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Genetic background may contribute to PAM50 gene expression breast cancer subtype assignments.

Hu Y, Bai L, Geiger T, Goldberger N, Walker RC, Green JE, Wakefield LM, Hunter KW - PLoS ONE (2013)

Bottom Line: Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer.It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations.These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Informatics and Information Technology, Bethesda, Maryland, United States of America.

ABSTRACT
Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer. Molecular signatures have been developed that stratify the conventional estrogen receptor positive or negative categories into subtypes that are associated with differing clinical outcomes. It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations. In this study however, using a genetically engineered mouse mammary tumor model we demonstrate that the PAM50 subtype signature of tumors driven by a common oncogenic event can be significantly influenced by the genetic background on which the tumor arises. These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.

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Related in: MedlinePlus

Haplotype associations with the Luminal B/HER2 subtype in the DO cross.Individual chromosomes are depicted on the X-axes. P value for association with tumor subtype is indicated on the Y-axes. Genome wide significance threshold (FDR = 0.05) is indicated by horizontal dashed lines. The strain origin for haplotypes is indicated by color.
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pone-0072287-g004: Haplotype associations with the Luminal B/HER2 subtype in the DO cross.Individual chromosomes are depicted on the X-axes. P value for association with tumor subtype is indicated on the Y-axes. Genome wide significance threshold (FDR = 0.05) is indicated by horizontal dashed lines. The strain origin for haplotypes is indicated by color.

Mentions: The clustering results are consistent with the presence of inherited loci that contribute to subtype gene expression signatures. If true, this suggests that it should be possible to map inherited loci that predispose tumors to assignment to specific intrinsic subtypes. Genotyping of the MOLF and DO mouse populations was therefore performed to attempt to map subtype susceptibility genes. Due to the relatively small number of samples in the NZB cross this data set was not included in this analysis. Genotyping was performed using spleen DNA on either the Illumina Mouse Medium Density Linkage Panel (MOLF, CIDR Genotyping Service) or high density MUGA SNP chip (DO; Genseek Inc.). The genotype data was then screened for SNPs that showed significant associations with subtype assignments based on the unsupervised hierarchical clustering analysis. A single locus on mouse chromosome 1 (53.8–61.9 mb; figure 3) in the MOLF cross was found to be significantly associated with the basal subtype (p = 0.0002, FDR = 0.033). Haplotype-based analysis of the DO cross was performed to identify both regions of the genome associated with subtype assignment and the probably strain of origin of the significant alleles. As can be observed in figure 4 six loci were associated with the HER2/Luminal B assignment in the DO samples as indicated by peaks exceeding the genome-wide significance threshold depicted by the dotted line (Chrs 1, 2, 9, 12, 16, 19; p = 6.39×10–5−1.79×10–6, FDR = 0.04–0.0073). The different colors of the peaks indicated that multiple DO progenitor strains contributed to the overall HER2/Luminal B susceptibility in this cross.


Genetic background may contribute to PAM50 gene expression breast cancer subtype assignments.

Hu Y, Bai L, Geiger T, Goldberger N, Walker RC, Green JE, Wakefield LM, Hunter KW - PLoS ONE (2013)

Haplotype associations with the Luminal B/HER2 subtype in the DO cross.Individual chromosomes are depicted on the X-axes. P value for association with tumor subtype is indicated on the Y-axes. Genome wide significance threshold (FDR = 0.05) is indicated by horizontal dashed lines. The strain origin for haplotypes is indicated by color.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756056&req=5

pone-0072287-g004: Haplotype associations with the Luminal B/HER2 subtype in the DO cross.Individual chromosomes are depicted on the X-axes. P value for association with tumor subtype is indicated on the Y-axes. Genome wide significance threshold (FDR = 0.05) is indicated by horizontal dashed lines. The strain origin for haplotypes is indicated by color.
Mentions: The clustering results are consistent with the presence of inherited loci that contribute to subtype gene expression signatures. If true, this suggests that it should be possible to map inherited loci that predispose tumors to assignment to specific intrinsic subtypes. Genotyping of the MOLF and DO mouse populations was therefore performed to attempt to map subtype susceptibility genes. Due to the relatively small number of samples in the NZB cross this data set was not included in this analysis. Genotyping was performed using spleen DNA on either the Illumina Mouse Medium Density Linkage Panel (MOLF, CIDR Genotyping Service) or high density MUGA SNP chip (DO; Genseek Inc.). The genotype data was then screened for SNPs that showed significant associations with subtype assignments based on the unsupervised hierarchical clustering analysis. A single locus on mouse chromosome 1 (53.8–61.9 mb; figure 3) in the MOLF cross was found to be significantly associated with the basal subtype (p = 0.0002, FDR = 0.033). Haplotype-based analysis of the DO cross was performed to identify both regions of the genome associated with subtype assignment and the probably strain of origin of the significant alleles. As can be observed in figure 4 six loci were associated with the HER2/Luminal B assignment in the DO samples as indicated by peaks exceeding the genome-wide significance threshold depicted by the dotted line (Chrs 1, 2, 9, 12, 16, 19; p = 6.39×10–5−1.79×10–6, FDR = 0.04–0.0073). The different colors of the peaks indicated that multiple DO progenitor strains contributed to the overall HER2/Luminal B susceptibility in this cross.

Bottom Line: Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer.It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations.These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.

View Article: PubMed Central - PubMed

Affiliation: Center for Biomedical Informatics and Information Technology, Bethesda, Maryland, United States of America.

ABSTRACT
Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer. Molecular signatures have been developed that stratify the conventional estrogen receptor positive or negative categories into subtypes that are associated with differing clinical outcomes. It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations. In this study however, using a genetically engineered mouse mammary tumor model we demonstrate that the PAM50 subtype signature of tumors driven by a common oncogenic event can be significantly influenced by the genetic background on which the tumor arises. These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.

Show MeSH
Related in: MedlinePlus