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

Aurel Prosz; Pranshu Sahgal; Brandon M Huffman; Zsofia Sztupinszki; Clare X Morris; David Chen; Judit Börcsök; Miklos Diossy; Viktoria Tisza; Sandor Spisak; Pornlada Likasitwatanakul; Orsolya Rusz; Istvan Csabai; Michael Cecchini; Yasmine Baca; Andrew Elliott; Peter Enzinger; Harshabad Singh; Jessalyn Ubellaker; Jean-Bernard Lazaro; James M Cleary; Zoltan Szallasi; Nilay S Sethi

doi:10.1038/s41698-024-00561-6

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

NPJ Precis Oncol. 2024 Apr 8;8(1):87. doi: 10.1038/s41698-024-00561-6.

Authors

Aurel Prosz^#¹, Pranshu Sahgal^#^{2

3

4

5}, Brandon M Huffman^{2

6}, Zsofia Sztupinszki^{1

4}, Clare X Morris², David Chen^{2

7}, Judit Börcsök¹, Miklos Diossy^{1

4}, Viktoria Tisza⁸, Sandor Spisak⁸, Pornlada Likasitwatanakul^{2

3

5}, Orsolya Rusz⁹, Istvan Csabai¹⁰, Michael Cecchini¹¹, Yasmine Baca¹², Andrew Elliott¹², Peter Enzinger^{2

3

6}, Harshabad Singh^{2

3

6}, Jessalyn Ubellaker¹³, Jean-Bernard Lazaro^{14

15}, James M Cleary^{2

3

6}, Zoltan Szallasi^{16

17

18}, Nilay S Sethi^{19

20

21

22}

Affiliations

¹ Danish Cancer Institute, Copenhagen, Denmark.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.
⁵ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.
⁶ Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁷ Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁸ Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary.
⁹ 2nd Department of Pathology, SE NAP, Brain Metastasis Research Group, Semmelweis University, Budapest, Hungary.
¹⁰ Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary.
¹¹ Department of Medical Oncology, Center for Gastrointestinal Cancers, Yale Medical Center, New Haven, CT, USA.
¹² Caris Life Sciences, Phoenix, AZ, USA.
¹³ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁴ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁵ Center for DNA Damage and Repair (CDDR), Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁶ Danish Cancer Institute, Copenhagen, Denmark. [email protected].
¹⁷ Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA. [email protected].
¹⁸ Department of Bioinformatics and Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary. [email protected].
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
²⁰ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
²¹ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA. [email protected].
²² Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].

^# Contributed equally.

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.

Abstract

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