br Discussion br Conflicts of interest br Acknowledgment

Discussion
Conflicts of interest
Acknowledgment
Introduction To maximize the benefits and minimize the toxicity of an oncotherapy, targeted therapy has emerged as one of the major modalities for cancer control, with impressive results obtained for a number of cancers. These targets are either surface markers such as human epithelial receptor 2 (HER2) (targeted by trastuzumab) [1]. or internal identifiers such as BRAF V600E mutation (targeted by vemurafenib) [2] and EML4-ALK fusion (targeted by crizobinib) [3]. It is estimated that gene fusions are responsible for 20% of global cancer morbidities [4]. Increasing evidences have elucidated many crucial oncogenic functionalities of fusion genes, from fusion generation mechanisms to pathological consequences, against which targeted therapies have demonstrated tremendous efficacies in clinics. Fusion genes are formed as the result of either structural chromosomal rearrangement including, primarily, translocation, inversion, amplification and deletion, or non-structural aberrations caused by cis- and trans-splicing or transcriptional read-through. Such events are known to play important roles in the initial steps of tumorigenesis [4]. Canonical structural fusions are featured by neoplastic MPEP Hydrochloride and are the demonstrated ideal markers for cancer cell identification and/or targeting (if oncogenic) such as in the case of NTRK fusions [5]. This offers particular benefits for tumors lacking surface markers such as triple negative breast cancer carcinomas which account for 15–20% of all breast cancer cases and still lack effective targeted therapies with acceptable adverse effects [6]. It was in 1960 that the first evidence of fusion genes in human cancer was pinpointed [7]. An abnormally small chromosome, namely the Philadelphia chromosome, was found in over 95% chronic myelogenous leukemia (CML) patients, where the q-arms of chromosomes 9 and 22 are mutually translocated and carry the BCR-ABL1 fusion gene (Table 1) [8]. It was shown later that the product of BCR-ABL1 is an aberrant ABL1 kinase consistently active in phosphorylating interleukin-3 receptor and, thus, a stimulant for the rewiring of myeloid cells towards CML [8]. Recently, a novel fusion pair ETV6-ABL1 was included in the Catalogue Of Somatic Mutations In Cancer (COSMIC), which is a rare but recurrent fusion (Table 1) that results in constitutive tyrosine kinase activity (similar to BCR-ABL1 fusion) in many hematological malignancies [9]. Initially associated with hematological malignancies, gene fusions have now been shown to occur in solid tumors [10] including, e.g., glioblastoma [11], melanoma [12], prostate [13], breast [14], lung [3], colorectal [15], head and neck [16] cancers. Next-generation sequencing at the transcriptome level (RNA-Seq) has aided in fusion gene discovery and verification as an unbiased instrument [17,18]. Bioinformatic predictions and computational tools such as FusionFinder [19] further automated such a process. The number of fusion genes has surged from 358 in 2007 [4] to approximately 20,000 in 2017 [9], with over 90% identified in the last 7 years due to advances in deep sequencing and detection algorithms [18]. According to November 2017 release (v83) of COSMIC, 18,029 fusions are associated with tumors [9], and the recurrence rates are 21% ± 7.1%, 28% ± 20% and 6% ± 10%, respectively, for hematological disorders, benign and malignant solid tumors [18].