Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. May 15, 2017; 9(5): 209-217
Published online May 15, 2017. doi: 10.4251/wjgo.v9.i5.209
Extramural vascular invasion and response to neoadjuvant chemoradiotherapy in rectal cancer: Influence of the CpG island methylator phenotype
Jeremy Stuart Williamson, Huw Geraint Jones, Namor Williams, Anthony Paul Griffiths, Gareth Jenkins, John Beynon, Dean Anthony Harris
Jeremy Stuart Williamson, Huw Geraint Jones, John Beynon, Dean Anthony Harris, Department of General and Colorectal Surgery, Singleton Hospital, Swansea SA2 8QA, United Kingdom
Namor Williams, Anthony Paul Griffiths, Department of Pathology, Singleton Hospital, Swansea SA2 8QA, United Kingdom
Gareth Jenkins, Department of Life Sciences, Swansea University, Swansea SA2 8PP, United Kingdom
Author contributions: All authors substantially contributed to the conception and design of the study as well as drafting and approving the final manuscript; Williamson JS and Jones HG contributed to the acquisition of data from experimental studies; all authors contributed to the analysis and interpretation of data.
Institutional review board statement: All patients in this study were treated in the South West Wales Oncology Centre (Singleton Hospital, Swansea, United Kingdom) and ethical approval for this study was granted by South West Wales REC (Project Ref No:11/WA/0256). Consent was not required in accordance with the Human Tissue Act 2004 (chapter 30).
Conflict-of-interest statement: All authors declare no conflict of interest.
Data sharing statement: Technical appendix and data set are available from the corresponding author at dean.a.harris2@wales.nhs.uk. Consent for data sharing was not obtained but the presented data are anonymised and the risk of identification is low.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Jeremy Stuart Williamson, Department of General and Colorectal Surgery, Singleton Hospital, Sketty Lane, Swansea SA2 8QA, United Kingdom. dean.a.harris@wales.nhs.uk
Telephone: +44-1792-205666
Received: July 26, 2016
Peer-review started: July 30, 2016
First decision: September 29, 2016
Revised: December 20, 2016
Accepted: March 23, 2017
Article in press: March 24, 2017
Published online: May 15, 2017
Abstract
AIM

To identify whether CpG island methylator phenotype (CIMP) is predictive of response to neoadjuvant chemoradiotherapy (NACRT) and outcomes in rectal cancer.

METHODS

Patients undergoing NACRT and surgical resection for rectal cancer in a tertiary referral centre between 2002-2011 were identified. Pre-treatment tumour biopsies were analysed for CIMP status (high, intermediate or low) using methylation specific PCR. KRAS and BRAF status were also determined using pyrosequencing analysis. Clinical information was extracted from case records and cancer services databases. Response to radiotherapy was measured by tumour regression scores determined upon histological examination of the resected specimen. The relationship between these molecular features, response to NACRT and oncological outcomes were analysed.

RESULTS

There were 160 patients analysed with a median follow-up time of 46.4 mo. Twenty-one (13%) patients demonstrated high levels of CIMP methylation (CIMP-H) and this was significantly associated with increased risk of extramural vascular invasion (EMVI) compared with CIMP-L [8/21 (38%) vs 15/99 (15%), P = 0.028]. CIMP status was not related to tumour regression after radiotherapy or survival, however EMVI was significantly associated with adverse survival (P < 0.001). Intermediate CIMP status was significantly associated with KRAS mutation (P = 0.01). There were 14 (9%) patients with a pathological complete response (pCR) compared to 116 (73%) patients having no or minimal regression after neoadjuvant chemoradiotherapy. Those patients with pCR had median survival of 106 mo compared to 65.8 mo with minimal regression, although this was not statistically significant (P = 0.26). Binary logistic regression analysis of the relationship between EMVI and other prognostic features revealed, EMVI positivity was associated with poor overall survival, advanced “T” stage and CIMP-H but not nodal status, age, sex, KRAS mutation status and presence of local or systemic recurrence.

CONCLUSION

We report a novel association of pre-treatment characterisation of CIMP-H with EMVI status which has prognostic implications and is not readily detectable on pre-treatment histological examination.

Keywords: Rectal cancer, CpG islands, Methylation

Core tip: There is wide and unpredictable response of rectal cancer to neoadjuvant therapy which carries significant side effects and relies on limited pre-treatment risk stratification. Methylation specific PCR was used to determine CpG island Methylator phenotype (CIMP) status in 160 rectal cancers and compared with response to therapy, clinical and pathological outcomes. CIMP status was not directly related to tumour regression but was related to extramural vascular invasion which confers an adverse survival risk.