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

Area of Science:

• Genetics
• Cancer Biology
• Genomics

Background:

• The FHIT gene, located at FRA3B, is frequently deleted in human cancers, with FHIT protein loss being an early event in cancer initiation.
• Its location at a common fragile site suggests FHIT loss might be a passenger event, but evidence points to a more active role.

Purpose of the Study:

• To summarize evidence on FHIT protein's function as a genome caretaker.
• To elucidate the consequences of FHIT loss on genome stability and cancer development.

Main Methods:

• Review of accumulated evidence on FHIT protein function.
• Analysis of FHIT's role in protecting against DNA damage.
• Investigation of FHIT loss-induced replication stress and genome instability.

Main Results:

• FHIT protein acts as a genome caretaker, essential for maintaining genome stability in normal cells against DNA damage.
• FHIT loss triggers intracellular replication stress and genome instability, creating a mutational landscape conducive to cancer-driving mutations.
• Loss of FHIT enhances activation of other common fragile sites (e.g., FRA16D/WWOX) and promotes APOBEC3B-mediated hypermutation.

Conclusions:

• FHIT is a critical tumor suppressor whose loss actively contributes to cancer initiation and progression through genome instability.
• FHIT loss creates a pro-mutagenic environment, facilitating the acquisition of oncogenic mutations.