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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.

Smith SL, Bowers NL, Betticher DC, Gautschi O, Ratschiller D, Hoban PR, Booton R, Santibáñez-Koref MF, Heighway J - Br. J. Cancer (2005)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: 1Gene Function Group, Roy Castle Lung Cancer Programme, University of Liverpool Cancer Research Centre, 200 London Road, Liverpool L3 9TA, UK.

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.

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AURKB allele-specific expression analyses and corresponding allelic imbalance measurements in matched primary tissues from lung cancer patients. Most tumour samples showed expression strongly biased towards one allele. This is frequently accompanied (six out of seven) by a marginal allelic imbalance in the genomic DNA. The marker track (on all gel images) is a ØX174 HaeIII digest. Bands representing parental alleles are marked A1/A2.
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fig3: AURKB allele-specific expression analyses and corresponding allelic imbalance measurements in matched primary tissues from lung cancer patients. Most tumour samples showed expression strongly biased towards one allele. This is frequently accompanied (six out of seven) by a marginal allelic imbalance in the genomic DNA. The marker track (on all gel images) is a ØX174 HaeIII digest. Bands representing parental alleles are marked A1/A2.

Mentions: Nine patients (nine out of 44, 20%) were heterozygous for a nonsynonymous cSNP in exon 9 of the gene. Using PCR-RFLP and RT–PCR-RFLP analyses, we were able to show that relative to the patient matched normal cDNA, seven out of nine of these samples showed a marked AEI favouring one or other AURKB allele (outside the range of mean allele ratio in normal tissue±3s.d.). In six out of seven of these cases, this AEI was associated with a phase-matched allelic imbalance in the tumour DNA (Figure 3). The allelic ratio in the matched normal samples suggested that both alleles were genomically balanced and expressed equally in each patient.


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.

Smith SL, Bowers NL, Betticher DC, Gautschi O, Ratschiller D, Hoban PR, Booton R, Santibáñez-Koref MF, Heighway J - Br. J. Cancer (2005)

AURKB allele-specific expression analyses and corresponding allelic imbalance measurements in matched primary tissues from lung cancer patients. Most tumour samples showed expression strongly biased towards one allele. This is frequently accompanied (six out of seven) by a marginal allelic imbalance in the genomic DNA. The marker track (on all gel images) is a ØX174 HaeIII digest. Bands representing parental alleles are marked A1/A2.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361619&req=5

fig3: AURKB allele-specific expression analyses and corresponding allelic imbalance measurements in matched primary tissues from lung cancer patients. Most tumour samples showed expression strongly biased towards one allele. This is frequently accompanied (six out of seven) by a marginal allelic imbalance in the genomic DNA. The marker track (on all gel images) is a ØX174 HaeIII digest. Bands representing parental alleles are marked A1/A2.
Mentions: Nine patients (nine out of 44, 20%) were heterozygous for a nonsynonymous cSNP in exon 9 of the gene. Using PCR-RFLP and RT–PCR-RFLP analyses, we were able to show that relative to the patient matched normal cDNA, seven out of nine of these samples showed a marked AEI favouring one or other AURKB allele (outside the range of mean allele ratio in normal tissue±3s.d.). In six out of seven of these cases, this AEI was associated with a phase-matched allelic imbalance in the tumour DNA (Figure 3). The allelic ratio in the matched normal samples suggested that both alleles were genomically balanced and expressed equally in each patient.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: 1Gene Function Group, Roy Castle Lung Cancer Programme, University of Liverpool Cancer Research Centre, 200 London Road, Liverpool L3 9TA, UK.

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.

Show MeSH
Related in: MedlinePlus