Abstract P1-05-26: Genomic analysis of molecular discordance of paired primary and recurrent triple negative breast cancer
Authors: Yuan Y , Li A , Yost S , Yuan Y-C , Chu P , Warden C , Wang J , Liu Z , Liang Y , Goldstein L , Wu X 
Published: May 2019

Background: Triple negative breast cancer (TNBC) is a heterogeneous disease with several molecular subtypes: basal-like1 (BL1), basal-like 2 (BL-2), mesenchymal(M), mesenchymal-stem-like(MSL), immune-modulatory(IM) and unclassified (UNC) Molecular evolution of TNBC through chemotherapy selection pressure is well recognized but poorly understood. This study was carried out to perform paired genomic analysis of TNBC comparing primary breast cancer with recurrent/refractory disease. Here we report the result of the first10 paired tissue analysis.

Methods: 49 paired specimens were identified through an IRB-approved protocol via COH biorepository search (2002- 2015). miRNA and mRNA profiling of 22 samples were performed. The miRNA libraries were prepared and sequenced on Hiseq2500. Sequences were aligned to hg19 genome and miRNA expression levels were counted by in house built R scripts. Go and pathway annotation was performed using DAVID online tool. Affymetrix human Genechip 2.0st was used for mRNA expression profiling. Raw data were normalized and processed using Expression Console, and linear regression was performed using Limma to identify the differentially expressed genes between primary and recurrent/refractory TNBCs.

Result: Through mRNA profiling, we identified several unique gene expression patterns comparing the paired TNBC. Significant mRNA expression alterations were observed in: cell cycle, DNA repair and adhesion. Using Vanderbilt TNBC sub-classification tool, we have identified “phenotype shift” between primary and recurrent TNBCs. Of the 8 paired specimen analyzed, 3 paired tissue remain in the same subclass (2 in IM, 1 in M). Phenotype shift observed in: 1 from BL1 to BL2, 1 from BL2 to BL1, 1 UNC to IM; 1 MSL to UNC; 1 from M to UNC. 15 up regulated and 13 down regulated miRNAs were identified. Most significantly differentially expressed miRNA (with more than 4 fold expression changes, P-value &lt; 0.001) included: miR-206, miR-203, miR-144, miR-16-2, miR-15b, and miR-20b (un-regulated) and miR-10b, miR-125b and let-7c(down-regulated). These miRNA genes are involved in regulation of hormonal receptor signaling, cell cycle, proliferation and metastases. Statistically significant differentially expressed miRNAs identified from our TNBC patient cohort will be further validated using RT-PCR.

Conclusion: A number of mRNA gene pathways and miRNAs showed differential expression between paired recurrent and primary TNBC tumor specimen. The underlying biology driven the phenotype shift is being studied. Further analysis to include a total of 49 paired TNBCs is currently underway.

Contact information: Yuan Yuan MD PhD, Email: yuyuan@coh.org.

Citation Format: Yuan Y, Li A, Yost S, Yuan Y-C, Chu P, Warden C, Wang J, Liu Z, Liang Y, Goldstein L, Wu X. Genomic analysis of molecular discordance of paired primary and recurrent triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-26.