Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis

Author:

Casolino Raffaella12ORCID,Paiella Salvatore3,Azzolina Danila45,Beer Philip A.16ORCID,Corbo Vincenzo78,Lorenzoni Giulia4ORCID,Gregori Dario4ORCID,Golan Talia9ORCID,Braconi Chiara110,Froeling Fieke E. M.1,Milella Michele11,Scarpa Aldo78,Pea Antonio3,Malleo Giuseppe3ORCID,Salvia Roberto3,Bassi Claudio3,Chang David K.112ORCID,Biankin Andrew V.11213ORCID

Affiliation:

1. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom

2. Department of Medicine, University and Hospital Trust of Verona, Verona, Italy

3. General and Pancreatic Surgery Unit, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy

4. Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences, and Public Health, University of Padova, Padova, Italy

5. Research Support Unit, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy

6. Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom

7. Section of Pathology, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy

8. ARC-Net Research Centre, University of Verona, Verona, Italy

9. The Oncology Institute, Sheba Medical Center at Tel-Hashomer, Tel Aviv University, Tel Aviv, Israel

10. Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom

11. Section of Oncology, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy

12. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom

13. Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Liverpool, Australia

Abstract

PURPOSE To analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS We conducted a systematic review and meta-analysis of the prevalence of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes ( BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, RAD51, and the FANC genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline BRCA1/2 mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813). RESULTS Sixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was BRCA1: 0.9%, BRCA2: 3.5%, PALB2: 0.2%, ATM: 2.2%, CHEK2: 0.3%, FANC: 0.5%, RAD51: 0.0%, and ATR: 0.1%. Prevalence of germline mutations was BRCA1: 0.9% (2.4% in AJ), BRCA2: 3.8% (8.2% in AJ), PALB2: 0.2%, ATM: 2%, CHEK2: 0.3%, and FANC: 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD). CONCLUSION Surrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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