Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers

Abstract

FHIT, located at FRA3B, is one of the most commonly deleted genes in human cancers, and loss of FHIT protein is one of the earliest events in cancer initiation. However, location of FHIT at a chromosomal fragile site, a locus prone to breakage and gap formation under even mild replication stress, has encouraged claims that FHIT loss is a passenger event in cancers. We summarize accumulated evidence that FHIT protein functions as a genome “caretaker” required to protect the stability of genomes of normal cells of most tissues from agents causing intrinsic and extrinsic DNA damage. FHIT loss leads to intracellular replication stress and subsequent genome instability, which provides an opportunistic mutational landscape in preneoplasias for selection of a variety of other cancer-driving mutations. We also review evidence showing that FHIT loss leads to enhanced activation of other common fragile sites, including the FRA16D/WWOX locus, and creates optimal single-stranded DNA substrates for the hypermutator enzyme, APOBEC3B.

The role of fork stalling and DNA structures in causing chromosome fragility

“…). Interestingly, 40‐80% of cancer cell lines with a deletion in FRA16D also contain a deletion in FRA3B and vice versa, which supports the idea of shared mechanisms of CFS fragility …”

Genomic instability in fragile sites—still adding the pieces

“…In vivo, replication stress is driven by genetic and/or environmental factors. The genetic factors involve the loss of TSGs or the aberrant expression of oncogenes . Several studies have investigated the mechanisms underlying oncogene‐induced replication stress (reviewed in the study by Sarni and Kerem).…”

Fragile sites in cancer: more than meets the eye

“…FHIT , WWOX and a number of other CFS-associated genes have been proposed to be tumor suppressor genes and their loss may lead to cancer development 122, 123 . This hypothesis has been supported by studies indicating that deletion and/or reduced expression of these genes is a predictor of poor outcome in many different cancers.…”

“…Most functional studies on CFS genes have also focused on FHIT , WWOX and, more recently, PARK2 , linking them to the DNA damage response in cultured cells and mouse cancer models 122 . Loss of FHIT has been reported to result in dNTP imbalance and spontaneous replication stress 130 and WWOX has been reported to function in activation of the ATR-mediated DNA damage checkpoint response activation 131 .…”