Kinase impact assessment in the landscape of fusion genes that retain kinase domains: a pan-cancer study

Abstract

Assessing the impact of kinase in gene fusion is essential for both identifying driver fusion genes (FGs) and developing molecular targeted therapies. Kinase domain retention is a crucial factor in kinase fusion genes (KFGs), but such a systematic investigation has not been done yet. To this end, we analyzed kinase domain retention (KDR) status in chimeric protein sequences of 914 KFGs covering 312 kinases across 13 major cancer types. Based on 171 kinase domain-retained KFGs including 101 kinases, we studied their recurrence, kinase groups, fusion partners, exon-based expression depth, short DNA motifs around the break points and networks. Our results, such as more KDR than 5'-kinase fusion genes, combinatorial effects between 3'-KDR kinases and their 5'-partners and a signal transduction-specific DNA sequence motif in the break point intronic sequences, supported positive selection on 3'-kinase fusion genes in cancer. We introduced a degree-of-frequency (DoF) score to measure the possible number of KFGs of a kinase. Interestingly, kinases with high DoF scores tended to undergo strong gene expression alteration at the break points. Furthermore, our KDR gene fusion network analysis revealed six of the seven kinases with the highest DoF scores (ALK, BRAF, MET, NTRK1, NTRK3 and RET) were all observed in thyroid carcinoma. Finally, we summarized common features of 'effective' (highly recurrent) kinases in gene fusions such as expression alteration at break point, redundant usage in multiple cancer types and 3'-location tendency. Collectively, our findings are useful for prioritizing driver kinases and FGs and provided insights into KFGs' clinical implications.

Figure 1.

Illustration of KDR in FGs and flow chart of KDR annotation. (A) Illustration of the KDR in the 5′- and 3′-KFGs. (B) Flow chart of annotation of KDR.

Figure 2.

KDR ratios and DNA motif sequences in the break point introns in 5′- and 3′-KFGs. (A) The relative percentage of KDR in 5′- and 3′-KFGs. (B) KDR kinases in classical kinase group. (C) Short DNA motif sequences in the break point introns of the 5′- and 3′-KDR FGs.

Figure 3.

KDR kinase classification based on the pattern of gene expression alteration at break points. (A) Gene expression plots of KDR kinases. Each dot presents RPKM value of an exon in each sample. Blue vertical line indicates the break point. X axis: exon of the kinase. Y axis: RPKM value. (B) Three kinase groups classified by the expression alteration at break points based on Figure 3A. We marked each kinase group by different color. The value in each cell is the number of samples having the corresponding class of the KDR kinase.

Figure 4.

The DoF score measures the impact of a kinase in gene fusion event. (A) Kinases of 3′-KDR FGs sorted by DoF score. (B) Kinases of 5′-KDR FGs sorted by DoF score. (C) The average number of gene fusion events for high DoF scored fusions and low DoF scored fusions. Red bar: high DoF scored fusions. Pink bar: low DoF scored fusions. (D) The enriched biological processes of partner genes for the high and low DoF scored cases in 3′-KDR FGs.

Figure 5.

KDR gene fusion network. A node represents a kinase and its color reflects the DoF score. The edge color denotes specific cancer type. The node boundary color reflects the kinase group. This gene fusion network of KDRs provides an overview of the impact of kinases in pan-cancer FGs. From this network, we may select kinases with potential clinical implications.

Figure 6.

Enriched biological processes of KDR kinases per cancer type. We used the ClueGO app in CytoScape (adjusted P-value <0.05, hypergeometric test followed by multiple test correction using the Bonferroni method).