br Mechanisms forming fusion genes br Clinical relevance

Mechanisms forming fusion genes
Clinical relevance of fusion genes
Fusion frequency and pattern The frequency of recurrent fusion MPEP Hydrochloride is much lower than other types of somatic mutations [43] and anti-correlated with that of other driver mutations [67]. For instance, the EML4-ALK driver fusion occurs at a rate of 6% in lung cancer, and those of driver mutations in KRAS and EGFR are 25% and 23%, respectively [101]. According to COSMIC November 2017 release (v83), approximately 83% fusions have the mutation counterparts in at least one of its fusion partners, and only around 2% mutations have associated fusion genes. Also, the number of observed coding mutations and copy number variations are 4,067,689 and 1,271,436, respectively, which are approximately 226 and 71 times that of the observed gene fusions [9]. These suggest that recurrent fusion genes are rare in comparison with other forms of somatic mutations due to, probably, complicated generation mechanisms, and pathological fusion events are likely highly penetrative with prominent transforming potential given their oncogenic redundancy with driver mutations [43]. The fusion pair and pattern vary considerably among cancer types [43,67]. While the majority of fusion genes pair with one single other gene, a few such as MLL, EWS and ETV6 are highly promiscuous [43]. The gene fusion network in acute myelogenous leukemia is densely connected around a few genes such as MLL, and that of ovarian cancer is much more dispersed [18]. The highest fusion rate occurs in bladder cancer and that of the lowest in thyroid carcinoma according to a survey of gene fusions in TCGA [67]. These warrant distinct strategies in the therapeutic design and differential utility of gene fusions across cancers. The same reservoir of genes is involved in fusions in all types of cancers, which predominantly encode kinases and transcriptional factors [102]. This makes fusion genes potential pan-cancer targets, and renders tumor categorization based on genetic profiling therapeutically reasonable. For instance, FGFR tyrosine kinase family fusions have been profiled across a dozen of solid tumors, and have emerged as promising therapeutic targets across a spectrum of cancers [103]. The roles played by fusion genes differ among cancer types [73], reflecting differential oncological mechanisms of various types of cancers and implicating distinct tumor-driving pathways and intervention strategies. Gene fusions in carcinomas are more likely associated with aberrant cell growth signaling than hematopoietic and mesenchymal cancers [73], due to possibly different differentiation histories [43]. Interestingly, in thyroid cancers which harbor the highest frequency of recurrent kinase fusions (13%), all kinase types of fusions involving ALK, BRAF, MET, NTRK1, NTRK2, RAF1, RET were mutually exclusive [68], suggesting the pivotal roles of the pathway they pathologically converge in driving tumorigenesis that needs particular focus regarding therapeutic intervention.