Abstract 5468: Gene fusions in breast cancer in Nigerian women
Authors: Woodard Anna Elizabeth , Yoshimatsu Toshio F. ,   WABCS Working Group, Pitt Jason J. , Zheng Yonglan , Olopade Olufunmilayo I. 
Published: September 2020

Abstract
Background: As a chromosomal rearrangement event, gene fusion plays a critical role in the pathogenesis of cancer by creating potentially oncogenic chimeric proteins. However, gene fusions have been understudied in breast cancer patients of African ancestry, who are often diagnosed at a younger age and with more aggressive molecular features of cancer than patients of other races/ethnicities.
Methods: Ninety-six women diagnosed with invasive breast cancer were recruited from Ibadan, Nigeria with mean age at diagnosis of 51.6 ± 12.4 years. Primary tumors were collected, of which 62 (64.6%) were hormone receptor negative (HR-) by immunohistochemistry, and 31 (32.3%) were basal-like subtype by PAM50 classification. Paired-end reads from RNA-seq on these tumors were used for gene fusion detection by three programs, STAR-Fusion, STAR-SEQR, and Arriba. To increase specificity, we applied an ensembling method by selecting fusions identified by at least two of the three callers. Multiple filters were applied to fusion candidates to remove likely false positives, including fusions containing genes of mitochondrial origin, fusions consisting of pairs of paralogues or orthologs, fusions involving HLA genes, and fusions found in several databases of non-cancer tissues. To investigate potentially druggable fusion transcripts, we compared our call set with the OncoKB precision oncology knowledge base.
Results: STAR-Fusion, STAR-SEQR, and Arriba identified 682, 4529, and 3056 unique fusion transcripts, respectively. Following application of the ensembling method and filtering to select final fusions, 709 unique fusions were identified. Comparison with 13 databases and published papers identified 62 of these fusions as previously reported. The mean fusion burden per sample was 7.7 ± 7.4. The fusion burden per sample was significantly smaller for tumors classified as Luminal A subtypes by PAM50 classification than Luminal B, Basal, and HER2 subtypes (P &lt; 0.03) as well as normal like (P &lt; 0.01). Fusion burden was highest in HER2 tumors (NS), consistent with previous reports. The number of fusion transcripts per sample did not differ significantly according to the patient's age. Ninety-six percent of fusion transcripts were only identified in a single sample, including the ETV6-NTRK3 fusion, previously reported in secretory breast carcinoma, and BCR-ABL1, both of which are targeted by a drug identified in OncoKB. The most commonly observed fusion, EDDM13–ZNF71, appeared in 4.2% (4/96) of samples.
Conclusion: The vast majority of breast cancer samples from Nigerian women demonstrate unique fusion transcripts in expressed RNA. Fusion burden per sample was related to PAM50 classification. Future work will incorporate functional studies of the recurrent gene fusion events identified in our cohort. We will additionally focus on validation and refinement of our approach to detecting gene fusions in this understudied population, in order to better identify patients who can benefit from new therapies.
Citation Format: Anna Elizabeth Woodard, Toshio F. Yoshimatsu, WABCS Working Group, Jason J. Pitt, Yonglan Zheng, Olufunmilayo I. Olopade. Gene fusions in breast cancer in Nigerian women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5468.