An epistatic interaction between the PAX8 and STK17B genes in papillary thyroid cancer susceptibility

PLoS One. 2013 Sep 23;8(9):e74765. doi: 10.1371/journal.pone.0074765. eCollection 2013.


Papillary Thyroid Cancer (PTC) is a heterogeneous and complex disease; susceptibility to PTC is influenced by the joint effects of multiple common, low-penetrance genes, although relatively few have been identified to date. Here we applied a rigorous combined approach to assess both the individual and epistatic contributions of genetic factors to PTC susceptibility, based on one of the largest series of thyroid cancer cases described to date. In addition to identifying the involvement of TSHR variation in classic PTC, our pioneer study of epistasis revealed a significant interaction between variants in STK17B and PAX8. The interaction was detected by MD-MBR (p = 0.00010) and confirmed by other methods, and then replicated in a second independent series of patients (MD-MBR p = 0.017). Furthermore, we demonstrated an inverse correlation between expression of PAX8 and STK17B in a set of cell lines derived from human thyroid carcinomas. Overall, our work sheds additional light on the genetic basis of thyroid cancer susceptibility, and suggests a new direction for the exploration of the inherited genetic contribution to disease using association studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics*
  • Carcinoma / genetics*
  • Carcinoma, Papillary
  • Cell Line, Tumor
  • Epistasis, Genetic*
  • Female
  • Forkhead Transcription Factors / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Middle Aged
  • Models, Genetic
  • PAX8 Transcription Factor
  • Paired Box Transcription Factors / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Protein Serine-Threonine Kinases / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Risk Factors
  • Thyroid Cancer, Papillary
  • Thyroid Neoplasms / genetics*


  • Apoptosis Regulatory Proteins
  • FOXE1 protein, human
  • Forkhead Transcription Factors
  • PAX8 Transcription Factor
  • PAX8 protein, human
  • Paired Box Transcription Factors
  • RNA, Messenger
  • Protein Serine-Threonine Kinases
  • STK17B protein, human

Grants and funding

This work was supported by Grants from the Fondo de Investigaciones Sanitarias (FIS) project PI11/01359 (to MR), the Red Temática de Investigación Cooperativa en Cáncer, the Instituto de Salud Carlos III, RD12/0030/0060 (to PS), RD12/0036/0050 (to NM) and S2011/BMD-2328 TIRONET from the Comunidad de Madrid (to MR and PS), and European Regional Development Fund. IL is supported by FIS grant FI07/00326; CB is supported by the FPI grant BES-2008-006332; LI-P is supported by Centro de Investigación Biomédica en Red de Enfermedades Raras, and AS-P is a predoctoral fellows of the FPU program (MICINN) respectively. SR-LL is a postdoctoral fellow of the FIS (contract # CD05-0055). RDU is supported by project BIO2009-12458 from the Spanish Ministry of Economy and Innovation. RM, SP and AV are supported by the Generalitat de Catalunya, CIRIT (2009SGR-725). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.