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

Michael J. Madsen, Stacey Knight, Carol Sweeney, Rachel Factor, Mohamed Salama, Inge J. Stijleman, Venkatesh Rajamanickam, Bryan E. Welm, Sasi Arunachalam, Brandt Jones, Rakesh Rachamadugu, Kerry Rowe, Melissa H. Cessna, Alun Thomas, Lawrence H. Kushi, Bette J. Caan, Philip S. Bernard, Nicola J. Camp

Research output: Contribution to journalArticle

2 Scopus citations

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 with 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 genome-wide significant region at 12q15. This region segregated through 32 meioses to 8 breast cancer cases with extreme PC3 tumors (P ¼ 2.6 10 8 ). Conclusions: PC 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. Cancer Epidemiol Biomarkers Prev; 27(6); 644–52. 2018 AACR.

Original languageEnglish (US)
Pages (from-to)644-652
Number of pages9
JournalCancer Epidemiology Biomarkers and Prevention
Volume27
Issue number6
DOIs
StatePublished - Jun 1 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Madsen, M. J., Knight, S., Sweeney, C., Factor, R., Salama, M., Stijleman, I. J., Rajamanickam, V., Welm, B. E., Arunachalam, S., Jones, B., Rachamadugu, R., Rowe, K., Cessna, M. H., Thomas, A., Kushi, L. H., Caan, B. J., Bernard, P. S., & Camp, N. J. (2018). Reparameterization of PAM50 expression identifies novel breast tumor dimensions and leads to discovery of a genome-Wide significant breast cancer locus at 12q15. Cancer Epidemiology Biomarkers and Prevention, 27(6), 644-652. https://doi.org/10.1158/1055-9965.EPI-17-0887