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The FOXE1 and NKX2-1 loci are associated with susceptibility to papillary thyroid carcinoma in the Japanese population
  1. Michiko Matsuse1,
  2. Meiko Takahashi2,
  3. Norisato Mitsutake1,3,
  4. Eijun Nishihara4,
  5. Mitsuyoshi Hirokawa4,
  6. Takahisa Kawaguchi2,
  7. Tatiana Rogounovitch1,
  8. Vladimir Saenko5,
  9. Andrey Bychkov1,
  10. Keiji Suzuki1,
  11. Keitaro Matsuo6,
  12. Kazuo Tajima6,
  13. Akira Miyauchi4,
  14. Ryo Yamada2,
  15. Fumihiko Matsuda2,7,
  16. Shunichi Yamashita1,5
  1. 1Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  2. 2Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  3. 3Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (NRGIC), Nagasaki, Japan
  4. 4Kuma Hospital, Kobe, Japan
  5. 5Department of International Health and Radiation Research, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  6. 6Aichi Cancer Center Hospital and Research Institute, Nagoya, Japan
  7. 7Institut National de la Santé et de la Recherche Médicale (INSERM) Unit U852, Paris, France
  1. Correspondence to Dr Norisato Mitsutake, Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan; mitsu{at}


Background FOXE1 and NKX2-1 are two known genetic risk factors for the predisposition to sporadic papillary thyroid carcinoma (PTC) in Europeans, but their association in other ethnicities is still unknown.

Objective We aim to examine the association of the two genes with Japanese sporadic PTC, which exhibits high BRAFV600E mutation rate.

Methods 507 Japanese sporadic PTC cases and 2766 controls were genotyped for rs965513 (FOXE1) and rs944289 (NKX2-1). PTC cases were also examined for their BRAFV600E mutational status.

Results The association of both rs965513 (p=1.27×10−4, OR=1.69, 95% CI 1.29 to 2.21) and rs944289 (p=0.0121, OR=1.21, 95% CI 1.04 to 1.39) with the risk of sporadic PTC was confirmed. Subgroup analysis based on the BRAF mutational status showed strong association of rs965513 with BRAFV600E-positive cases (p=2.26×10−4, OR=1.72, 95% CI 1.29 to 2.29), but not with BRAFV600E-negative cases (p=0.143, OR=1.52, 95% CI 0.87 to 2.65). However, there was no difference in the observed effect size between both subgroups. For rs944289, both subgroups showed marginal association (p=0.0585, OR=1.17, 95% CI 0.99 to 1.37 for BRAFV600E-positive cases; p=0.0492, OR=1.35, 95% CI 1.00 to 1.81 for BRAFV600E-negative cases).

Conclusions Both FOXE1 and NKX2-1 were associated with the increased risk of sporadic Japanese PTC. No clear associations were observed for either SNP with BRAFV600E status.

  • FOXE1
  • NKX2-1
  • papillary thyroid carcinoma
  • genotyping
  • SNP
  • cancer: endocrine
  • genetics
  • genome-wide
  • molecular genetics
  • cancer: thyroid
  • epidemiology
  • academic medicine

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  • MM, MT and NM are the authors who contributed equally to this work.

  • Funding This work was supported in part by Grant-in-Aid for Scientific Research (#22256004 and #22390189), Grant-in-Aid for Young Scientists (#22791204 and #21790337) and Global COE Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. FM was in part supported by INSERM. NM was in part supported by The Yasuda Medical Foundation.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Nagasaki University, Kuma Hospital and Kyoto University.

  • Provenance and peer review Not commissioned; externally peer reviewed.