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Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic
Aurel Prosz1, Pranshu Sahgal2,3,4,5, Brandon M Huffman2,6
1Danish Cancer Institute, Copenhagen, Denmark.
Abstract:
Homologous recombination (HR) and nucleotide excision repair (NER) are the two most frequently disabled DNA repair pathways in cancer. HR-deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, the frequency of HR deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Using whole exome and genome sequencing data, we found that a significant subset of GEA, but very few colorectal adenocarcinomas, show evidence of HR deficiency by mutational signature analysis (HRD score). High HRD gastric cancer cell lines demonstrated functional HR deficiency by RAD51 foci assay and increased sensitivity to platinum chemotherapy and PARP inhibitors. Of clinical relevance, analysis of three different GEA patient cohorts demonstrated that platinum treated HR deficient cancers had better outcomes. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by two photoproduct repair assays. Single-cell RNA-sequencing revealed that, in addition to inducing apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, validated by intracellular GSH assay. Overall, our study provides preclinical evidence that a subset of GEAs harbor genomic features of HR and NER deficiency and may therefore benefit from platinum chemotherapy and PARP inhibitors.
Insights
Homologous recombination (HR) and nucleotide excision repair (NER) deficiencies are common in gastric and esophageal cancers. These deficiencies predict better outcomes with platinum chemotherapy and PARP inhibitors, offering new therapeutic strategies.
Area of Science:
- Genomic instability and DNA repair mechanisms in cancer biology.
Background:
- Homologous recombination (HR) and nucleotide excision repair (NER) are critical DNA repair pathways frequently altered in various cancers.
- HR deficiency confers sensitivity to platinum chemotherapy and PARP inhibitors in breast, ovarian, pancreatic, and prostate cancers.
- The prevalence and functional significance of HR deficiency in gastric and esophageal adenocarcinoma (GEA) remain underexplored.
Purpose of the Study:
- To investigate the frequency and functional validation of HR deficiency in GEA.
- To explore the role of NER deficiency in GEA and its response to platinum chemotherapy.
- To assess the clinical relevance of HR and NER deficiencies for platinum-based therapies in GEA.
Main Methods:
- Whole exome and genome sequencing for mutational signature analysis (HRD score).
- RAD51 foci assay to assess functional HR deficiency in gastric cancer cell lines.
- Photoproduct repair assays to evaluate NER proficiency.
- Single-cell RNA-sequencing and intracellular GSH assays to analyze cisplatin treatment response.
- Analysis of three GEA patient cohorts treated with platinum chemotherapy.
Main Results:
- A significant subset of GEA exhibits evidence of HR deficiency based on mutational signatures, unlike colorectal adenocarcinomas.
- Gastric cancer cell lines with high HRD scores demonstrated functional HR deficiency and sensitivity to platinum drugs and PARP inhibitors.
- Platinum-treated HR-deficient GEA patients showed improved outcomes across three independent cohorts.
- A cisplatin-sensitive gastric cancer cell line, proficient in HR, displayed NER deficiency.
- Cisplatin treatment induced apoptosis and ferroptosis in NER-deficient gastric cancer cells.
Conclusions:
- Genomic analysis reveals a subset of GEA with HR and/or NER deficiencies.
- These deficiencies suggest potential benefit from platinum chemotherapy and PARP inhibitors for a subset of GEA patients.
- The study provides preclinical rationale for targeting DNA repair pathways in GEA treatment strategies.
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