20P - Mutational signature-based identification of DNA repair deficient gastroesophageal adenocarcinomas for therapeutic targeting

Background

DNA repair deficiency is a common feature of cancer. Homologous recombination (HR) and nucleotide excision repair (NER) are two most frequently disabled DNA repair pathways in solid tumors. HR deficient breast, ovarian, pancreatic and prostate cancers respond well to platinum chemotherapy and PARP inhibitors. However, frequency of DNA repair pathway deficiency in gastric and esophageal adenocarcinoma (GEA) still lacks diagnostic and functional validation. Furthermore, whether DNA repair deficient GEA have enhanced responsiveness to platinum chemotherapy and sensitivity to PARP inhibitors is not well characterized.

Methods

Using whole exome and genome sequencing data, we measured various HR deficiency-associated mutational signatures in patient specimen of gastric, esophageal and colorectal cancer specimens and gastric cancer cell lines. Gold-standard immunofluorescence assays were used to confirm HR and NER deficiency in cancer cell lines. Relationship between PARP inhibitor treatment and tumor response was evaluated in patients with gastric cancer. Drug sensitivity was determined using standard in vitro cell culture assays. Single-cell RNA-sequencing was done to evaluate gastric cancer response to commonly used chemotherapeutics.

Results

We found that a significant subset of GEA, but very few colorectal tumors, show evidence of HR deficiency by mutational signature analysis (HRD score). Gastric cancer cell lines with high HRD mutational signature scores demonstrated functional HR deficiency by RAD51 assay and increased sensitivity to platinum and PARP inhibitors. A gastric cancer cell line with strong sensitivity to cisplatin showed HR proficiency but exhibited NER deficiency by DDB2 proteo-probe assay. Single-cell RNA-sequencing revealed that, in addition to inducing general apoptosis, cisplatin treatment triggered ferroptosis in a NER-deficient gastric cancer, which may explain the outlier sensitivity.

Conclusions

A subset of upper gastrointestinal tumors have genomic features of HR and NER deficiency and therefore may be more likely to benefit from platinum chemotherapy and PARP inhibition.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The author.

Funding

Research and Technology Innovation Fund (KTIA_NAP_13-2014-0021 and 2017-1.2.1-NKP-2017-00002), Breast Cancer Research Foundation (BCRF-20-159), Kræftens Bekæmpelse (R281-A16566), Degregorio Family Foundation, AGA Augustyn Award in Digestive Diseases.

Disclosure

The author has declared no conflicts of interest.