Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis

Srikanth Nagalla, Jeff W. Chou, Mark C. Willingham, Jimmy Ruiz, James P. Vaughn, Purnima Dubey, Timothy L. Lash, Stephen J. Hamilton-Dutoit, Jonas Bergh, Christos Sotiriou, Michael A. Black, Lance D. Miller

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Background: Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified. Results: To investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes. Conclusions: These findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.

Original languageEnglish (US)
Article numberR34
JournalGenome Biology
Volume14
Issue number4
DOIs
StatePublished - Apr 24 2013

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immunity
tumor
breast neoplasms
prognosis
Immunity
cancer
Breast Neoplasms
neoplasms
Neoplasms
metastasis
gene
Neoplasm Metastasis
genes
plasma cells
natural killer cells
Genetic Association Studies
dendritic cells
Plasma Cells
Transcriptome
Cell Communication

Keywords

  • Breast cancer
  • Gene signatures
  • Hierarchical clustering
  • Immune metagene
  • Intrinsic subtypes
  • Metagene tertiles
  • Multivariable analysis
  • Prognosis
  • Proliferation metagene
  • Survival analysis

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

Nagalla, S., Chou, J. W., Willingham, M. C., Ruiz, J., Vaughn, J. P., Dubey, P., ... Miller, L. D. (2013). Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis. Genome Biology, 14(4), [R34]. https://doi.org/10.1186/gb-2013-14-4-r34

Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis. / Nagalla, Srikanth; Chou, Jeff W.; Willingham, Mark C.; Ruiz, Jimmy; Vaughn, James P.; Dubey, Purnima; Lash, Timothy L.; Hamilton-Dutoit, Stephen J.; Bergh, Jonas; Sotiriou, Christos; Black, Michael A.; Miller, Lance D.

In: Genome Biology, Vol. 14, No. 4, R34, 24.04.2013.

Research output: Contribution to journalArticle

Nagalla, S, Chou, JW, Willingham, MC, Ruiz, J, Vaughn, JP, Dubey, P, Lash, TL, Hamilton-Dutoit, SJ, Bergh, J, Sotiriou, C, Black, MA & Miller, LD 2013, 'Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis', Genome Biology, vol. 14, no. 4, R34. https://doi.org/10.1186/gb-2013-14-4-r34
Nagalla, Srikanth ; Chou, Jeff W. ; Willingham, Mark C. ; Ruiz, Jimmy ; Vaughn, James P. ; Dubey, Purnima ; Lash, Timothy L. ; Hamilton-Dutoit, Stephen J. ; Bergh, Jonas ; Sotiriou, Christos ; Black, Michael A. ; Miller, Lance D. / Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis. In: Genome Biology. 2013 ; Vol. 14, No. 4.
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AU - Vaughn, James P.

AU - Dubey, Purnima

AU - Lash, Timothy L.

AU - Hamilton-Dutoit, Stephen J.

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AU - Sotiriou, Christos

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AU - Miller, Lance D.

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N2 - Background: Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified. Results: To investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes. Conclusions: These findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.

AB - Background: Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified. Results: To investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes. Conclusions: These findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.

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