The ubiquitous ‘cancer mutational signature’ 5 occurs specifically in cancers with deleted FHIT alleles

// Stefano Volinia 1 , Teresa Druck 2 , Carolyn A. Paisie 3 , Morgan S. Schrock 2 and Kay Huebner 2 1 Department of Morphology, Surgery & Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy 2 Department of Cancer Biology & Genetics, The Ohio State University Comprehensive Cancer Center & Wexner Medical Center, Biomedical Research Tower, Columbus, OH 43210, USA 3 University of Washington, Department of Biomedical Informatics & Medical Education, Center for Infectious Disease Research, Seattle, WA 98109, USA Correspondence to: Kay Huebner, email: kay.huebner@osumc.edu Keywords: exome sequences; mutational signatures; data mining; clock-like signatures; cancer genes Received: September 07, 2017      Accepted: October 25, 2017      Published: November 06, 2017 ABSTRACT The FHIT gene is located at the fragile FRA3B locus where activation by carcinogen-induced and endogenous replication stress causes FHIT deletions even in normal cells over a lifetime. Our lab has shown that loss of FHIT expression causes genome instability and provides single-strand DNA substrates for APOBEC3B hypermutation, in line with evidence that FHIT locus deletions occur in many cancers. Based on these biological features, we hypothesized that FHIT loss drives development of COSMIC mutational signature 5 and here provide evidence, including data mining of >6,500 TCGA samples, that FHIT is the cancer-associated gene with copy number alterations correlating most significantly with signature 5 mutation rate. In addition, tissues of Fhit-deficient mice exhibit a mutational signature strongly resembling signature 5 (cosine similarity value = 0.89). We conclude that FHIT loss is a molecular determinant for signature 5 mutations, which occur in all cancer types early in cancer development, are clock-like, and accelerated by carcinogen exposure. Loss of FHIT caretaker function may be a predictive and preventive marker for cancer development.