The rs6983267 SNP Is Associated with MYC Transcription Efficiency, Which Promotes Progression and Worsens Prognosis of Colorectal Cancer (original) (raw)

Abstract

Background

The oncogenic single nucleotide polymorphism rs6983267, located on 8q24.21, may affect copy number aberrations and/or expression profiles in colorectal cancer (CRC). We investigated the role of this single nucleotide polymorphism in the clinical outcome of CRC.

Methods

Array comparative genomic hybridization (aCGH) and oligomicroarrays were performed on cancer cells from 157 primary CRC tissues. Expression profiles were analyzed by means of extraction expression module (EEM) analyses. Mutations in TP53, KRAS, and BRAF and microsatellite instability were also examined in 107 of the 157 cases.

Results

aCGH analysis revealed two clusters; more frequent genomic copy number alteration (CNA) was observed in the 89 cases in cluster B than in the 18 cases in cluster A. The average CNA was higher in samples containing the major allele (GT/TT) of rs6983267 than in those containing the minor allele (GG). Additionally, MYC expression was the highest in samples containing the GG allele (n = 18), followed by the GT and TT alleles (n = 41 and 48, respectively). EEM analysis revealed dominant up-regulation of MYC in samples containing the minor allele. Moreover, the presence of the minor allele in a _MYC_-positive, CNA-negative context predicted a poorer prognosis than the presence of the major allele in a _MYC_-negative, CNA-positive context in CRC.

Conclusions

The presence of the minor allele of rs6983267 at 8q24.21 worsened the prognosis of CRC through up-regulation of MYC transcription. Furthermore, progression of CRC may require global CNA in the presence of the major allele and with lack of MYC transcription.

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Acknowledgment

We would like to thank T. Shimooka, K. Ogata, M. Kasagi, Y. Nakagawa, and T. Kawano for their technical assistance. This work was supported in part by the following grants and foundations: CREST, Japan Science and Technology Agency (JST); Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research, grant numbers 21591644, 21791295, 21791297, 215921014, and 21679006; NEDO (New Energy and Industrial Technology Development Organization) Technological Development for Chromosome Analysis; Grant of the Clinical Research Foundation (2008–2010); and the Funding Program for Next Generation World-Leading Researchers (NEXT), LS-094. We also thank Prof. Seiji Ogawa, University of Tokyo, for assistance with editing.

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Authors and Affiliations

1. Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan
   Yasushi Takatsuno MD, Koshi Mimori MD, PhD, Hiroshi Inoue MD, PhD, Shinya Ishimaru MD, PhD & Hideshi Ishii MD, PhD
2. Department of Molecular and Cellular Biology, Kyushu University, Fukuoka, Japan
   Ken Yamamoto PhD
3. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
   Atsushi Niida PhD, Seiya Imoto PhD, Shuhei Kawano PhD, Rui Yamaguchi PhD & Satoru Miyano PhD
4. Division of Molecular Design, Kyushu University, Fukuoka, Japan
   Tetsuya Sato PhD & Hiroyuki Toh PhD
5. Department of Surgery, Teikyo University, Tokyo, Japan
   Hisae Iinuma MD, PhD
6. Department of the Public Health, Nagoya City University, Nagoya, Japan
   Sadao Suzuki MD, PhD & Shinkan Tokudome MD, PhD
7. Department of Surgery, Kitazato University, Kanagawa, Japan
   Masahiko Watanabe MD, PhD
8. Digestive Disease Center, Northern Yokohama Hospital, Showa University, Yokohama, Japan
   Jun-ichi Tanaka MD, PhD & Shin-ei Kudo MD, PhD
9. Department of Surgery, Defence Medical College, Tokorozawa, Japan
   Hidetaka Mochizuki MD, PhD
10. Department of Surgery, Mie University, Mie, Japan
    Masato Kusunoki MD, PhD
11. Department of Surgery, Takano Hospital, Kumamoto, Japan
    Kazutaka Yamada MD, PhD
12. Department of Surgery and Digestive Tract Medicine, National Cancer Center, Tokyo, Japan
    Yasuhiro Shimada MD, PhD & Yoshihiro Moriya MD, PhD
13. Department of Surgical Oncology, Tokyo Medical and Dental University, Tokyo, Japan
    Yasushi Takatsuno MD, Shinya Ishimaru MD, PhD & Kenichi Sugihara MD, PhD
14. Department of Gastroenterological Surgery, Osaka University, Suita, Japan
    Hideshi Ishii MD, PhD & Masaki Mori MD, PhD, FACS

Authors

1. Yasushi Takatsuno MD
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2. Koshi Mimori MD, PhD
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3. Ken Yamamoto PhD
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4. Tetsuya Sato PhD
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5. Atsushi Niida PhD
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6. Hiroshi Inoue MD, PhD
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7. Seiya Imoto PhD
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8. Shuhei Kawano PhD
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9. Rui Yamaguchi PhD
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10. Hiroyuki Toh PhD
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11. Hisae Iinuma MD, PhD
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12. Shinya Ishimaru MD, PhD
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13. Hideshi Ishii MD, PhD
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14. Sadao Suzuki MD, PhD
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15. Shinkan Tokudome MD, PhD
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16. Masahiko Watanabe MD, PhD
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17. Jun-ichi Tanaka MD, PhD
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18. Shin-ei Kudo MD, PhD
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19. Hidetaka Mochizuki MD, PhD
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20. Masato Kusunoki MD, PhD
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21. Kazutaka Yamada MD, PhD
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22. Yasuhiro Shimada MD, PhD
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23. Yoshihiro Moriya MD, PhD
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24. Satoru Miyano PhD
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25. Kenichi Sugihara MD, PhD
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26. Masaki Mori MD, PhD, FACS
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Corresponding author

Correspondence toKoshi Mimori MD, PhD.

Additional information

The first four authors contributed equally to this work, and all should be considered first author.

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Takatsuno, Y., Mimori, K., Yamamoto, K. et al. The rs6983267 SNP Is Associated with MYC Transcription Efficiency, Which Promotes Progression and Worsens Prognosis of Colorectal Cancer.Ann Surg Oncol 20, 1395–1402 (2013). https://doi.org/10.1245/s10434-012-2657-z

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• Received: 20 January 2012
• Published: 14 September 2012
• Issue Date: April 2013
• DOI: https://doi.org/10.1245/s10434-012-2657-z

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