posters International Association for Breast Cancer Research 2014

Targets of microRNAs involved in radiation response are promising biomarkers in silico (#28)

Harriet E. Gee 1 2 , Joanne Toohey 2 , Susan Carroll 2 , Jane Beith 2 , Adrian L. Harris 3 , Francesca M. Buffa 3 , Sandra O'Toole 4 , Timothy Molloy 1
  1. Functional Oncogenomics Group, Cancer Research Division, The Kinghorn Cancer Centre / Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. Chris O'Brien Lifehouse, Camperdown, NSW, Australia
  3. Department of Oncology, The University of Oxford, Oxford, UK
  4. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

Background and Purpose:

Radiotherapy following breast cancer (BrC) surgery is highly effective, with an improvement in local control translating into a survival benefit1. However, local recurrence and distant failure remain significant clinical problems, poorly predicted by conventional clinico-pathological markers. Previous work carried out by our group has identified specific microRNAs (miRNAs), 139-5p and 222, as key regulators of the response to radiation in BrC cells in vitro. We therefore hypothesized that these miRNAs and their target genes were promising biomarkers in four large cohorts of BrC patients.

Methods and Materials:

Four publically-available microarray mRNA/miRNA expression datasets (METABRIC2, Oxford-GSE222203, Lund-GSE318634 and NKI-2955) totalling > 1,700 early-stage BrC patients, treated with adjuvant radiotherapy, each with >10 years of follow-up, were included in the analyses. More detailed clinic-pathological and radiotherapy information was obtained for the Oxford cohort. The expression of 4 putative miRNA target biomarkers – TOP2A, POLQ, RAD54L, and NEK1 – were correlated to outcome and to standard clinico-pathological variables using non-parametric tests and Kaplan-Meier/Cox Regression as appropriate.

Results:

Low expression of miR-139-5p and miR-222 and/or high expression of their putative targets TOP2A, POLQ, RAD54L, and NEK1 were correlated with poor prognosis in radiotherapy-treated patients in multiple datasets. Target genes ‘outperformed’ their miRNAs as biomarkers. Importantly, in the dataset derived from a randomised radiotherapy clinical trial, RAD54L was significantly prognostic specifically in patients that received radiotherapy but not in matched patients who did not receive radiotherapy, suggesting a true predictive role. Target gene expression was also significantly correlated with clinico-pathological variables associated with poor outcome, including grade, size, stage, and intrinsic subtype.

Conclusion:

Targets of miRNAs involved in response to radiotherapy are promising novel biomarkers of response to adjuvant radiotherapy for breast cancer. We next aim to validate these by immunohistochemistry in independent clinical cohorts for which tissue microarrays are available.

  1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Darby S, McGale P et al, Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011 Nov 12;378(9804):1707-16.
  2. Dvinge H, Git A, Gräf S et al, The shaping and functional consequences of the microRNA landscape in breast cancer. Nature. 2013 May 16;497(7449):378-82.
  3. Buffa FM, Camps C, Winchester L et al, microRNA-associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer. Cancer Res. 2011 Sep 1;71(17):5635-45.
  4. Niméus-Malmström E, Krogh M, Malmström P et al. Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy. Breast Cancer Res 2008;10(2):R34.
  5. Chang HY, Nuyten DS, Sneddon JB et al, Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3738-43.