Comprehensive analysis of ALK , ROS1 and RET rearrangements in locally advanced rectal cancer
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Indian Academy of Sciences (0123456789().,-volV) (0123456789().,-volV)
RESEARCH ARTICLE
Comprehensive analysis of ALK, ROS1 and RET rearrangements in locally advanced rectal cancer CHUNLIAN ZHOU1, MIN LI1,2, ZHIWEI GUO1, KUN LI1, XIANGMING ZHAI1, YINGCHAO XIE1, XUEXI YANG1, YINGSONG WU1, WEIWEI XIAO2 and WEIWEN XU1* 1Institute
of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, People’s Republic of China 2Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China *For correspondence. E-mail: [email protected]. Received 12 October 2019; revised 9 June 2020; accepted 12 June 2020 Abstract. Gene rearrangements, such as anaplastic lymphoma kinase (ALK), c-ros oncogene 1 receptor tyrosine kinase (ROS1), rearranged during transfection (RET) and neurotrophic receptor tyrosine kinase 1 (NTRK1), identified in cancer have been indicated to be robust therapeutic targets in lung carcinomas. However, a few studies have focussed on locally advanced rectal cancer (LARC). The discovery of novel gene fusions is also valuable for LARC research. We used mass spectrometry-based assays and RNA sequencing to detect both known ALK, ROS1, RET and NTRK1 rearrangements and novel gene fusions in LARC patients. FusionMap was also used to find gene fusions. None of the ALK, ROS1, RET or NTRK1 gene fusions were detected by mass spectrometry-based assays or RNA sequencing. Three fusion candidates, integrin subunit beta 7 (ITGB7)-ROS1, lamin A/C (LMNA)-NTRK1 and Golgi-associated PDZ and coiled-coil motif containing (GOPC)-keratin 8 (KRT8), showed relatively high junction-spanning reads by the FusionMap algorithm, but did not pass validation. These results suggest that no ALK, ROS1 or RET rearrangements were found in LARC. Keywords.
rectal neoplasms; neoadjuvant therapy; RNA sequencing; mass spectrometry.
Introduction Fusion genes form as a result of chromosomal rearrangements from abnormal transcription and have been shown to act as drivers of malignant transformation and progression in many cancers (Annala et al. 2013). For example, anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), ret proto-oncogene (RET) and neurotrophic receptor tyrosine kinase 1 (NTRK1) can activate kinases, and a number of them have been found to be an important class of oncogenes associated with tumours (Stransky et al. 2014). Many of the recurrent gene fusions identified in cancer have been proven to be robust therapeutic targets and represent the driving force of modern precision therapeutics. For example, imatinib induces remission in leukaemia patients who are positive for BCR–ABL1 fusions (Goldman and Melo 2003). Chunlian Zhou and Min Li contributed equally to this work.
Recently, crizotinib and ceritinib have produced significant clinical benefits in patients with lung carcinomas and mesenchymal tumours harbouring gene fusions (Luo et al. 2010; Sartore-Bianchi et al. 2016). There is also growing evidence in support of important
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