Assessment of tumor heterogeneity, as evidenced by gene expression profiles, pathway activation, and gene copy number, in patients with multifocal invasive lobular breast tumors

Nadine Norton, Pooja P. Advani, Daniel J. Serie, Xochiquetzal J. Geiger, Brian M. Necela, Bianca C. Axenfeld, Jennifer M. Kachergus, Ryan W. Feathers, Jennifer M. Carr, Julia E. Crook, Alvaro Moreno-Aspitia, Panos Z. Anastasiadis, Edith A. Perez, E. Aubrey Thompson

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Background: Invasive lobular carcinoma (ILC) comprises approximately ∼10-20% of breast cancers. In general, multifocal/multicentric (MF/MC) breast cancer has been associated with an increased rate of regional lymph node metastases. Tumor heterogeneity between foci represents a largely unstudied source of genomic variation in those rare patients with MF/MC ILC. Methods: We characterized gene expression and copy number in 2 ormore foci from 11 patients with MF/MC ILC (all ER+, HER2-) and adjacent normal tissue. RNA and DNA were extracted from 3x1.5mm cores from all foci. Gene expression (730 genes) and copy number (80 genes) were measured using Nanostring PanCancer and Cancer CNV panels. Linear mixed models were employed to compare expression in tumor versus normal samples fromthe same patient, and to assess heterogeneity (variability) in expression among multiple ILC within an individual. Results: 35 and 34 genes were upregulated (FC>2) and down-regulated (FC<0.5) respectively in ILC tumor relative to adjacent normal tissue, q<0.05. 9/34 down-regulated genes (FIGF, RELN, PROM1, SFRP1, MMP7, NTRK2, LAMB3, SPRY2, KIT) had changes larger than CDH1, a hallmark of ILC. Copy number changes in these patients were relatively few but consistent across foci within each patient. Amplification of three genes (CCND1, FADD, ORAOV1) at 11q13.3 was present in 2/11 patients in both foci. We observed significant evidence of within-patient between-foci variability (heterogeneity) in gene expression for 466 genes (p<0.05 with FDR 8%), including CDH1, FIGF, RELN, SFRP1, MMP7, NTRK2, LAMB3, SPRY2 and KIT. Conclusions: There was substantial variation in gene expression between ILC foci within patients, including known markers of ILC, suggesting an additional level of complexity that should be addressed.

Original languageEnglish (US)
Article numbere0153411
JournalPloS one
Volume11
Issue number4
DOIs
StatePublished - Apr 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'Assessment of tumor heterogeneity, as evidenced by gene expression profiles, pathway activation, and gene copy number, in patients with multifocal invasive lobular breast tumors'. Together they form a unique fingerprint.

  • Cite this