Limits...
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.

Show MeSH

Related in: MedlinePlus

a Schematic stratification of breast cancer subtypes based on receptor status, ER and Her2, and PAM50 mRNA-derived signatures. b The table shows statistically significant intersections between the PAM50 subtypes (arranged horizontally) and copy number-driven clusters (arranged vertically) from the METABRIC and TCGA datasets. c Average number of mutations per sample (white) and number of recurrently mutated genes (black) are shown for the four major PAM50 subtypes. Luminal tumors have fewer mutations per samples, but they tend to affect similar genes. d Boxplot statistics of disease survival is shown for deceased patients from the METABRIC dataset across the four major PAM50 subtypes. While Luminal A tumors have the longest average survival, they also have the largest diversity
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3824397&req=5

Fig1: a Schematic stratification of breast cancer subtypes based on receptor status, ER and Her2, and PAM50 mRNA-derived signatures. b The table shows statistically significant intersections between the PAM50 subtypes (arranged horizontally) and copy number-driven clusters (arranged vertically) from the METABRIC and TCGA datasets. c Average number of mutations per sample (white) and number of recurrently mutated genes (black) are shown for the four major PAM50 subtypes. Luminal tumors have fewer mutations per samples, but they tend to affect similar genes. d Boxplot statistics of disease survival is shown for deceased patients from the METABRIC dataset across the four major PAM50 subtypes. While Luminal A tumors have the longest average survival, they also have the largest diversity

Mentions: RNA expression-based signatures [6, 7] provided further insights into the diversity of breast tumors. By expression profiling, the large majority of ER+ and/or PR+ tumors are of the “luminal subtypes” [7, 8]. These tumors can be subdivided into Luminal A and Luminal B, with the former being typically low grade and associated with a better prognosis [9]. Luminal A is overall the most frequently occurring breast cancer expression subtype in the population. mRNA-derived subtypes also include Basal-like breast tumors, which are predominantly negative for ER, PR, and Her2, and Her2-enriched tumors, which are positive for Her2 (Fig. 1a).Fig. 1


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)

a Schematic stratification of breast cancer subtypes based on receptor status, ER and Her2, and PAM50 mRNA-derived signatures. b The table shows statistically significant intersections between the PAM50 subtypes (arranged horizontally) and copy number-driven clusters (arranged vertically) from the METABRIC and TCGA datasets. c Average number of mutations per sample (white) and number of recurrently mutated genes (black) are shown for the four major PAM50 subtypes. Luminal tumors have fewer mutations per samples, but they tend to affect similar genes. d Boxplot statistics of disease survival is shown for deceased patients from the METABRIC dataset across the four major PAM50 subtypes. While Luminal A tumors have the longest average survival, they also have the largest diversity
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: a Schematic stratification of breast cancer subtypes based on receptor status, ER and Her2, and PAM50 mRNA-derived signatures. b The table shows statistically significant intersections between the PAM50 subtypes (arranged horizontally) and copy number-driven clusters (arranged vertically) from the METABRIC and TCGA datasets. c Average number of mutations per sample (white) and number of recurrently mutated genes (black) are shown for the four major PAM50 subtypes. Luminal tumors have fewer mutations per samples, but they tend to affect similar genes. d Boxplot statistics of disease survival is shown for deceased patients from the METABRIC dataset across the four major PAM50 subtypes. While Luminal A tumors have the longest average survival, they also have the largest diversity
Mentions: RNA expression-based signatures [6, 7] provided further insights into the diversity of breast tumors. By expression profiling, the large majority of ER+ and/or PR+ tumors are of the “luminal subtypes” [7, 8]. These tumors can be subdivided into Luminal A and Luminal B, with the former being typically low grade and associated with a better prognosis [9]. Luminal A is overall the most frequently occurring breast cancer expression subtype in the population. mRNA-derived subtypes also include Basal-like breast tumors, which are predominantly negative for ER, PR, and Her2, and Her2-enriched tumors, which are positive for Her2 (Fig. 1a).Fig. 1

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