A mutational signature in gastric cancer suggests therapeutic strategies

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• Targeting DNA repair defects in cancer, such as BRCA1/BRCA2 mutations, is a therapeutic strategy for breast, ovarian, and pancreatic cancers.
• A specific mutational signature indicates failed homologous recombination (HR) DNA repair, often linked to BRCA1/BRCA2 mutations.
• This signature is present in platinum-therapy responders with pancreatic cancer, even those without BRCA1/BRCA2 defects.

Purpose of the Study:

• To investigate the prevalence of the homologous recombination deficiency (HRD) mutational signature across diverse cancer types.
• To identify if gastric cancer exhibits this HRD signature and assess its potential therapeutic implications.

Main Methods:

• Analysis of 10,250 cancer genomes from 36 distinct cancer types.
• Identification and characterization of a specific mutational signature associated with homologous recombination repair deficiency.

Main Results:

• The HRD-associated mutational signature was identified in gastric cancer, in addition to breast, ovarian, and pancreatic cancers.
• An estimated 7-12% of gastric cancers display this signature, indicating defective homologous recombination repair.
• The findings suggest a potential subset of gastric cancers may respond to DNA-damaging agents.

Conclusions:

• Gastric cancer is a new type exhibiting the HRD mutational signature.
• A significant proportion of gastric cancers (7-12%) may have homologous recombination defects.
• These patients could be candidates for platinum-based chemotherapy or PARP inhibitors.