O-009
Landscape of FMS-like tyrosine kinase 3 (FLT3) and associated molecular alterations in 44,766 gastrointestinal (GI) cancers
Introduction
Index cases of response to promiscuous kinase inhibitors have suggested the activity of FLT3 inhibitors in FLT3 amplified (FLT3amp) colorectal cancer (CRC) patients. FLT3 regulates the lymphoid system in a physiologic context, but the oncogenic role of FLT3amp in GI cancers has not yet been well established and the genomic landscape has yet to be delineated.
Index cases of response to promiscuous kinase inhibitors have suggested the activity of FLT3 inhibitors in FLT3 amplified (FLT3amp) colorectal cancer (CRC) patients. FLT3 regulates the lymphoid system in a physiologic context, but the oncogenic role of FLT3amp in GI cancers has not yet been well established and the genomic landscape has yet to be delineated.
Methods
Tissue samples from 44,766 unique patients with primarily advanced GI cancer were sequenced using hybrid-capture NGS based comprehensive genomic profiling of 186 to 315 genes plus introns from 14 to 28 genes commonly rearranged in cancer. Tumor mutational burden (TMB) was determined on 0.8–1.1 Mb of sequenced DNA and microsatellite instability (MSI) was assessed across 114 homopolymeric loci.
Tissue samples from 44,766 unique patients with primarily advanced GI cancer were sequenced using hybrid-capture NGS based comprehensive genomic profiling of 186 to 315 genes plus introns from 14 to 28 genes commonly rearranged in cancer. Tumor mutational burden (TMB) was determined on 0.8–1.1 Mb of sequenced DNA and microsatellite instability (MSI) was assessed across 114 homopolymeric loci.
Results
FLT3 amplification was observed in 3.5% (1575/44,766) of GI cases with a median copy number of 10 (range 6-123); other classes of FLT3 alterations were uncommon (< 0.0001), but KRAS mutation frequency was similar in both (not shown). In contrast, activating alterations were seen in BRAF (4.2% vs 8.9%, p < 0.0001) and PIK3CA (11% vs 19%, p < 0.1). No MSI-High FLT3amp CRC cases were observed while 4.9% of non- FLT3amp CRC were MSI-High. Non-focal (>20 Mb segment) FLT3amp was excluded from this analysis but will be investigated in follow up studies.
FLT3 amplification was observed in 3.5% (1575/44,766) of GI cases with a median copy number of 10 (range 6-123); other classes of FLT3 alterations were uncommon (< 0.0001), but KRAS mutation frequency was similar in both (not shown). In contrast, activating alterations were seen in BRAF (4.2% vs 8.9%, p < 0.0001) and PIK3CA (11% vs 19%, p < 0.1). No MSI-High FLT3amp CRC cases were observed while 4.9% of non- FLT3amp CRC were MSI-High. Non-focal (>20 Mb segment) FLT3amp was excluded from this analysis but will be investigated in follow up studies.
Conclusion
FLT3amp co-occurs with KRAS mutations at a frequency similar to the overall CRC population, unlike HER2amp CRC which has a lower frequency of KRAS co-mutation and is thought to activate downstream signaling pathways (PMID: 29338072). In contrast, both FLT3amp and HER2amp CRC are enriched for TP53 mutations. The distinct genomic landscape of FLT3amp relative to HER2amp CRC combined with the response of FLT3amp index cases may suggest FLT3amp has a distinct oncogenic role for colon cancer that extends beyond signaling activation only. Further investigation of the oncogenic role of FLT3amp is needed in a clinical context and an appropriate model system.
FLT3amp co-occurs with KRAS mutations at a frequency similar to the overall CRC population, unlike HER2amp CRC which has a lower frequency of KRAS co-mutation and is thought to activate downstream signaling pathways (PMID: 29338072). In contrast, both FLT3amp and HER2amp CRC are enriched for TP53 mutations. The distinct genomic landscape of FLT3amp relative to HER2amp CRC combined with the response of FLT3amp index cases may suggest FLT3amp has a distinct oncogenic role for colon cancer that extends beyond signaling activation only. Further investigation of the oncogenic role of FLT3amp is needed in a clinical context and an appropriate model system.
Publisher
Oxford University Press
Source Journal
Annals of Oncology
