Rory F Kokelaar1,2, Huw G Jones1, Jeremy Williamson1, Namor Williams3, A Paul Griffiths3, John Beynon1, Gareth J Jenkins2, Dean A Harris1. 1. a Departments of Colorectal Surgery and Pathology , Abertawe Bro Morgannwg University Health Board , Swansea , Wales , United Kingdom. 2. c Cancer Biomarker Group, Institute of Life Science, School of Medicine, Swansea University , Swansea , Wales , United Kingdom. 3. b Pathology, Abertawe Bro Morgannwg University Health Board , Swansea , Wales , United Kingdom.
Abstract
PURPOSE: DNA hypermethylation in gene promoter regions (CpG islands) is emerging as an important pathway in colorectal cancer tumourigenesis. Whilst genetic mutations have been associated with extramural vascular invasion (EMVI) in rectal cancer, no such association has yet been made with epigenetic factors. METHODS: 100 consecutive neoadjuvant-naïve patients undergoing curative surgery for rectal were classified according to the presence or absence of EMVI on histopathological examination. DNA was extracted from tumours and subjected to bisulfite conversion and methylation-specific PCR to determine CIMP status (high, intermediate, or low; according to a validated panel of 8 genes). CIMP status was correlated with EMVI status, histopathological, clinical, and demographic variables, in addition to overall (OS) and disease free (DFS) survival. RESULTS: 51 patients were characterised as CIMP-low, 48 CIMP-intermediate, and one patient CIMP-high. EMVI-positivity was associated with CIMP-intermediate epigenotype (p < 0.001). Patients with EMVI-positive tumours were found to have significantly more advanced disease by pT, pN, and pAJCC categorisation (p = 0.002, p < 0.001, and = p < 0.001, respectively). EMVI-positivity was significantly associated with the requirement for adjuvant chemotherapy (p < 0.001), and worse DFS but not OS (p = 0.012 and p = 0.052). CONCLUSIONS: Given the association between CIMP-intermediate epigenotype and EMVI-positivity, and the subsequent disadvantage in pathological stage, requirement for adjuvant therapy and worse survival, tumour epigenotyping could potentially play an important role in personalising patients' cancer care. Further work is required to understand the mechanisms that underlie the observed effect, with the hope that they may provide novel opportunities for intervention and inform treatment decisions in rectal cancer.
PURPOSE: DNA hypermethylation in gene promoter regions (CpG islands) is emerging as an important pathway in colorectal cancer tumourigenesis. Whilst genetic mutations have been associated with extramural vascular invasion (EMVI) in rectal cancer, no such association has yet been made with epigenetic factors. METHODS: 100 consecutive neoadjuvant-naïve patients undergoing curative surgery for rectal were classified according to the presence or absence of EMVI on histopathological examination. DNA was extracted from tumours and subjected to bisulfite conversion and methylation-specific PCR to determine CIMP status (high, intermediate, or low; according to a validated panel of 8 genes). CIMP status was correlated with EMVI status, histopathological, clinical, and demographic variables, in addition to overall (OS) and disease free (DFS) survival. RESULTS: 51 patients were characterised as CIMP-low, 48 CIMP-intermediate, and one patientCIMP-high. EMVI-positivity was associated with CIMP-intermediate epigenotype (p < 0.001). Patients with EMVI-positive tumours were found to have significantly more advanced disease by pT, pN, and pAJCC categorisation (p = 0.002, p < 0.001, and = p < 0.001, respectively). EMVI-positivity was significantly associated with the requirement for adjuvant chemotherapy (p < 0.001), and worse DFS but not OS (p = 0.012 and p = 0.052). CONCLUSIONS: Given the association between CIMP-intermediate epigenotype and EMVI-positivity, and the subsequent disadvantage in pathological stage, requirement for adjuvant therapy and worse survival, tumour epigenotyping could potentially play an important role in personalising patients' cancer care. Further work is required to understand the mechanisms that underlie the observed effect, with the hope that they may provide novel opportunities for intervention and inform treatment decisions in rectal cancer.
Authors: Rodrigo Jover; Thuy-Phuong Nguyen; Lucía Pérez-Carbonell; Pedro Zapater; Artemio Payá; Cristina Alenda; Estefanía Rojas; Joaquín Cubiella; Francesc Balaguer; Juan D Morillas; Juan Clofent; Luis Bujanda; Josep M Reñé; Xavier Bessa; Rosa M Xicola; David Nicolás-Pérez; Antoni Castells; Montserrat Andreu; Xavier Llor; C Richard Boland; Ajay Goel Journal: Gastroenterology Date: 2010-12-24 Impact factor: 22.682
Authors: Stacey Shiovitz; Monica M Bertagnolli; Lindsay A Renfro; Eunmi Nam; Nathan R Foster; Slavomir Dzieciatkowski; Yanxin Luo; Victoria Valinluck Lao; Raymond J Monnat; Mary J Emond; Nancy Maizels; Donna Niedzwiecki; Richard M Goldberg; Leonard B Saltz; Alan Venook; Robert S Warren; William M Grady Journal: Gastroenterology Date: 2014-05-21 Impact factor: 22.682
Authors: Swati Sonal; Vikram Deshpande; David T Ting; James C Cusack; Aparna R Parikh; Azfar Neyaz; Amaya Pankaj; Martin S Taylor; Anne M Dinaux; Lieve G J Leijssen; Chloe Boudreau; Joseph J Locascio; Hiroko Kunitake; Robert N Goldstone; Liliana G Bordeianou; Christy E Cauley; Rocco Ricciardi; David L Berger Journal: Ann Surg Oncol Date: 2022-08-02 Impact factor: 4.339
Authors: Shailesh M Advani; Pragati Advani; Stacia M DeSantis; Derek Brown; Helena M VonVille; Michael Lam; Jonathan M Loree; Amir Mehrvarz Sarshekeh; Jan Bressler; David S Lopez; Carrie R Daniel; Michael D Swartz; Scott Kopetz Journal: Transl Oncol Date: 2018-07-30 Impact factor: 4.243
Authors: Shailesh Mahesh Advani; Pragati Shailesh Advani; Derek W Brown; Stacia M DeSantis; Krittiya Korphaisarn; Helena M VonVille; Jan Bressler; David S Lopez; Jennifer S Davis; Carrie R Daniel; Amir Mehrvarz Sarshekeh; Dejana Braithwaite; Michael D Swartz; Scott Kopetz Journal: BMC Cancer Date: 2019-10-17 Impact factor: 4.430