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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention

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Research Article

Reparameterization of PAM50 expression identifies novel breast tumor dimensions and leads to discovery of a genomewide significant breast cancer locus at 12q15

Michael J Madsen, Stacey Knight, Carol Sweeney, Rachel E Factor, Mohamed E Salama, Inge J Stijleman, Venkatesh Rajamanickam, Bryan E Welm, Sasi Arunachalam, Brandt Jones, Rakesh Rachamadugu, Kerry Rowe, Melissa Cessna, Alun Thomas, Lawrence H. Kushi, Bette Caan, Philip S. Bernard and Nicola J. Camp
Michael J Madsen
Huntsman Cancer Institute, University of Utah
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Stacey Knight
Intermountain Heart Institute, Intermountain Medical Center
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  • ORCID record for Stacey Knight
Carol Sweeney
Internal Medicine, Div of Epidemiology, University of Utah
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Rachel E Factor
Department of Pathology, University of Utah
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Mohamed E Salama
Department of Pathology, The University of Utah
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Inge J Stijleman
Pathology, University of Utah
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Venkatesh Rajamanickam
Clinical Genomics, Providence Health and Services
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Bryan E Welm
Surgery, University of Utah
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Sasi Arunachalam
School of Medicine, University of Utah
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Brandt Jones
School of Medicine, University of Utah
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Rakesh Rachamadugu
Department of Pathology, University of Utah / Huntsman Cancer Center
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Kerry Rowe
Oncology, Intermountain Healthcare
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Melissa Cessna
Intermountain BioRepository and Central Region Pathology Department, Intermountain Healthcare
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Alun Thomas
Division of Genetic Epidemiology, University of Utah
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Lawrence H. Kushi
Division of Research, Kaiser Permanente
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Bette Caan
Division of Research, Kaiser Permanente Northern California
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Philip S. Bernard
Huntsman Cancer Institute, 936
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Nicola J. Camp
Internal Medicine, University of Utah School of Medicine
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  • For correspondence: Nicola.Camp@hci.utah.edu
DOI: 10.1158/1055-9965.EPI-17-0887
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Abstract

Background: Breast tumor subtyping has failed to provide impact in susceptibility genetics. The PAM50 assay categorizes breast tumors into: Luminal A, Luminal B, HER2-enriched and Basal-like. However, tumors are often more complex than simple categorization can describe. The identification of heritable tumor characteristics has potential to decrease heterogeneity and increase power for gene-finding. Methods: We used 911 sporadic breast tumors with PAM50 expression data to derive tumor dimensions using principal components (PC). Dimensions in 238 tumors from high-risk pedigrees were compared to the sporadic tumors. Proof-of-concept gene mapping, informed by tumor dimension, was performed using Shared Genomic Segment (SGS) analysis. Results: Five dimensions (PC1-5) explained the majority of the PAM50 expression variance: three captured intrinsic subtype, two were novel (PC3, PC5). All five replicated in 745 TCGA tumors. Both novel dimensions were significantly enriched in the high-risk pedigrees (intrinsic subtypes were not). SGS gene-mapping in a pedigree identified a 0.5 Mb genomewide significant region at 12q15. This region segregated through 32 meioses to 8 breast cancer cases with extreme PC3 tumors (p=2.6×10-8). Conclusions: Principal component analysis of PAM50 gene expression revealed multiple independent, quantitative measures of tumor diversity. These tumor dimensions show evidence for heritability and potential as powerful traits for gene-mapping. Impact: Our study suggests a new approach to describe tumor expression diversity, provides new avenues for germline studies, and proposes a new breast cancer locus. Similar reparameterization of expression patterns may inform other studies attempting to model the effects of tumor heterogeneity.

  • Received September 29, 2017.
  • Revision received November 30, 2017.
  • Accepted April 2, 2018.
  • Copyright ©2018, American Association for Cancer Research.
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Published OnlineFirst April 12, 2018
doi: 10.1158/1055-9965.EPI-17-0887

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Reparameterization of PAM50 expression identifies novel breast tumor dimensions and leads to discovery of a genomewide significant breast cancer locus at 12q15
Michael J Madsen, Stacey Knight, Carol Sweeney, Rachel E Factor, Mohamed E Salama, Inge J Stijleman, Venkatesh Rajamanickam, Bryan E Welm, Sasi Arunachalam, Brandt Jones, Rakesh Rachamadugu, Kerry Rowe, Melissa Cessna, Alun Thomas, Lawrence H. Kushi, Bette Caan, Philip S. Bernard and Nicola J. Camp
Cancer Epidemiol Biomarkers Prev April 12 2018 DOI: 10.1158/1055-9965.EPI-17-0887

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Reparameterization of PAM50 expression identifies novel breast tumor dimensions and leads to discovery of a genomewide significant breast cancer locus at 12q15
Michael J Madsen, Stacey Knight, Carol Sweeney, Rachel E Factor, Mohamed E Salama, Inge J Stijleman, Venkatesh Rajamanickam, Bryan E Welm, Sasi Arunachalam, Brandt Jones, Rakesh Rachamadugu, Kerry Rowe, Melissa Cessna, Alun Thomas, Lawrence H. Kushi, Bette Caan, Philip S. Bernard and Nicola J. Camp
Cancer Epidemiol Biomarkers Prev April 12 2018 DOI: 10.1158/1055-9965.EPI-17-0887
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