BRCA1 L1780P mutation
Using patient-derived xenograft (PDX) models and a PDX-derived cell line (PDXDC) from two triple-negative breast cancer patients carrying the BRCA1 L1780P germline mutation, the authors performed whole-genome/exome sequencing and RNA-seq analyses. They evaluated HRD status using HRDetect and CHORD algorithms and tested drug responses to the PARP inhibitor olaparib and the ATM inhibitor AZD0156, both alone and in combination.
Opposite Patterns of Allelic Loss (LOH vs. Reversion):
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In SBP60, loss of the wild-type BRCA1 allele resulted in homozygosity for the L1780P mutation, producing complete loss of BRCA1 function.
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In SBP77, a reversion mutation occurred: the mutant allele was deleted, and only the wild-type allele was retained. This effectively restored normal BRCA1 function.
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These opposite allelic outcomes were clearly resolved through high-purity sequencing of PDX tissues (near 100% tumor content), which overcame the low-purity limitation of primary tumors.
HRD Predictions Showed Consistently High Scores:
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Despite their opposing allelic states, both models demonstrated extremely high HRDetect scores (0.96 and 0.99) and CHORD probabilities (>0.85), placing them within the top HRD-positive range compared with 568 breast cancer genomes.
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This suggested that static HRD predictors—based on genomic scars and mutational signatures—may not reflect real-time HR functionality after reversion events.
Divergent Drug Sensitivity Patterns:
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SBP60 (homozygous L1780P):
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Showed significant tumor regression upon treatment with both olaparib and AZD0156 (p ≈ 0.01 in PDX models).
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The combination therapy produced slightly greater reduction, although not statistically synergistic.
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Functional assays using the BRCA1-null cell line (HCC1937) transfected with BRCA1 L1780P confirmed increased olaparib sensitivity, validating the mutation as HRD-inducing.
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SBP77 (reverted wild-type):
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Displayed no significant response to either olaparib or ATMi, resembling BRCA1-proficient cell lines (MDA-MB-231).
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The reverted tumor thus behaved as HR-proficient, showing acquired resistance to HRD-targeting drugs despite high HRD prediction scores.
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Mechanistic Interpretation:
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The L1780P mutation likely disrupts the BRCT domain’s phospho-protein binding function, impairing HR repair and conferring PARPi/ATMi sensitivity.
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When a reversion event deletes the mutant allele, the dominant-negative effect of L1780P is removed, allowing BRCA1-mediated HR restoration and therapy resistance.
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This finding aligns with clinical observations of BRCA1/2 reversion mutations causing resistance to platinum or PARP inhibitors.
Conclusion
The findings establish BRCA1 L1780P as a functionally pathogenic mutation that initially confers HRD and PARP/ATM inhibitor sensitivity. However, reversion mutations can restore HR function and lead to therapeutic failure despite high HRD prediction scores. Therefore, reliance on HRD scoring alone may misguide treatment decisions. Continuous genomic monitoring for reversion or LOH events is essential to improve precision therapy in BRCA1/2-mutated breast cancers.
DOI: https://doi.org/10.1016/j.isci.2024.110469