Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival.

Kosuke Mima,Tsuyoshi Hamada,Hideo Baba,Yan Shi,Zhi Rong Qian,Wanwan Li,Yohei Masugi,Mingyang Song,Yin Cao,Reiko Nishihara,Xuehong Zhang,Andrew T Chan,Jeffrey A Meyerhardt,Kana Wu,Mancang Gu,Shuji Ogino,Jonathan A Nowak,Charles S Fuchs,Annacarolina Da Silva,Edward Giovannucci

doi:10.18632/oncotarget.10398

Abstract

Colorectal tumors arise with genomic and epigenomic alterations through interactions between neoplastic cells, immune cells, and microbiota that vary along the proximal to distal axis of colorectum. Long interspersed nucleotide element-1 (LINE-1) hypomethylation in colorectal cancer has been associated with worse clinical outcome. Utilizing 1,317 colon and rectal carcinoma cases in two U.S.-nationwide prospective cohort studies, we examined patient survival according to LINE-1 methylation level stratified by tumor location. Cox proportional hazards model was used to assess a statistical interaction between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations. A statistically significant interaction was found between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis (Pinteraction = 0.011). The association of LINE-1 hypomethylation with higher colorectal cancer-specific mortality was stronger in proximal colon cancers (multivariable hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.21 to 2.28) than in distal colon cancers (multivariable HR, 1.18; 95% CI, 0.81 to 1.72) or rectal cancers (multivariable HR, 0.87; 95% CI, 0.57 to 1.34). Our data suggest the interactive effect of LINE-1 methylation level and colorectal cancer location on clinical outcome.

Highlights

PATIENTS AND METHODSEwing sarcomas are defined by t(11;22)(q24;q12) derived EWS/ETS fusion oncogenes [1]
Design: Of 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996
After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without bone marrow (BM) involvement, in contrast to 0/5 patients with BM involvement

Summary

Introduction

Ewing sarcomas are defined by t(11;22)(q24;q12) derived EWS/ETS fusion oncogenes [1]. They occur in both bone and soft tissue [2]. Advanced Ewing sarcoma comprises early relapse or metastatic to multiple bones (i.e. more than one) or bone marrow (BM) [3, 4]. In the MetaEICESS 1992 protocol we used induction chemotherapy, whole-body MRI (whole-body MRI) and PET based primary and metastatic tumor irradiation combined with autologous stem cell rescue, followed by tandem high-dose chemotherapy with additional autologous rescue as consolidation [4]. Results of diseasefree survival of both MetaEICESS protocols were compared with advanced Ewing sarcoma patients who received the EICESS 1992 regimen with induction and consolidation chemotherapy and primary tumor radiation only. Results of the MetaEICESS 1992 [4] and the EICESS 1992 groups [22] previously published are updated here

Methods

Results

Conclusion