Genomic profiling of 114,200 advanced cancers identifies recurrent kinase domain duplications (KDD) and oncogenic rearrangements (RE) across diverse tumor types

Abstract

Background: Kinase fusions (KFN) are well recognized as targetable drivers in some cancers, and KFN common in one disease can be found in unrelated histologies, as for BRAF. Recently, oncogenic KDD in BRAF and EGFR were reported, along with responses to tyrosine kinase inhibitors (TKI). We assessed the frequency of KDD and KFN across 114,200 advanced cancers to reveal the landscape of oncogenic KFN and non-canonical rearrangements (KRE) in a wide variety of subtypes. Method(s): CGP was performed on DNA and/or RNA from 114,200 solid tumors or heme malignancy samples for 184-406 cancer-related genes and select introns from 14- 28 genes commonly rearranged in cancer. RNA sequencing for 265 genes was available for some cases. Selected genomic events were confirmed by manual inspection. Result(s): KDD were observed in 598 cases (0.62%): BRAF (127), EGFR (115), FGFR3 (94), FGFR1 (40), RET (37), ERBB2 (35), PDGFRA (35), FGFR2 (28), MET (19), ROS1 (14), ALK (13), KIT (8), NTRK1 (8), FLT3 (6), FGFR4 (5), ERBB4 (4), PDGFRB (3), NTRK2 (2). KDD were seen in 2.7%of brain tumors, most often EGFR (66), BRAF (52), PDGFRA (13), and FGFR3 (26). In extracranial tumors, KDD were common for RET (13-16% of breast, lung, and thyroid KDD+ cases), MET (15-20%of uterine and brain KDD+cases), and ALK (54% of lung KDD+ cases). KDD possibly related to TKI resistance were seen in BRAF V600E-positive melanoma and ALK-related NSCLC. Table 1 summarizes KFE and KFN for ALK, FGFR2/3, RET, and ROS1; 48-57 tumor types are affected Per gene. KFN partner varied by tumor site; for ROS1, GOPC KFN predominate in gliomas and CRC, TFG KFN in sarcomas, and CD74 and EZR in NSCLC. Conclusion(s): KDD are enriched in brain tumors. Diverse KDD are found extracranially and may underlie acquired resistance. Index cases with clinical responses to matched TKIs suggest KDD, KFN and KRE can be targeted therapeutically in many histological subtypes. Recurrent KFN are found widely in cancer, with gene partner varying by subtype.