukushima Medical University, Fukushima 960-1295, Japan.
⁵ School of Biomolecular and Physical Sciences and Eskitis Institute for Drug Discovery, Griffith University, Brisbane, QLD 4111, Australia.
⁶ Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia ; The School of Medicine, The University of Queensland, Brisbane, QLD 4006, Australia ; Department of Gastroenterology and Hepatology, The Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
⁷ Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Brisbane, QLD 4029, Australia ; School of Biomolecular and Physical Sciences, Griffith University, Brisbane, QLD 4111, Australia ; Ingham Institute, Liverpool Hospital and Liverpool Clinical School, University of Western Sydney, Sydney, NSW 2170, Australia.

Abstract

Colorectal cancers arising via the serrated pathway are often associated with BRAF V600E mutation, CpG island methylator phenotype (CIMP), and microsatellite instability. Previous studies have shown a strong association between BRAF V600E mutation and serrated polyps. This study aims to evaluate CIMP status of all the serrated polyp subtypes and its association with functionally important genes such as MLH1, p16, and IGFBP7. CIMP status and methylation were evaluated using the real-time based MethyLight assay in 154 serrated polyps and 63 conventional adenomas. Results showed that CIMP-high serrated polyps were strongly associated with BRAF mutation and proximal colon. CIMP-high was uncommon in conventional adenomas (1.59%), occurred in 8.25% of hyperplastic polyps (HPs), and became common in sessile serrated adenomas (SSAs) (51.43%). MLH1 methylation was mainly observed in the proximal colon and was significantly associated with BRAF mutation and CIMP-high. The number of samples methylated for p16 and IGFBP7 was the highest in SSAs. The methylation panel we used to detect CIMP is highly specific for CIMP-high cancers. With this panel, we demonstrate that CIMP-high is much more common in SSAs than HPs. This suggests that CIMP-high correlates with increased risk of malignant transformation which was also observed in methylation of functionally important genes.