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Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer.

Silva GO, He X, Parker JS, Gatza ML, Carey LA, Hou JP, Moulder SL, Marcom PK, Ma J, Rosen JM, Perou CM - Breast Cancer Res. Treat. (2015)

Bottom Line: Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1.Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria.Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA, silvag@email.unc.edu.

ABSTRACT
A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.

No MeSH data available.


Related in: MedlinePlus

Expanded view of a chromosome 1 Basal-like conserved copy number frequency landscape plots from SWITCHplus. Segments of copy number gains are plotted above the x-axis and segments of copy number loss are plotted below the x-axis. The conserved segments are colored according to the mouse model(s) in which they appear. The frequency of alterations is indicated on the y-axis. Regions shaded gray indicate segments that are any combination of either not subtype-specific, not mouse group-specific, or not high frequent (greater than or equal to 15 %). b View of the genomic location of candidate chromosome 1 driver genes. Genes colored red are Basal-like-specific or subtype-associated, demonstrate DNA and RNA concordance in human tumors and had a top DawnRank score; genes underlined are Basal-like-specific or Basal-like-associated, demonstrate DNA and RNA concordance in human tumors and labeled as a growth enhancer and oncogene (“GO gene”) in the Solimini et al. [15] RNAi screen on human mammary epithelial cells; the remaining genes surrounded by a box are additional potential drivers in this region. A color bar is placed above the genes conserved for a particular mouse group
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Fig3: Expanded view of a chromosome 1 Basal-like conserved copy number frequency landscape plots from SWITCHplus. Segments of copy number gains are plotted above the x-axis and segments of copy number loss are plotted below the x-axis. The conserved segments are colored according to the mouse model(s) in which they appear. The frequency of alterations is indicated on the y-axis. Regions shaded gray indicate segments that are any combination of either not subtype-specific, not mouse group-specific, or not high frequent (greater than or equal to 15 %). b View of the genomic location of candidate chromosome 1 driver genes. Genes colored red are Basal-like-specific or subtype-associated, demonstrate DNA and RNA concordance in human tumors and had a top DawnRank score; genes underlined are Basal-like-specific or Basal-like-associated, demonstrate DNA and RNA concordance in human tumors and labeled as a growth enhancer and oncogene (“GO gene”) in the Solimini et al. [15] RNAi screen on human mammary epithelial cells; the remaining genes surrounded by a box are additional potential drivers in this region. A color bar is placed above the genes conserved for a particular mouse group

Mentions: Across all breast tumors, amplification of human chromosome 1q was the most frequent copy number altered event (not depicted). However, as can be seen in Supplemental Figs. 2 and 3, the “shape” of the chromosome 1 amplification varies by subtype, with the subtype-enriched amplification regions being identified within this largest of human chromosome arms. Among the 662 conserved regions identified across the genome, chromosome 1 harbored 18 % of all conserved CNAs (Supplemental Table 7). Focusing on chromosome 1, we determined that chromosome 1q harbored more than twice the number of conserved segments when compared to the 1p arm (Supplemental Table 7). Of particular note, a number of 1q amplified regions that were identified as human Basal-like-specific were also altered in the mouse C3Tag and/or p53 groups (Fig. 3b; Supplemental Table 7); thus our results indicate that this region of human chromosome 1q21-23 is being repeatedly selected for both mouse and human Basal-like breast cancers.Fig. 3


Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer.

Silva GO, He X, Parker JS, Gatza ML, Carey LA, Hou JP, Moulder SL, Marcom PK, Ma J, Rosen JM, Perou CM - Breast Cancer Res. Treat. (2015)

Expanded view of a chromosome 1 Basal-like conserved copy number frequency landscape plots from SWITCHplus. Segments of copy number gains are plotted above the x-axis and segments of copy number loss are plotted below the x-axis. The conserved segments are colored according to the mouse model(s) in which they appear. The frequency of alterations is indicated on the y-axis. Regions shaded gray indicate segments that are any combination of either not subtype-specific, not mouse group-specific, or not high frequent (greater than or equal to 15 %). b View of the genomic location of candidate chromosome 1 driver genes. Genes colored red are Basal-like-specific or subtype-associated, demonstrate DNA and RNA concordance in human tumors and had a top DawnRank score; genes underlined are Basal-like-specific or Basal-like-associated, demonstrate DNA and RNA concordance in human tumors and labeled as a growth enhancer and oncogene (“GO gene”) in the Solimini et al. [15] RNAi screen on human mammary epithelial cells; the remaining genes surrounded by a box are additional potential drivers in this region. A color bar is placed above the genes conserved for a particular mouse group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4491106&req=5

Fig3: Expanded view of a chromosome 1 Basal-like conserved copy number frequency landscape plots from SWITCHplus. Segments of copy number gains are plotted above the x-axis and segments of copy number loss are plotted below the x-axis. The conserved segments are colored according to the mouse model(s) in which they appear. The frequency of alterations is indicated on the y-axis. Regions shaded gray indicate segments that are any combination of either not subtype-specific, not mouse group-specific, or not high frequent (greater than or equal to 15 %). b View of the genomic location of candidate chromosome 1 driver genes. Genes colored red are Basal-like-specific or subtype-associated, demonstrate DNA and RNA concordance in human tumors and had a top DawnRank score; genes underlined are Basal-like-specific or Basal-like-associated, demonstrate DNA and RNA concordance in human tumors and labeled as a growth enhancer and oncogene (“GO gene”) in the Solimini et al. [15] RNAi screen on human mammary epithelial cells; the remaining genes surrounded by a box are additional potential drivers in this region. A color bar is placed above the genes conserved for a particular mouse group
Mentions: Across all breast tumors, amplification of human chromosome 1q was the most frequent copy number altered event (not depicted). However, as can be seen in Supplemental Figs. 2 and 3, the “shape” of the chromosome 1 amplification varies by subtype, with the subtype-enriched amplification regions being identified within this largest of human chromosome arms. Among the 662 conserved regions identified across the genome, chromosome 1 harbored 18 % of all conserved CNAs (Supplemental Table 7). Focusing on chromosome 1, we determined that chromosome 1q harbored more than twice the number of conserved segments when compared to the 1p arm (Supplemental Table 7). Of particular note, a number of 1q amplified regions that were identified as human Basal-like-specific were also altered in the mouse C3Tag and/or p53 groups (Fig. 3b; Supplemental Table 7); thus our results indicate that this region of human chromosome 1q21-23 is being repeatedly selected for both mouse and human Basal-like breast cancers.Fig. 3

Bottom Line: Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1.Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria.Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC, 27599, USA, silvag@email.unc.edu.

ABSTRACT
A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.

No MeSH data available.


Related in: MedlinePlus