Abstract P3-13-08: Fusion analysis including NTRK fusion in breast cancers (BC): From RNASeq data analysis from 629 BC tissue samples
Authors: Kim Ji-Yeon , Park Kyunghee , Park Woong-Yang , Lee Jeong Eon , Kim Seok Won , Nam Seok Jin , Yu Jonghan , Im Young-Hyuck , Ahn Jin Seok , Park Yeon Hee 
Published: March 2022

Background: Neutrotrophin receptor tyrosine kinase (NTRK) gene fusions (NTRK1, NTRK2, or NTRK3) are oncogenic drivers of various tumor types. The NTRK fusion was detected in less than 5% of breast, colorectal, lung or any other types of cancers. However, large scaled next generation sequencing data for NTRK fusion in breast cancer have not existed. In this study, we performed RNASeq and fusion analysis including NTRK genes. Methods: We prospectively collected BC tumor tissues from the translational research conducted in Samsung Medical Center. Fusion was predicted from RNAseq using the following seven softwares(SWs): ChimeraScan, DeFuse, MapSplice, TophatFusion, STAR.Arriba, STAR.fusion, and STAR.SEQR. To remove false-positive fusion calls, calls less than 3 left/right spanning reads and 10 total supporting reads were removed. After filtering out the blacklist fusion calls which were recurrently detected, calls commonly predicted in more than two SWs were analyzed. Results: In total 629 BC samples, 613 samples were finally analyzed after quality control (QC) of RNASeq. According to immunohistochemistry (IHC) profile, 356(58.7%) was hormone receptor (HR) positive human epidermal growth factor receptor 2 (HER2) negative BC, 42 (6.9%) of HR positive HER2 positive BC, 53 (8.7%) of HR negative, HER2 positive and 155(25.6%) of triple negative BC (TNBC). PAM50 prediction informed that 174(28.9%) of luminal A, 151(24.6%) of luminal B, 170 (27.7%) of basal-like, 85 (13.9%) of HER2-enriched and 33 (5.4%) of normal. In median number of fusion events, 12 was called by ChimeraScan (Interquartile range [IQR]: 5, 33), 57 by DeFuse (IQR: 33, 82), eight by Mapsplice (IQR: 5, 12), two by TophatFusion (IQR: 0, 4), five by STAR.Arriba (IQR: 2, 12), two by STAR.fusion (IQR:0, 5) and three by STAR.SEQR fusion caller (IQR: 1, 7) after call filtering. After initial fusion call, we excluded the results from ChimeraScan and DeFuse fusion callers because of discrepancy of number of called fusion events. In five fusion callers, median number of fusion events was eight (IQR :2,20) per BC sample. In terms of NTRK fusion, we detected NTRK2-BANCR fusion event in one TNBC patients (1/425, 0.2%). This fusion was detected in four of five SWs for fusion detection with significant number of supporting reads in RNASeq. NTRK2-BANCR fusion was the out-of-frame fusion, which C-terminal truncated protein kinase domain of NTRK2 and its partner long non-coding RNA BANCR was combined and RNA expression of this fusion was increased. Other fusion events of BCs were NCOR2-PARP4 (3.7%), BRD4-NWD1 (3.7%), ESR1-RGS17 (1.8%), FGFR1-TACC1 (0.2%) and MKRN1-BRAF (0.2%). In BC subtype according to IHC, fusion events were more frequently observed in TNBC compared with other subtypes regardless of the type of fusion filters. In terms of intrinsic subtype, fusion events were most frequently observed in basal like type and least in normal like intrinsic subtype (all ps&lt;0.05, respectively). Conclusions: In this large scaled RNASeq data analysis, a few fusion events were observed in BC patients. Prevalence of NTRK was extremely rare. Additional investigation including functional validation would be followed.

Citation Format: Ji-Yeon Kim, Kyunghee Park, Woong-Yang Park, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam, Jonghan Yu, Young-Hyuck Im, Jin Seok Ahn, Yeon Hee Park. Fusion analysis including NTRK fusion in breast cancers (BC): From RNASeq data analysis from 629 BC tissue samples [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-13-08.