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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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Pathway analysis. Altered pathways across Luminal A tumors identified by the MEMo algorithm. a MEMo identified multiple modules recapitulating Akt, MAPK, and Ras signaling. Gene activation is shown in shades of red, inactivation in shades of blue. b MEMo found network modules highlighting multiple alterations of nuclear co-repressors. Genes are arranged vertically, and altered tumors from left to right. c Nuclear co-repressors and co-activators regulate ER transcription and Tamoxifen anti-proliferative effects. d Alterations identified by MEMo compromise co-repressor activities and may predict response to therapy
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Fig5: Pathway analysis. Altered pathways across Luminal A tumors identified by the MEMo algorithm. a MEMo identified multiple modules recapitulating Akt, MAPK, and Ras signaling. Gene activation is shown in shades of red, inactivation in shades of blue. b MEMo found network modules highlighting multiple alterations of nuclear co-repressors. Genes are arranged vertically, and altered tumors from left to right. c Nuclear co-repressors and co-activators regulate ER transcription and Tamoxifen anti-proliferative effects. d Alterations identified by MEMo compromise co-repressor activities and may predict response to therapy

Mentions: Modules extracted by MEMo in a Luminal A-only analysis highlight frequent alteration to the PI(3)K/Akt, MAP-kinase, and Ras/ERK signaling cascades (Figs. 5a, S3; Table S7). Alterations include PTEN inactivation, mutations of PIK3CA and AKT1, inactivation of MAP3K1 and MAP2K4, amplification of receptor tyrosine kinases (ERBB2 and IGF1R), and RAS activation either through activating mutations of KRAS or NF1 depletion by either DNA homozygous deletion or mRNA down-regulation (Fig. S6). Mutually exclusive inactivation of MAP3K1 and MAP2K4 was confirmed in the Ellis et al. [11] dataset, corroborating the hypothesis of reduced JNK signaling in Luminal A tumors and providing further insights into MAP3K1 mutations.Fig. 5


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)

Pathway analysis. Altered pathways across Luminal A tumors identified by the MEMo algorithm. a MEMo identified multiple modules recapitulating Akt, MAPK, and Ras signaling. Gene activation is shown in shades of red, inactivation in shades of blue. b MEMo found network modules highlighting multiple alterations of nuclear co-repressors. Genes are arranged vertically, and altered tumors from left to right. c Nuclear co-repressors and co-activators regulate ER transcription and Tamoxifen anti-proliferative effects. d Alterations identified by MEMo compromise co-repressor activities and may predict response to therapy
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Pathway analysis. Altered pathways across Luminal A tumors identified by the MEMo algorithm. a MEMo identified multiple modules recapitulating Akt, MAPK, and Ras signaling. Gene activation is shown in shades of red, inactivation in shades of blue. b MEMo found network modules highlighting multiple alterations of nuclear co-repressors. Genes are arranged vertically, and altered tumors from left to right. c Nuclear co-repressors and co-activators regulate ER transcription and Tamoxifen anti-proliferative effects. d Alterations identified by MEMo compromise co-repressor activities and may predict response to therapy
Mentions: Modules extracted by MEMo in a Luminal A-only analysis highlight frequent alteration to the PI(3)K/Akt, MAP-kinase, and Ras/ERK signaling cascades (Figs. 5a, S3; Table S7). Alterations include PTEN inactivation, mutations of PIK3CA and AKT1, inactivation of MAP3K1 and MAP2K4, amplification of receptor tyrosine kinases (ERBB2 and IGF1R), and RAS activation either through activating mutations of KRAS or NF1 depletion by either DNA homozygous deletion or mRNA down-regulation (Fig. S6). Mutually exclusive inactivation of MAP3K1 and MAP2K4 was confirmed in the Ellis et al. [11] dataset, corroborating the hypothesis of reduced JNK signaling in Luminal A tumors and providing further insights into MAP3K1 mutations.Fig. 5

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