Oncotarget

Research Papers:

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

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

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Oncotarget. 2016; 7:55098-55109. https://doi.org/10.18632/oncotarget.10398

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Abstract

Kosuke Mima1,*, Jonathan A. Nowak2,*, Zhi Rong Qian1,*, Yin Cao3,4,5, Mingyang Song3,4,5, Yohei Masugi1, Yan Shi1, Annacarolina da Silva1, Mancang Gu1, Wanwan Li1, Tsuyoshi Hamada1, Xuehong Zhang6, Kana Wu5,6, Jeffrey A. Meyerhardt1, Hideo Baba7, Edward L. Giovannucci5,6,8, Andrew T. Chan3,4,6,*, Charles S. Fuchs1,6,*, Shuji Ogino1,2,8,*, Reiko Nishihara1,5,*

1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

2Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

3Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

4Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA

5Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

6Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

7Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan

8Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

*These authors have contributed equally to this work

Correspondence to:

Shuji Ogino, email: shuji_ogino@dfci.harvard.edu

Reiko Nishihara, email: rnishiha@hsph.harvard.edu

Keywords: epigenetics, left-sided, molecular pathological epidemiology, prognosis, right-sided

Received: January 30, 2016    Accepted: June 17, 2016    Published: July 04, 2016

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.


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