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Amplification of Chromosome 1q Genes Encoding the Phosphoinositide Signalling Enzymes PI4KB, AKT3, PIP5K1A and PI3KC2B in Breast Cancer.

Waugh MG - J Cancer (2014)

Bottom Line: Point mutations in the phosphatidylinositol 4-kinase genes were uncommon and appeared in less than 1% of the patient samples however, 62% of the tumours had increases in gene copy number for PI4KB which encodes the phosphatidylinositol 4-kinase IIIbeta isozyme.Extending this analysis to subsequent enzymes in the phosphoinositide signalling cascades revealed that the only PIP5K1A, PI3KC2B and AKT3 genes exhibited similar patterns of gene copy number variation.By comparison, gene copy number increases for established oncogenes such as EGFR and HER2/Neu were only evident in 20% of the samples.

View Article: PubMed Central - PubMed

Affiliation: Lipid and Membrane Biology Group, Institute for Liver and Digestive Health, UCL, Royal Free Campus, Rowland Hill Street, London, NW3 2PF United Kingdom.

ABSTRACT
Little is known about the possible oncogenic roles of genes encoding for the phosphatidylinositol 4-kinases, a family of enzymes that regulate an early step in phosphoinositide signalling. To address this issue, the mutational status of all four human phosphatidylinositol 4-kinases genes was analyzed across 852 breast cancer samples using the COSMIC data resource. Point mutations in the phosphatidylinositol 4-kinase genes were uncommon and appeared in less than 1% of the patient samples however, 62% of the tumours had increases in gene copy number for PI4KB which encodes the phosphatidylinositol 4-kinase IIIbeta isozyme. Extending this analysis to subsequent enzymes in the phosphoinositide signalling cascades revealed that the only PIP5K1A, PI3KC2B and AKT3 genes exhibited similar patterns of gene copy number variation. By comparison, gene copy number increases for established oncogenes such as EGFR and HER2/Neu were only evident in 20% of the samples. The PI4KB, PIP5K1A, PI3KC2B and AKT3 genes are related in that they all localize to chromosome 1q which is often structurally and numerically abnormal in breast cancer. These results demonstrate that a gene quartet encoding a potential phosphoinositide signalling pathway is amplified in a subset of breast cancers.

No MeSH data available.


Related in: MedlinePlus

Copy number increases in genes encoding for enzymes downstream of the PtdIns 4-kinases in the COSMIC breast cancer database. The chromosomal localization of each gene is given in brackets.
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Figure 2: Copy number increases in genes encoding for enzymes downstream of the PtdIns 4-kinases in the COSMIC breast cancer database. The chromosomal localization of each gene is given in brackets.

Mentions: This data mining strategy was extended to encompass copy number variation for genes encoding proteins involved in subsequent steps in phosphoinositide signalling (Figure 2). Investigating the copy number status of genes for the PtdIns4P 5-kinases which produce PtdIns(4,5)P2 by D5 phosphorylation of PtdIns4P and the PtdIns5P 4-kinases which produce the same lipid product via phosphorylation of PtdIns5P on the D4 position, revealed that of the five candidate genes examined, only PI4P5K1A demonstrated increased copy number in breast cancer. A similar approach focused on the phosphoinositide 3-kinase gene family, identified a substantial gene copy number increase for PIK3C2B which encodes a PtdIns4P 3-kinase. To complete this analysis the status of all three human AKT genes was assessed and copy number gains were most noteworthy for the gene encoding the Akt3 isoform and again this was in over 60% of the patient samples. Hence in the majority of the breast cancer cases represented on the COSMIC database there was an elevation in gene copy number for PI4KB, PIP5K1A, PIK3C2B and AKT3. Interestingly, this phosphoinositide gene quartet maps to chromosome 1q - a chromosome which is numerically abnormal in up to 50-60% of breast cancers 22-25. Comparisons with established oncogenes (Figure 3) indicated that the copy number increase for PI4KB was 2-3 fold higher than for tumour promoter genes such as EGFR and HER2/NEU. Furthermore the magnitude of PI4KB copy number amplification mirrored the scale of copy number loss for tumour suppressor genes such as TP53 and PTEN.


Amplification of Chromosome 1q Genes Encoding the Phosphoinositide Signalling Enzymes PI4KB, AKT3, PIP5K1A and PI3KC2B in Breast Cancer.

Waugh MG - J Cancer (2014)

Copy number increases in genes encoding for enzymes downstream of the PtdIns 4-kinases in the COSMIC breast cancer database. The chromosomal localization of each gene is given in brackets.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4216804&req=5

Figure 2: Copy number increases in genes encoding for enzymes downstream of the PtdIns 4-kinases in the COSMIC breast cancer database. The chromosomal localization of each gene is given in brackets.
Mentions: This data mining strategy was extended to encompass copy number variation for genes encoding proteins involved in subsequent steps in phosphoinositide signalling (Figure 2). Investigating the copy number status of genes for the PtdIns4P 5-kinases which produce PtdIns(4,5)P2 by D5 phosphorylation of PtdIns4P and the PtdIns5P 4-kinases which produce the same lipid product via phosphorylation of PtdIns5P on the D4 position, revealed that of the five candidate genes examined, only PI4P5K1A demonstrated increased copy number in breast cancer. A similar approach focused on the phosphoinositide 3-kinase gene family, identified a substantial gene copy number increase for PIK3C2B which encodes a PtdIns4P 3-kinase. To complete this analysis the status of all three human AKT genes was assessed and copy number gains were most noteworthy for the gene encoding the Akt3 isoform and again this was in over 60% of the patient samples. Hence in the majority of the breast cancer cases represented on the COSMIC database there was an elevation in gene copy number for PI4KB, PIP5K1A, PIK3C2B and AKT3. Interestingly, this phosphoinositide gene quartet maps to chromosome 1q - a chromosome which is numerically abnormal in up to 50-60% of breast cancers 22-25. Comparisons with established oncogenes (Figure 3) indicated that the copy number increase for PI4KB was 2-3 fold higher than for tumour promoter genes such as EGFR and HER2/NEU. Furthermore the magnitude of PI4KB copy number amplification mirrored the scale of copy number loss for tumour suppressor genes such as TP53 and PTEN.

Bottom Line: Point mutations in the phosphatidylinositol 4-kinase genes were uncommon and appeared in less than 1% of the patient samples however, 62% of the tumours had increases in gene copy number for PI4KB which encodes the phosphatidylinositol 4-kinase IIIbeta isozyme.Extending this analysis to subsequent enzymes in the phosphoinositide signalling cascades revealed that the only PIP5K1A, PI3KC2B and AKT3 genes exhibited similar patterns of gene copy number variation.By comparison, gene copy number increases for established oncogenes such as EGFR and HER2/Neu were only evident in 20% of the samples.

View Article: PubMed Central - PubMed

Affiliation: Lipid and Membrane Biology Group, Institute for Liver and Digestive Health, UCL, Royal Free Campus, Rowland Hill Street, London, NW3 2PF United Kingdom.

ABSTRACT
Little is known about the possible oncogenic roles of genes encoding for the phosphatidylinositol 4-kinases, a family of enzymes that regulate an early step in phosphoinositide signalling. To address this issue, the mutational status of all four human phosphatidylinositol 4-kinases genes was analyzed across 852 breast cancer samples using the COSMIC data resource. Point mutations in the phosphatidylinositol 4-kinase genes were uncommon and appeared in less than 1% of the patient samples however, 62% of the tumours had increases in gene copy number for PI4KB which encodes the phosphatidylinositol 4-kinase IIIbeta isozyme. Extending this analysis to subsequent enzymes in the phosphoinositide signalling cascades revealed that the only PIP5K1A, PI3KC2B and AKT3 genes exhibited similar patterns of gene copy number variation. By comparison, gene copy number increases for established oncogenes such as EGFR and HER2/Neu were only evident in 20% of the samples. The PI4KB, PIP5K1A, PI3KC2B and AKT3 genes are related in that they all localize to chromosome 1q which is often structurally and numerically abnormal in breast cancer. These results demonstrate that a gene quartet encoding a potential phosphoinositide signalling pathway is amplified in a subset of breast cancers.

No MeSH data available.


Related in: MedlinePlus