01.15 MYC expression but not Amplification Associates with Worse Outocome in Triple-Negative Breast Cancer

E. Katsuta1, L. Yan2, K. Takabe1  1Roswell Park Cancer Institute,Breast Surgery, Department Of Surgical Oncology,Buffalo, NY, USA 2Roswell Park Cancer Institute,Department Of Biostatistics And Bioinformatics,Buffalo, NY, USA

Introduction: The use of clinical targeted DNA-sequencing to detect genomic alterations, including mutation and copy number alterations has become a routine in clinical practice for targeted therapy. However, the interpretation of the results in each gene is still understudied. MYC is one of the essential oncogenes and it plays a crucial role in regulation of the cell cycle and proliferation in various types of cancers including Triple-Negative Breast Cancer (TNBC). It is known that MYC amplification and high expression are associated with TNBC; however, the difference between a MYC amplified vs high expressing tumors in TNBC is not fully elucidated.

Methods:  Clinical and genomic data, including mRNA and Genomic Identification of Significant Targets in Cancer (GISTIC), were obtained from The Cancer Genome Atlas (TCGA) through cBioportal. MYC amplification was defined based upon copy-number GISTIC; GISTIC 2 was defined as tumor with amplification, remaining GISTIC -1, 0 and 1 were defined as tumor without amplification.

Results: Among 1080 patients with DNA copy-number data, 229 tumors (21.2%) showed MYC amplification, which was the most common copy-number alteration in the whole TCGA breast cancer cohort. Although MYC mRNA expression level was higher in MYC amplified tumors compared to non-amplified tumors (p<0.001), the mRNA expression levels were highly overlapped between amplified and non-amplified tumors. MYC amplification (p=0.112) as well as high expression (p=0.390) were not associated with overall survival (OS) in the whole cohort. 156 patients (15.5%) were classified as TNBC based on ER, PgR, immunohistochemistry status and HER2 immunohistochemistry and FISH method. In agreement with previous reports, there was greater proportion of TNBC subtypes in MYC amplified tumors (p<0.001), as well as in MYC high expressing tumors (p<0.001). Thus, we focused on TNBCs. There was no significant difference in MYC mRNA expression level between MYC amplified and non-amplified tumors in the TNBCs (p=0.074). Interestingly, none of the clinicopathological demographics were associated with either MYC amplification or high expression. However, high expression of MYC was significantly associated with worse OS (5-year OS rates: 61.6% vs 78.3%, p=0.026), whereas MYC amplification was not associated with OS (5-year OS rates: 75.7% vs 70.9%, p=0.515) in TNBC. Gene Set Enrichment Analysis (GSEA) demonstrated that MYC target gene sets (v1; p<0.001, v2; p<0.001) as well as cell cycle related gene sets, including E2F targets (p=0.013) and G2/M check point (p=0.018) gene sets, and WNT/beta-catenin gene set (p=0.017) were significantly enriched in MYC high expressing tumors, whereas out of 50 hall mark gene sets, none of them were enriched in MYC amplified tumors.

Conclusion: TNBCs with MYC higher expression, but not amplification, has worse prognosis in TNBC. It is important to consider that amplification is not always equal to high expression in some genes.