Given that epigenetic promoter alterations can change the chromatin accessibility of transcription regulatory elements binding to transcription factors (11, 12, 50, 60–63), the upstream hypermethylation of PRSS3 may impact tissue-specific cis-regulatory modules that may alter the transcriptional activity of PRSS3-SVs in HCC. The gene discussed is PRSS3; the disease is hepatocellular carcinoma.