The landscape of kinase fusions in cancer

Abstract

Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered numerous genes recurrently mutated, deleted or amplified, but gene fusions have not been characterized as extensively. Here we develop heuristics for reliably detecting gene fusion events in RNA-seq data and apply them to nearly 7,000 samples from The Cancer Genome Atlas. We thereby are able to discover several novel and recurrent fusions involving kinases. These findings have immediate clinical implications and expand the therapeutic options for cancer patients, as approved or exploratory drugs exist for many of these kinases.

Figure 1. Landscape of recurrent kinase fusions in solid tumours.

Tumour types are indicated at the bottom and ordered by frequency of samples harbouring recurrent fusions (%; bar chart at the top). For each gene, the number of fusions found in TCGA samples is displayed in the matrix and coloured by the type of novelty. Yellow denotes kinase fusions that have been described previously in this particular indication; orange denotes kinase fusions for which one or more partner genes are novel but the indication is not; purple denotes a novel indication for a particular kinase fusion regardless of the identity of the partner gene; red denotes novel, recurrent kinase fusions.

Figure 2. Structural details of MET fusions.

Novel fusions of MET proto-oncogene in five cancer types. Protein domains, sample details, cancer type, gene partners, as well as genomic and amino-acid sequence are indicated for each of the six predicted MET kinase fusion proteins. In addition, the protein coordinates of the fusion breakpoints and the total amino-acid length of the fusion protein are noted under each protein structure. The protein tyrosine kinase domains are coloured in purple, the transmembrane domains (TM) are indicated in teal, CC dimerization domains are indicated in yellow, whereas other domains are left in white. Fusion breakpoints are delineated by red arrows. IMD, IRSp53/MIM homology domain; PSI, Plexin repeat domain; TIG, IPT/TIG immunoglobulin-like domain; LysM, lysin motif domain; PB1, Phox and Bem1p domain.

Figure 3. PIK3CA promoter fusions.

Novel fusions of PIK3CA in three cancer types. (a) Genomic structure of TBL1XR1–PIK3CA and FNDC3B–PIK3CA fusions. In both cases, the entire coding sequence of PIK3CA is present in the predicted fusion sequence. RefSeq IDs, exon numbers and genomic coordinates are indicated. Exon 1 of TBL1XR1 (5′UTR) is fused to exon 2 of PIK3CA (5′UTR). In the case of FNDC3B–PIK3CA, exon 3 of FNDC3B is fused to the 5′UTR of PIK3CA. (b–d) Scatter plots of PIK3CA DNA copy number versus mRNA expression across all TCGA samples for which both data types are available. Samples harbouring a PIK3CA fusion are depicted in red (along with TCGA sample ID) and show a high expression of PIK3CA relative to the other samples. FPKM, fragments per kilobase of transcript per million mapped reads.

Figure 4. Mutual exclusivity of fusions in thyroid cancer.

All samples harbouring a recurrent kinase fusion in any of the genes indicated on the left are displayed on the x axis. The type of fusion is depicted as a coloured box with the same color-coding scheme as in Fig. 1. Yellow denotes kinase fusions that have been described previously in thyroid cancer; orange denotes kinase fusions in which the partner gene is novel; red denotes novel recurrent kinase fusions. In all cases, the presence of a kinase fusion is exclusive of any other fusion involving kinases recurrently fused.

Figure 5. Novel TRIO–TERT fusions in liposarcoma samples.

(a) Protein domains as well as genomic and amino-acid sequences are indicated for the TRIO–TERT fusion protein. Protein coordinates of the fusion breakpoints and the total amino-acid length of the fusion protein are noted under the protein structure; fusion breakpoint is delineated by a red arrow. CRAL TRIO 2, divergent CRAL/TRIO domain; Telomerase RBD, telomerase ribonucleoprotein complex–RNA binding domain; RVT 1: reverse transcriptase (RNA-dependent DNA polymerase). (b) Scatter plot of TERT DNA copy number versus mRNA expression across all TCGA samples for which both data types are available. Samples harbouring a TERT fusion are depicted in red (along with TCGA sample ID) and show a high expression of TERT relative to the other samples. FPKM: Fragments per kilobase of transcript per million mapped reads.