New insights from Whole Genome Sequencing: BCLAF1 deletion as a structural variant that predisposes cells towards cellular transformation

Cancer arises from a multi‑step cellular transformation process where some mutations may be inherited, while others are acquired during the process of malignant transformation. Aberrations in the BCL2 associated transcription factor 1 ( BCLAF1 ) gene have previously been identified in patients with cancer and the aim of the present study was to identify structural variants (SVs) and the effects of BCLAF1 gene silencing on cell transformation. Whole‑genome sequencing was performed on DNA isolated from tumour biopsies with a histologically confirmed diagnosis of oesophageal squamous cell carcinoma (OSCC). Paired‑end sequencing was performed on the Illumina HiSeq2000, with 300 bp reads. Reads were aligned to the Homo sapiens reference genome (NCBI37) using ELAND and CASAVA software. SVs reported from the alignment were collated with gene loci, using the variant effect predictor of Ensembl. The affected genes were subsequently cross‑checked against the Genetic Association Database for disease and cancer associations. BCLAF1 deletion was identified as a noteworthy SV that could be associated with OSCC. Transient small interfering RNA‑mediated knockdown of BCLAF1 resulted in the altered expression of several downstream genes, including downregulation of the proapoptotic genes Caspase‑3 and BAX and the DNA damage repair genes exonuclease 1, ATR‑interacting protein and transcription regulator protein BACH1. BCLAF1 deficiency also attenuated P53 gene expression. Inhibition of BCLAF1 expression also resulted in increased colony formation. These results provide evidence that the abrogation of BCLAF1 expression results in the dysregulation of several cancer signalling pathways and abnormal cell proliferation.