The BRCAness Landscape of Cancer

Area of Science:

• Oncology
• Genetics
• Cancer Therapeutics

Background:

• BRCAness signifies impaired homologous recombination (HR) repair due to defects in non-BRCA1/2 genes.
• BRCAness is a key biomarker for PARP inhibitor (PARPi) therapy in breast and ovarian cancers.
• The efficacy of PARPi in these cancers suggests potential applications in other BRCAness-positive malignancies.

Purpose of the Study:

• To systematically characterize BRCAness across diverse cancer types beyond breast and ovarian cancers.
• To identify novel cancer types that exhibit BRCAness features and could be candidates for PARPi therapy.

Main Methods:

• Comprehensive analysis of 40 BRCAness-related genes in over 10,000 cases across 33 cancer types.
• Evaluation included pathogenic variations, homozygous deletions, promoter hypermethylation, gene expression, and clinical correlations.
• BRCA1/2-mutated breast and ovarian cancers served as controls for comparison.

Main Results:

• BRCAness features were observed in a wide range of cancer types beyond the established ones.
• 21 cancer types were identified as potential candidates for PARPi therapy based on the cumulative BRCAness score.
• These include adrenocortical carcinoma, bladder, brain lower grade glioma, colon, esophageal, head and neck, kidney (3 types), liver, lung (2 types), mesothelioma, pancreatic, prostate, rectum, sarcoma, skin melanoma, stomach, and uterine (2 types) cancers.

Conclusions:

• BRCAness is a prevalent feature across numerous cancer types, extending beyond breast and ovarian cancers.
• The study provides a comprehensive map of BRCAness, highlighting 21 new potential targets for PARP inhibitor therapy.
• This research broadens the scope for utilizing synthetic lethality-based treatments in a wider oncology patient population.