Identification and Targeting of POLQ-Associated Hereditary Colorectal Cancer

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Hereditary colorectal cancer (CRC) syndromes are not fully understood, with many cases lacking identified genetic causes.
• Identifying genetic drivers is crucial for understanding CRC pathogenesis and developing targeted therapies.

Purpose of the Study:

• To identify pathogenic mutations in hereditary colorectal cancer.
• To explore the potential of targeting identified mutations for novel therapeutic strategies.

Main Methods:

• Whole-exome sequencing of individuals from families with hereditary CRC and polyposis.
• In vivo and in vitro assays to assess mutation effects on tumorigenesis.
• Screening of sporadic CRC cases and an expanded cohort for potential hereditary CRC.

Main Results:

• A germline mutation (p.Arg1953X) in the polymerase θ (POLQ) gene was identified in multiple families with CRC.
• This POLQ mutation leads to hyperactivation of θ-mediated end-joining (TMEJ), resulting in high tumor mutational burden and resistance to DNA-damaging agents.
• Treatment with a POLQ inhibitor (novobiocin) suppressed TMEJ and restored sensitivity to DNA damage in preclinical models.

Conclusions:

• POLQ is identified as a pathogenic gene in hereditary colorectal cancer, defining a new POLQ-type CRC driven by TMEJ hyperactivation.
• Screening for POLQ mutations can aid in early diagnosis and personalized treatment of hereditary CRC.
• Further clinical validation is needed to confirm the therapeutic potential of targeting POLQ in CRC.