Abstract 5370: Targeted Sequencing of Actionable Mutations to Enhance the Prognostication of Concurrent Genes-Defined High-Risk Breast Cancers

Abstract Purpose: The aim of the study is to perform targeted sequencing to enhance the prognostic power of breast cancer concurrent genes. Somatic mutations with clinical significance will be identified. Materials and Methods: Our previous study had identified the concurrent genes signature from the coherent patterns between genomic and transcriptional profiles among Taiwanese breast cancers, and those predicted into the high-risk group were furthered assayed by targeted sequencing. Target-enrichment sequencing was performed with Illumina SolexaTM technology with read length of 150 bp and was analyzed with Agilent SureCallTM software. Results: In total, 109 breast cancer samples were collected during surgery and analyzed with AffymetrixTM U133 plus 2.0 microarrays. Breast cancer risk prediction was performed with the published concurrent genes signature. Targeted sequencing of 61 high-risk breast cancers revealed 1061 variants, including 76 pathogenic and 545 likely pathogenic variants based on ACMG classification. The most impacted genes were NOTCH, BRCA1, AR, ERBB2, FANCA, ATM, and BRCA2, harboring 57, 36, 30, 27, 27, 26, and 26 variants. Table 1 showed that the most frequent pathogenic deletions were FGFR1 , ATM, and WT1 (47, 47, and 37 patients) while BRCA1 (rs1799965, non-sense mutation), FGFR2 (missense mutation), and BRCA1 (rs1799949, non-sense mutation) were the most frequent pathogenic SNPs (44, 35, and 11 breast cancers, respectively). The distributions of deletions and pathogenic SNPs were similar across ER+, HER2+, and triple-negative breast cancers. Conclusion: This two-stage predictive model, concurrent genes signature risk stratification followed by targeted sequencing of actionable genes, is believed to provide clinical applicability and substantial benefits for Taiwanese breast cancer patients. Table 1. Pathogenic mutations affecting more than 10 high-risk breast cancers.GeneMutation typeEffectAffected subjectsPathwayPotential therapyFGFR1DeletionFRAME_SHIFT|NM_00117406347PI3K, FGF signalingDovitinibATMDeletionFRAME_SHIFT|NM_00005147DNA damage responseATR inhibitor, PARP inhibitor, Chk 1/2 inhibitorWT1DeletionFRAME_SHIFT|NM_00037837Mutated in Wilm's tumorPDGFRADeletionFRAME_SHIFT|NM_00620618PDGF signalingSorafenib, imatinib, sunitinibPIK3RDeletionFRAME_SHIFT|NM_18152316PI3K signalingBuparlisibRUNX1DeletionFRAME_SHIFT|NM_00100189015Transcription factor, mutated in AMLBRCA1 (rs1799965)SNPnonsense44DNA damage responsePARP inhibitor, cisplatinFGFR2 (chr10:123298158:T:C )SNPmissense35PI3K, FGF signalingBrivanib, nintedanib, dovitinibBRCA1 (rs1799949)SNPnonsense11DNA damage responsePARP inhibitor, cisplatin Citation Format: Chi-Cheng Huang, Chao-Chiang Tu, Ching-Shui Huang. Targeted sequencing of actionable mutations to enhance the prognostication of concurrent genes-defined high-risk breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5370.