Int. J. Dev. Biol. 62: 857 - 864 (2018)

https://doi.org/10.1387/ijdb.180210yb

Vol 62, Issue 11-12

Special Issue: Homeobox genes

Lung cancer susceptibility genetic variants modulate HOXB2 expression in the lung

Published: 14 December 2018

Alisson Clemenceau^#,1, Olivier Boucherat^#,2, Kim Landry-Truchon^#,2, Maxime Lamontagne¹, Sabrina Biardel¹, Philippe Joubert^1,3, Stéphane Gobeil^4,5, Blandine Secco¹, Mathieu Laplante^1,3, Mathieu Morissette^1,3, Ma’en Obeidat⁷, Wim Timens⁸, Lucie Jeannotte*^,2,3,6 and Yohan Bossé*^,1,3,5

¹Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Canada, ²CRCHU Québec-Université Laval, Québec, Canada, ³Centre de Recherche sur le Cancer de l'Université Laval, Québec, Canada, ⁴CRCHU de Québec, CHUL, Québec, Canada, ⁵Department of Molecular Medicine, Université Laval, Québec, Canada, ⁶Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, Canada, ⁷The University of British Columbia, Centre for Heart Lung Innovation, St Paul’s Hospital, Vancouver, BC, Canada, ⁸Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, The Netherlands

Abstract

The HOX genes are transcription factors that are expressed in coordinated spatiotemporal patterns to ensure normal development. Ectopic expression may instead lead to the development and progression of tumors. Genetic polymorphisms in the regions of four HOX gene clusters were tested for association with lung cancer in 420 cases and 3,151 controls. The effect of these variants on lung gene expression (expression quantitative trait loci, eQTL) was tested in a discovery set of 409 non-tumor lung samples and validated in two lung eQTL replication sets (n = 287 and 342). The expression levels of HOXB2 were evaluated at the mRNA and protein levels by quantitative real-time PCR and immunohistochemistry in paired tumor and non-tumor lung tissue samples. The most significant SNP associated with lung cancer in the HOXB cluster was rs10853100 located upstream of the HOXB cluster. HOXB2 was the top eQTL-regulated gene with several polymorphisms associated with its mRNA expression levels in lung tissue. This includes the lung cancer SNP rs10853100 that was significantly associated with HOXB2 expression (P=3.39E-7). In the lung eQTL discovery and replication sets, the lung cancer risk allele (T) for rs10853100 was associated with lower HOXB2 expression levels. In paired normal-tumor samples, HOXB2 mRNA and protein levels were significantly reduced in tumors when compared to non-tumor lung tissues. Genetic variants in the HOXB cluster may confer susceptibility to lung cancer by modulating the expression of HOXB2 in the lung.

Keywords

HOXB2, lung adenocarcinoma, lung eQTL