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Research Papers:

Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer

Yoshifumi Shimada, Hitoshi Kameyama, Masayuki Nagahashi, Hiroshi Ichikawa, Yusuke Muneoka, Ryoma Yagi, Yosuke Tajima, Takuma Okamura, Masato Nakano, Jun Sakata, Takashi Kobayashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Tetsu Hayashida, Hiromasa Takaishi, Yuko Kitagawa, Eiji Oki, Tsuyoshi Konishi, Fumio Ishida, Shin-ei Kudo, Jennifer E. Ring, Alexei Protopopov, Stephen Lyle, Yiwei Ling, Shujiro Okuda, Takashi Ishikawa, Kohei Akazawa, Kazuaki Takabe, Toshifumi Wakai _

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Oncotarget. 2017; 8:93567-93579. https://doi.org/10.18632/oncotarget.20510

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Abstract

Yoshifumi Shimada1, Hitoshi Kameyama1, Masayuki Nagahashi1, Hiroshi Ichikawa1, Yusuke Muneoka1, Ryoma Yagi1,2, Yosuke Tajima1, Takuma Okamura1, Masato Nakano1, Jun Sakata1, Takashi Kobayashi1, Hitoshi Nogami2, Satoshi Maruyama2, Yasumasa Takii2, Tetsu Hayashida3, Hiromasa Takaishi4, Yuko Kitagawa3, Eiji Oki5, Tsuyoshi Konishi6, Fumio Ishida7, Shin-ei Kudo7, Jennifer E. Ring8, Alexei Protopopov8, Stephen Lyle8,9, Yiwei Ling10, Shujiro Okuda10, Takashi Ishikawa1,11, Kohei Akazawa11, Kazuaki Takabe12,13 and Toshifumi Wakai1

1Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

2Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan

3Department of Surgery, Keio University School of Medicine, Tokyo, Japan

4Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan

5Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

6Department of Gastroenterological Surgery, Gastroenterological Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

7Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan

8KEW, Inc., Cambridge, MA, USA

9University of Massachusetts Medical School, Worcester, MA, USA

10Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

11Department of Medical Informatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

12Breast Surgery, Roswell Park Cancer Institute, Buffalo, NY, USA

13Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA

Correspondence to:

Toshifumi Wakai, email: wakait@med.niigata-u.ac.jp

Kazuaki Takabe, email: Kazuaki.Takabe@RoswellPark.org

Yoshifumi Shimada, email: shimaday@med.niigata-u.ac.jp

Keywords: colorectal cancer, right-sided, anti-EGFR therapy, next-generation sequencing, comprehensive genomic sequencing

Received: April 08, 2017    Accepted: August 08, 2017    Published: August 24, 2017

ABSTRACT

Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing.

Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as “all wild-type”, while remaining patients were defined as “mutant-type”.

Results: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were “all wild-type” compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and “mutant-type” RCRC showed significantly worse PFS compared with “all wild-type” LCRC (P = 0.004).

Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.


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