High-risk breast cancer genes at 8q22-24 and their role in over 5,000 patients evaluated with the 70-gene risk of recurrence assay.

Abstract

3569 Background: Previous studies have shown that CCNE2 expression is higher in patients’ cancers resistant to CDK4/6 inhibitors. Increased expression of CCNE2, MTDH, or TSPYL5, genes contained within the 70-gene risk of distant recurrence signature (70GS), has also been implicated in breast oncogenesis, poor prognosis, and chemoresistance. These genes are located on chromosome region 8q22.1, one of the most recurrently amplified regions out of all 70GS genes in breast tumors (Fatima et al. 2017). MYC, located on 8q24, is overexpressed in 40% of all breast cancers (BC). Here we examined the expression of CCNE2, MTDH, and TSPYL5 in relation to 70GS risk and the 80-gene molecular subtype signature (80GS), and their correlation with MYC expression in early stage BC patients. Methods: CCNE2, MTDH, TSPYL5, and MYC mRNA expression was measured in 5022 BC samples sent to Agendia (Irvine, CA) for 70GS and 80GS testing, which included FFPE microarray full-transcriptome data. 70GS was used to stratify patients into Ultra Low Risk (UL), Low Risk (LR), High Risk (HR), and Ultra High Risk (UH). Both 70GS and 80GS were used to classify patient samples into Luminal A, Luminal B, HER2, or Basal type. Wilcoxon rank sum test was used to assess expression differences. Results: The expression of CCNE2, MTDH, and TSPYL5 significantly correlated with each other and was higher in HR patients compared to LR patients (p < 0.001) and higher in UH patients compared to HR patients (p < 0.001). Expression of these genes was highest in Basal type tumors, 83% of which were UH, followed by Luminal B type tumors, and lowest in Luminal A type tumors. CCNE2 and MYC expression was elevated in LR compared to UL patients (p < 0.001 and p = 0.0043). There was no difference in MYC expression between HR vs. LR or UH vs. HR. Lastly, there was no association between the expression of 8q22.1 genes and MYC in any 70GS subgroup. Conclusions: Within the 70GS, CCNE2, MTDH, and TSPYL5 have similar expression patterns and when overexpressed may identify an UH cohort of BC. This observation, in addition to their physical proximity at 8q22.1 suggests a possible amplicon in this region. The highest expression of CCNE2, MTDH, and TSPYL5 associated with UH patients and is concordant with previous studies that support the role of these genes in BC metastasis. Furthermore, this analysis suggests MYC may not stratify patients based on metastatic potential. These data may be clinically relevant for stratifying patients in ongoing clinical trials evaluating response and resistance to targeted therapies in early stage BC.