Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability

Abstract

Aurora kinases are key regulators of chromosome segregation during mitosis. We have previously shown by microarray analysis of primary lung carcinomas and matched normal tissue that AURKB (22 out of 37) and AURKA (15 out of 37) transcripts are frequently over-represented in these tumours. We now confirm these observations in a second series of 44 carcinomas and also show that aurora B kinase protein levels are raised in the tumours compared to normal tissue. Elevated levels of expression in tumours are not a consequence of high-level amplification of the AURKB gene. Using a coding sequence polymorphism we show that in most cases (seven out of nine) tumour expression is predominantly driven from one AURKB allele. Given the function of aurora B kinase, we examined whether there was an association between expression levels and genetic instability. We defined two groups of high and low AURKB expression. Using a panel of 10 microsatellite markers, we found that the group showing the higher level of expression had a higher frequency of allelic imbalance (P=0.0012). Analysis of a number of other genes that are strongly and specifically expressed in tumour over normal lung, including SERPINB5, TERT and PRAME, showed marked allelic expression imbalances in the tumour tissue in the context of balanced or only marginally imbalanced relative allelic copy numbers. Our data support a model of early carcinogenesis wherein defects in the process of inactivation of lung stem-cell associated genes during differentiation, contributes to the development of carcinogenesis.

Frequent overexpression of aurora B kinase, a novel drug target, in non–small cell lung carcinoma patients

“…Using immunohistochemical analysis of a large series of tumors, we show frequent expression of aurora B protein in NSCLC samples, whereas normal lung tissue is negative. This finding suggests a role for aurora B as tumor marker in NSCLC, and confirms at the protein level the recently reported up-regulation of aurora B mRNA in lung tumors (30).…”

“…A recent report has shown a general up-regulation of aurora B mRNA levels compared with normal epithelium in the majority of samples of a small cohort of resected lung cancer patients (30). However, aurora B protein expression has not been previously characterized in human NSCLC by immunohistochemistry, and its role in NSCLC progression has not been well documented.…”

AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer

“…AURKA serves a central role in recruiting other mitotic spindle members (5). A number of previous studies conducted in lung cancer have investigated the prognostic value of various of the aforementioned genes, including TPX2 (15), AURKA (16)(17)(18) and AURKB (18)(19)(20)(21); however, the prognostic value of AURKA and AURKB remains a matter of debate. No information on the potential prognostic significance in human NSCLC has yet been provided for DLGAP5, CKAP5 or TTK.…”

Frequent T cell responses against immunogenic targets in lung cancer patients for targeted immunotherapy

“…It is then localized to the midzone spindle during telophase and thereafter to midbody during cytokinesis. Aura B is overexpressed in lung cancer and an excessive overexpression correlates with poorer prognosis (44). Their frequent expression in lung cancer but also their ability to induce a specific immune response indicates that Aurora kinases could be novel targets in vaccination strategies.…”