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The molecular diversity of Luminal A breast tumors.

Ciriello G, Sinha R, Hoadley KA, Jacobsen AS, Reva B, Perou CM, Sander C, Schultz N - Breast Cancer Res. Treat. (2013)

Bottom Line: We identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis.Aberrations of chromosomes 1, 8, and 16, together with PIK3CA, GATA3, AKT1, and MAP3K1 mutations drive the other subtypes.Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, ciriello@cbio.mskcc.org.

ABSTRACT
Breast cancer is a collection of diseases with distinct molecular traits, prognosis, and therapeutic options. Luminal A breast cancer is the most heterogeneous, both molecularly and clinically. Using genomic data from over 1,000 Luminal A tumors from multiple studies, we analyzed the copy number and mutational landscape of this tumor subtype. This integrated analysis revealed four major subtypes defined by distinct copy-number and mutation profiles. We identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis. Aberrations of chromosomes 1, 8, and 16, together with PIK3CA, GATA3, AKT1, and MAP3K1 mutations drive the other subtypes. Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT. These rare alterations were the most prevalent in Luminal A tumors and may predict resistance to endocrine therapy. Our work provides for a further molecular stratification of Luminal A breast tumors, with potential direct clinical implications.

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Related in: MedlinePlus

CNH tumors. a Survival analysis across two independent datasets shows significantly worse outcome for the CNH Luminal A tumors. b Unbiased enrichment analysis of genomic alterations found CNH tumors to be enriched for TP53 mutations, focal amplification of MYC, 5q loss, 20q gain, and depleted for PIK3CA mutations. c Differential expression analysis shows that significantly up-regulated genes in CNH tumors are enriched for regulators of mitosis and Aurora kinase pathway components. The heatmap shows all genes that are differentially expressed in CNH tumors when compared to other Luminal A samples (red indicates high expression, green low expression). Aurora kinase is a mitotic serine/threonine kinase that phosphorylates multiple proteins including PLK1 and Cdc25; it is required for CDK1 activation and regulates mitotic events
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Fig4: CNH tumors. a Survival analysis across two independent datasets shows significantly worse outcome for the CNH Luminal A tumors. b Unbiased enrichment analysis of genomic alterations found CNH tumors to be enriched for TP53 mutations, focal amplification of MYC, 5q loss, 20q gain, and depleted for PIK3CA mutations. c Differential expression analysis shows that significantly up-regulated genes in CNH tumors are enriched for regulators of mitosis and Aurora kinase pathway components. The heatmap shows all genes that are differentially expressed in CNH tumors when compared to other Luminal A samples (red indicates high expression, green low expression). Aurora kinase is a mitotic serine/threonine kinase that phosphorylates multiple proteins including PLK1 and Cdc25; it is required for CDK1 activation and regulates mitotic events

Mentions: The characterization of Luminal A tumors provided so far clearly identifies distinct subgroups within this tumor subtype, whose clinical relevance needs to be addressed now. The large dataset analyzed by Curtis et al. [12] has extensive clinical follow-up, enabling a reliable survival analysis. Kaplan–Meier analysis showed significantly different disease survival within the Luminal A subgroups (log-rank p = 0.015, Fig. S4). In particular, the CNH subgroup had significantly worse outcome (log-rank p = 4.6E−5, Fig. 4a) despite receiving similar treatments (Table S3). We validated the poor prognosis for the CNH tumors in an independent dataset consisting of 77 Luminal A tumors from three different cohorts [19] (log-rank p = 0.003, Fig. 4b; Table S4).Fig. 4


The molecular diversity of Luminal A breast tumors.

Ciriello G, Sinha R, Hoadley KA, Jacobsen AS, Reva B, Perou CM, Sander C, Schultz N - Breast Cancer Res. Treat. (2013)

CNH tumors. a Survival analysis across two independent datasets shows significantly worse outcome for the CNH Luminal A tumors. b Unbiased enrichment analysis of genomic alterations found CNH tumors to be enriched for TP53 mutations, focal amplification of MYC, 5q loss, 20q gain, and depleted for PIK3CA mutations. c Differential expression analysis shows that significantly up-regulated genes in CNH tumors are enriched for regulators of mitosis and Aurora kinase pathway components. The heatmap shows all genes that are differentially expressed in CNH tumors when compared to other Luminal A samples (red indicates high expression, green low expression). Aurora kinase is a mitotic serine/threonine kinase that phosphorylates multiple proteins including PLK1 and Cdc25; it is required for CDK1 activation and regulates mitotic events
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824397&req=5

Fig4: CNH tumors. a Survival analysis across two independent datasets shows significantly worse outcome for the CNH Luminal A tumors. b Unbiased enrichment analysis of genomic alterations found CNH tumors to be enriched for TP53 mutations, focal amplification of MYC, 5q loss, 20q gain, and depleted for PIK3CA mutations. c Differential expression analysis shows that significantly up-regulated genes in CNH tumors are enriched for regulators of mitosis and Aurora kinase pathway components. The heatmap shows all genes that are differentially expressed in CNH tumors when compared to other Luminal A samples (red indicates high expression, green low expression). Aurora kinase is a mitotic serine/threonine kinase that phosphorylates multiple proteins including PLK1 and Cdc25; it is required for CDK1 activation and regulates mitotic events
Mentions: The characterization of Luminal A tumors provided so far clearly identifies distinct subgroups within this tumor subtype, whose clinical relevance needs to be addressed now. The large dataset analyzed by Curtis et al. [12] has extensive clinical follow-up, enabling a reliable survival analysis. Kaplan–Meier analysis showed significantly different disease survival within the Luminal A subgroups (log-rank p = 0.015, Fig. S4). In particular, the CNH subgroup had significantly worse outcome (log-rank p = 4.6E−5, Fig. 4a) despite receiving similar treatments (Table S3). We validated the poor prognosis for the CNH tumors in an independent dataset consisting of 77 Luminal A tumors from three different cohorts [19] (log-rank p = 0.003, Fig. 4b; Table S4).Fig. 4

Bottom Line: We identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis.Aberrations of chromosomes 1, 8, and 16, together with PIK3CA, GATA3, AKT1, and MAP3K1 mutations drive the other subtypes.Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT.

View Article: PubMed Central - PubMed

Affiliation: Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, ciriello@cbio.mskcc.org.

ABSTRACT
Breast cancer is a collection of diseases with distinct molecular traits, prognosis, and therapeutic options. Luminal A breast cancer is the most heterogeneous, both molecularly and clinically. Using genomic data from over 1,000 Luminal A tumors from multiple studies, we analyzed the copy number and mutational landscape of this tumor subtype. This integrated analysis revealed four major subtypes defined by distinct copy-number and mutation profiles. We identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis. Aberrations of chromosomes 1, 8, and 16, together with PIK3CA, GATA3, AKT1, and MAP3K1 mutations drive the other subtypes. Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT. These rare alterations were the most prevalent in Luminal A tumors and may predict resistance to endocrine therapy. Our work provides for a further molecular stratification of Luminal A breast tumors, with potential direct clinical implications.

Show MeSH
Related in: MedlinePlus