Mechanisms shaping the mutational landscape of the FRA3B/FHIT‐deficient cancer genome

Abstract

Genome instability is an enabling characteristic of cancer that facilitates the acquisition of oncogenic mutations that drive tumorigenesis. Underlying much of the instability in cancer is DNA replication stress, which causes both chromosome structural changes and single base‐pair mutations. Common fragile sites are some of the earliest and most frequently altered loci in tumors. Notably, the fragile locus, FRA3B, lies within the fragile histidine triad (FHIT) gene, and consequently deletions within FHIT are common in cancer. We review the evidence in support of FHIT as a DNA caretaker and discuss the mechanism by which FHIT promotes genome stability. FHIT increases thymidine kinase 1 (TK1) translation to balance the deoxyribonucleotide triphosphates (dNTPs) for efficient DNA replication. Consequently, FHIT‐loss causes replication stress, DNA breaks, aneuploidy, copy‐number changes (CNCs), small insertions and deletions, and point mutations. Moreover, FHIT‐loss‐induced replication stress and DNA breaks cooperate with APOBEC3B overexpression to catalyze DNA hypermutation in cancer, as APOBEC family enzymes prefer single‐stranded DNA (ssDNA) as substrates and ssDNA is enriched at sites of both replication stress and DNA breaks. Consistent with the frequent loss of FHIT across a broad spectrum of cancer types, FHIT‐deficiency is highly associated with the ubiquitous, clock‐like mutation signature 5 occurring in all cancer types thus far examined. The ongoing destabilization of the genome caused by FHIT loss underlies recurrent inactivation of tumor suppressors and activation of oncogenes. Considering that more than 50% of cancers are FHIT‐deficient, we propose that FRA3B/FHIT fragility shapes the mutational landscape of cancer genomes.

Probing the tumorigenic potential of genetic interactions reconstituted in murine fallopian tube organoids

“…It is conceivable that selection pressure for a higher grade of Kras activation may underlie sarcomagenesis, which is canceled once p53 is deleted, although underlying molecular mechanisms remain unknown. By analogy with the frequent deletion of the FRA3B common fragile site in multiple cancer types [39], we speculate the presence of putative fragile sites around the Kras locus that are predisposed to deletion, especially in cancers with Kras mutation – with high penetrance of deletion, the current model would provide a unique opportunity to verify this. Furthermore, consistent with the crucial roles of TGF‐β signaling in Kras ‐associated EMT [40], loss of Tgfbr2 directed the development of adenocarcinoma, but not sarcoma.…”

Whole genome deep sequencing analysis of cell-free DNA in samples with low tumour content

“…It has been reported that Signature 5 is driven by the loss of FHIT gene [ 41 ]. Depletion of FHIT causes replication stress-induced DNA double-strand breaks and defects in replication fork progression and prevents activation of DNA damage response [ 54 ]. It is likely that the majority of somatic mutations in plasma are likely due to the result of replication errors and lack of DNA damage responses.…”

DNA replication stress: oncogenes in the spotlight

“…FRA3B and FRA16D are the two most frequently affected CFS in human cancers, including breast, lung, colon, esophageal, and renal carcinomas (Durkin and Glover, 2007). FRA3B is located at 3p14.2 and overlaps with the 1.5 Mb-long Fragile Histidine Triad (FHIT) tumor suppressor gene, which is involved in nucleotide metabolism (Saldivar and Park, 2019). FRA3B instability is caused by a paucity of replication initiation events at the central region of this fragile site, as well as transcription-replication collisions due to extended transcription of the large FHIT gene (Helmrich et al, 2011;Letessier et al, 2011).…”