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Association of MicroRNA-31-5p with Clinical Efficacy of Anti-EGFR Therapy in Patients with Metastatic Colorectal Cancer

  • Colorectal Cancer
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Gene mutations in the pathway downstream of epidermal growth factor receptor (EGFR) are considered to induce resistance to anti-EGFR therapy in colorectal cancer (CRC). We recently reported that microRNA-31 (miR-31)-5p may regulate BRAF activation and play a role in the signaling pathway downstream of EGFR in CRC. Therefore, we hypothesized that miR-31-5p can be a useful biomarker for anti-EGFR therapy in CRC.

Methods

We evaluated miR-31-5p expression and gene mutations [KRAS (codon 61 or 146), NRAS (codon 12, 13, or 61), and BRAF (V600E)] in the EGFR downstream pathway in 102 CRC patients harboring KRAS (codon 12 or 13) wild-type who were treated with anti-EGFR therapeutics. Progression-free survival (PFS) and overall survival (OS) were evaluated.

Results

KRAS (codon 61 or 146), NRAS, and BRAF mutations were detected in 6.9, 6.9, and 5.9 % patients, respectively. Compared with CRCs with at least one mutation (n = 20), significantly better PFS (P = 0.0003) but insignificantly better OS were observed in CRCs harboring all wild-type genes (KRAS, NRAS, and BRAF). High miR-31-5p expression was identified in 11 % (n = 11) patients and was significantly associated with shorter PFS (P = 0.003). In CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS (P = 0.027).

Conclusions

High miR-31-5p expression was associated with shorter PFS in patients with CRC treated with anti-EGFR therapeutics. Moreover, in CRCs carrying all wild-type genes, high miR-31-5p was associated with shorter PFS, suggesting that it may be a useful and additional prognostic biomarker for anti-EGFR therapy.

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Acknowledgment

The authors thank the pathology departments of Sapporo Medical University Hospital and Keiyukai Sapporo Hospital for providing the tissue specimens. The authors also thank Enago (www.enago.jp) for English language review. This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research [Grant Numbers: 23790800 (to K.N.) and 23390200 (to Y.S.)], A-STEP (Adaptable & Seamless, Technology Transfer Program through Target-driven R&D) (to K.N.), Sapporo Jikeikai Tomoiki Foundation (to K.N.), Takeda Science Foundation (to K.N.), and Daiwa Securities Health Foundation (to H.I.).

Disclosure

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Authors and Affiliations

  1. Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Hisayoshi Igarashi MD, PhD, Hiroyoshi Kurihara MD, Kei Mitsuhashi MD, Miki Ito MD, Shinichi Kanno MD, Takafumi Naito MD, Yasutaka Sukawa MD, PhD, Yasushi Adachi MD, PhD, Katsuhiko Nosho MD, PhD & Yasuhisa Shinomura MD, PhD

  2. Department of Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan

    Hiroyuki Okuda MD, PhD

  3. Department of Gastroenterology, Keiyukai Sapporo Hospital, Sapporo, Japan

    Shinji Yoshii MD & Hiroaki Takahashi MD, PhD

  4. Department of Gastroenterology, NTT East Sapporo Hospital, Sapporo, Japan

    Shinji Yoshii MD

  5. Department of Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan

    Takaya Kusumi MD

  6. Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Tadashi Hasegawa MD, PhD

  7. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Yasutaka Sukawa MD, PhD

  8. Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan

    Kenji Okita MD, PhD & Koichi Hirata MD, PhD

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

    Yu Imamura MD, PhD & Yoshifumi Baba MD, PhD

  10. Division of Cancer Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Kohzoh Imai MD, PhD

  11. Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Hiromu Suzuki MD, PhD

  12. Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan

    Hiroyuki Yamamoto MD, PhD

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  1. Hisayoshi Igarashi MD, PhD
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  2. Hiroyoshi Kurihara MD
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  3. Kei Mitsuhashi MD
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  4. Miki Ito MD
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  5. Hiroyuki Okuda MD, PhD
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  6. Shinichi Kanno MD
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  7. Takafumi Naito MD
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  8. Shinji Yoshii MD
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  9. Hiroaki Takahashi MD, PhD
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  20. Hiroyuki Yamamoto MD, PhD
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  21. Katsuhiko Nosho MD, PhD
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  22. Yasuhisa Shinomura MD, PhD
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Corresponding author

Correspondence to Katsuhiko Nosho MD, PhD.

Additional information

Hisayoshi Igarashi, Hiroyoshi Kurihara, Kei Mitsuhashi, and Miki Ito have contributed equally to this work.

Hiroyuki Yamamoto, Katsuhiko Nosho, and Yasuhisa Shinomura have contributed equally to this work.

Electronic supplementary material

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Supplementary material 1 Supplementary Method (DOCX 49 kb)

10434_2014_4264_MOESM2_ESM.tif

Supplementary material 2 Supplementary Figure 1 The scatter diagram of relative expression levels of micorRNA-31-5p and -3p of 102 colorectal cancer (CRC) patients who received anti-EGFR therapy (TIFF 78 kb)

10434_2014_4264_MOESM3_ESM.tif

Supplementary material 3 Supplementary Figure 2. Kaplan–Meier survival curves of patients treated with anti-EGFR therapy according to the mutational status in KRAS, NRAS, and BRAF genes. (a) Overall survival (OS) of patients with at least one mutation in KRAS (codon 61 or 146) or NRAS (codon 12, 13, or 61) versus patients with all wild-type copies of the 2 genes. (b) OS of patients with mutation in BRAF versus patients with wild-type copies of BRAF. (c) OS of patients with at least one mutation in KRAS, NRAS, and BRAF versus all wild-type copies of the 3 genes. (TIFF 117 kb)

10434_2014_4264_MOESM4_ESM.tif

Supplementary material Supplementary Figure 3. Kaplan–Meier survival curves of patients treated with anti-EGFR therapy according to microRNA-31-5p expression. Overall survival of the high-expression group versus the low-expression group 4 (TIFF 60 kb)

10434_2014_4264_MOESM5_ESM.tif

Supplementary material Supplementary Figure 4. Kaplan–Meier survival curves of patients treated with anti-EGFR therapy according to microRNA-31-3p expression. (a) Progression-free survival and (b) overall survival of the high-expression group versus the low-expression group 5 (TIFF 88 kb)

10434_2014_4264_MOESM6_ESM.tif

Supplementary material 6 Supplementary Figure 5. The distribution of relative expression levels of miR-31-5p or -3p of colon cancer cell lines. (TIFF 44 kb)

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Igarashi, H., Kurihara, H., Mitsuhashi, K. et al. Association of MicroRNA-31-5p with Clinical Efficacy of Anti-EGFR Therapy in Patients with Metastatic Colorectal Cancer. Ann Surg Oncol 22, 2640–2648 (2015). https://doi.org/10.1245/s10434-014-4264-7

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