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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

DawnRank identified NCSTN gene expression network. The plot represents the local neighborhood of NCSTN and all direct genes downstream. The green and red colors represent whether the gene is up-regulated or down-regulated, respectively. The intensity of the color represents the magnitude of gene expression change. The size of each node indicates the DawnRank score of that gene, representing the gene’s impact on downstream expression changes in the network
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Fig4: DawnRank identified NCSTN gene expression network. The plot represents the local neighborhood of NCSTN and all direct genes downstream. The green and red colors represent whether the gene is up-regulated or down-regulated, respectively. The intensity of the color represents the magnitude of gene expression change. The size of each node indicates the DawnRank score of that gene, representing the gene’s impact on downstream expression changes in the network

Mentions: Numerous studies have implicated the Notch signaling pathway in Basal-like breast and/or triple-negative breast cancers [22, 23]. Importantly, numerous studies on the functional role of NCSTN have already been performed [24–26]. To evaluate the effect of 1q21-23/NCSTN amplification, we first examined the DawnRank network space around NCSTN and noted that when NCSTN was amplified NOTCH1–3 were also more highly expressed (Fig. 4). In addition, NCSTN is one of the three components of the gamma-secretase complex (GSC), a protein complex that cleaves and activates Notch receptors. Two other GSC members, namely APH1A and PSEN2, were also both altered within the network (Fig. 4), and were also higher in NCSTN amplified samples versus not amplified (Supplemental Fig. 4a). Also, APH1A and PSEN2 are physically located on human chromosome 1q21.2 and 1q42, and are often co-amplified along with NCSTN (although PSEN2 is not within a Basal-like-specific CNA). Thus, three components of the GSC are often co-amplified together, and are more highly expressed, and the NCSTN/Notch network is perturbed in these NCSTN amplified tumors. Following up on these network findings, NCSTN amplification was also correlated with higher NOTCH1 and NOTCH3 mRNA levels (Supplemental Fig. 4b), with this feature showing an even greater difference when examined just among Basal-like breast cancers (Supplemental Fig. 4c). As expected from the previous work, Basal-like tumors as a whole exhibited significantly lower LFNG expression (i.e., a negative regulator of Notch signaling) along with significantly higher expression of NOTCH1, NCSTN, APH1A, MYC, and HEY2 mRNAs (Supplemental Fig. 5), the latter two of which are thought to be targets of activated Notch pathway.Fig. 4


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)

DawnRank identified NCSTN gene expression network. The plot represents the local neighborhood of NCSTN and all direct genes downstream. The green and red colors represent whether the gene is up-regulated or down-regulated, respectively. The intensity of the color represents the magnitude of gene expression change. The size of each node indicates the DawnRank score of that gene, representing the gene’s impact on downstream expression changes in the network
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig4: DawnRank identified NCSTN gene expression network. The plot represents the local neighborhood of NCSTN and all direct genes downstream. The green and red colors represent whether the gene is up-regulated or down-regulated, respectively. The intensity of the color represents the magnitude of gene expression change. The size of each node indicates the DawnRank score of that gene, representing the gene’s impact on downstream expression changes in the network
Mentions: Numerous studies have implicated the Notch signaling pathway in Basal-like breast and/or triple-negative breast cancers [22, 23]. Importantly, numerous studies on the functional role of NCSTN have already been performed [24–26]. To evaluate the effect of 1q21-23/NCSTN amplification, we first examined the DawnRank network space around NCSTN and noted that when NCSTN was amplified NOTCH1–3 were also more highly expressed (Fig. 4). In addition, NCSTN is one of the three components of the gamma-secretase complex (GSC), a protein complex that cleaves and activates Notch receptors. Two other GSC members, namely APH1A and PSEN2, were also both altered within the network (Fig. 4), and were also higher in NCSTN amplified samples versus not amplified (Supplemental Fig. 4a). Also, APH1A and PSEN2 are physically located on human chromosome 1q21.2 and 1q42, and are often co-amplified along with NCSTN (although PSEN2 is not within a Basal-like-specific CNA). Thus, three components of the GSC are often co-amplified together, and are more highly expressed, and the NCSTN/Notch network is perturbed in these NCSTN amplified tumors. Following up on these network findings, NCSTN amplification was also correlated with higher NOTCH1 and NOTCH3 mRNA levels (Supplemental Fig. 4b), with this feature showing an even greater difference when examined just among Basal-like breast cancers (Supplemental Fig. 4c). As expected from the previous work, Basal-like tumors as a whole exhibited significantly lower LFNG expression (i.e., a negative regulator of Notch signaling) along with significantly higher expression of NOTCH1, NCSTN, APH1A, MYC, and HEY2 mRNAs (Supplemental Fig. 5), the latter two of which are thought to be targets of activated Notch pathway.Fig. 4

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