Getting unlucky with chromosome number 7

From the Holland lab, Human Biology Division

Glioblastoma is the most common and fatal primary brain cancer in adults. In the last decade, significant advances in sequencing technologies have identified important genetic defects that appear to be important for the development and progression of this disease. Particularly, the presence or absence of mutations in the isocitrate dehydrogenase (IDH) gene has shed new light on the glioblastoma molecular landscape and has become one of the most critical biomarkers for the molecular classification and prognostication of the disease. Interestingly, IDH wild-type glioblastomas are defined by large chromosomal aberrations, specifically in the form of a gain of chromosome 7 and loss of chromosome 10. Gain-of-function genes on chromosome 7 that drive tumor growth in IDH wild-type glioblastomas would most likely select for neoplastic cells harboring gain of chromosome 7 in the tumorigenesis process. The identification of these genes located on chromosome 7 that favorably drive its gain and selection, and therefore fuels gliomagenesis in IDH wild-type glioblastomas would increase opportunities for finding targeted therapies for this devastating disease.

Dr. Patrick Cimino, together with his colleagues from the Holland lab in the Human Biology Division, and collaborators from various institutions did just that.  To identify genes on chromosome 7 whose expression may provide such a selection advantage for the gain of chromosome 7, they used an unbiased bioinformatics approach to query the publically available The Cancer Genome Atlas (TCGA) IDH wild-type glioblastoma data set. In their recent paper published in Genes & Development, they found that expression of the homeobox A5 (HOXA5) gene on chromosome 7 correlated best with chromosome 7 gain and survival in proneural glioblastomas.  Using a combination of in vivo and in vitro studies, the authors proceeded to test the functional role by which HOXA5 overexpression might confer a selective advantage for gain of chromosome 7. Overexpression of ectopic HoxA5 in an established mouse model of proneural glioblastoma decreased survival. HoxA5-overexpressing tumors also showed a significant up-regulation of cell cycle and DNA damage repair genes, suggestive of pathways through which HoxA5 can promote an aggressive glioma phenotype.

Image of Schematic summary
Schematic summary of the functional impact of HOXA5 overexpression in adult glioblastoma. HOXA5 expression leading to increased radioresistance in recurrent human IDH wild-type glioblastoma is highest in the proneural (PN) subtype compared to the mesenchymal (MES), classical (CL) and meural (NEU) subtypes. Figure provided by Dr. Holland

Since ionizing radiation is a mainstay in the standard of care for patients with glioblastoma, the authors examined if HoxA5 expression influenced radiosensitivity using the glioblastoma mouse model. HoxA5 overexpression in mouse glioblastoma was associated with decreased post-irradiation survival, indicating that HoxA5 confers reduced sensitivity to radiation. Experiments performed in a human glioblastoma cell line also confirmed that HOXA5 expression was associated with increased proliferation after radiation, and decreased DNA damage signaling pathways more rapidly following radiation, thus making the cells less likely to undergo apoptosis or maintain cell cycle arrest.

Radioresistance may result in recurrent tumors, which could overexpress HOXA5. To investigate if HOXA5 overexpression may be enriched in recurrent tumors, the authors compared primary and recurrent post-radiation glioblastoma gene expression profiles for both mouse and human tumors, and found that HOXA5 expression was indeed enriched in recurrent tumors. Dr. Eric Holland commented that HoxA5 had “shown up as one of the most increased in expression in mouse gliomas after they recur from radiation.  It supports the similarity between the gliomas arising in different species”.

In this study, the authors identified HOXA5 overexpression in IDH wild-type glioblastomas to be a selective advantage for the gain of whole chromosome 7, resulting in increased cell proliferation and radioresistance that drives an aggressive phenotype. Increased expression of HOX genes, transcription factors that regulate cell fate decisions, have been found to be associated with a variety of cancers, though the precise role of HOXA genes in glioblastomas is not fully understood. Nonetheless, this study bodes well for patients with IDH wild-type glioblastomas – perhaps someday targeting HOXA genes may increase response to radiation therapy. 

Cimino PJ, Kim Y, Wu H, Alexander J, Lim J, Wirsching H, Szulzewsky F, Pitter K, Ozawa T, Wang J, Vazquez J, Arora S, Rabadan R, Levine R, Michor F, Holland EC. 2018. Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma. Genes & Development. Apr 1;32(7-8):512-523.

Funding was provided by the National Institutes of Health.