The 4q12 amplicon (4q12amp) which harbors the tyrosine kinases KIT, KDR and PDGFRA has been thought to occur as frequently as 3-7% in lung adenocarcinoma (LA) (Ramos et al, 2009) and 5-15% in glioblastoma (GBM) (Holtkamp, 2006; Szerlip, 2012) as assessed by a variety of techniques. As 4q12amp is hypothesized to be an oncogenic driver, it remains unclear whether all three kinases participate equally in oncogenesis, or if one kinase can be preferentially targeted by a tyrosine kinase inhibitor (TKI) for patient benefit. We undertook a large-scale genomic analysis to describe the frequency of 4q12 across solid tumors.
We prospectively analyzed 114,200 primarily advanced stage solid tumors in the course of clinical care using hybrid-capture based comprehensive genomic profiling (CGP) of 186 to 315 genes plus introns from 14 to 28 genes commonly rearranged in cancer.
4q12amp was present in 0.65% of all cases (740/114,200), with a median copy number of 10, and was most abundant in the following cancers: 4.8% of GBM (155/3,222), 0.83% of lung cancers (191/22,857, 2/3 approximately being LA), 1.9% of sarcomas (106/5,391), and 0.77% of breast cancers (92/11,980). Of sarcomas, 7.1% of osteosarcomas (26/367) and 2.82% of soft tissue sarcomas NOS (22/780) harbored 4q12amp. Of 4q12amp lung cancer cases, the supramajority (86%) did not harbor known oncogenic drivers of NSCLC (alterations of EGFR/HER2/MET, ALK/ROS/RET fusions, or BRAF V600E). Index cases of durable responses to pazopanib and imatinib will be described in undifferentiated sarcoma, synovial sarcoma, and head and neck/salivary cancers.
4q12amp is significantly less frequent in GBM and lung cancer than previously reported by non-sequencing techniques, but is enriched in osteosarcoma and undifferentiated sarcomas. The driver status of 4q12amp is supported both by the predominant mutual exclusivity with other known drivers in lung cancer, and responses to various multi-TKIs. The specificities of the latter may help shed insight into whether singly or multiply targeting KIT/KDR/PDGFRA is a preferred approach for patient benefit.
Clinical trial identification
Legal entity responsible for the study
Foundation medicine, Inc funded a small part of the study
U. Disel: Research agreement with Foundation Medicine, which provided funding to run a small number of genomic profiling assay (