Partner and localizer of BRCA2 (PALB2) pathogenic variants and ovarian cancer: A systematic review and meta-analysis.

person Priyanka Narayan Weill Cornell Medicine, New York, NY info_outline Muhammad Danyal Ahsan, Shanice Beaumont, Jenny Lin, Luiza Perez, Leslie Bull, Isabel Wolfe, Andy Hickner, Eloise Chapman-Davis, Evelyn Cantillo, Kevin Holcomb, Ravi Sharaf, Melissa Kristen Frey, Priyanka Narayan

Authors person Priyanka Narayan Weill Cornell Medicine, New York, NY info_outline Muhammad Danyal Ahsan, Shanice Beaumont, Jenny Lin, Luiza Perez, Leslie Bull, Isabel Wolfe, Andy Hickner, Eloise Chapman-Davis, Evelyn Cantillo, Kevin Holcomb, Ravi Sharaf, Melissa Kristen Frey, Priyanka Narayan Organizations Weill Cornell Medicine, New York, NY, Weill Cornell Medical College, New York, NY, New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY Abstract Disclosures Research Funding No funding received Background: Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), there are other genes for which the cancer risk is less certain and management recommendations remain controversial, including partner and localizer of BRCA 2 (PALB2). We sought to evaluate the association between PALB2 germline pathogenic mutations and ovarian cancer in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO no.: CRD42021281325). We searched key electronic databases to identify studies evaluating multigene panel testing in patients with ovarian cancer. Eligible trials were subjected to meta-analysis. Results: Thirty-seven studies met inclusion criteria. We found 55,137 cases of ovarian cancer with information available on germline PALB2 pathogenic variant status. Reported histological subtypes included serous adenocarcinoma (74.8%), endometroid (6.5%), clear cell (2.1%), mucinous (3.1%), and other (13.5%). Most ovarian cancers were stages III (73.5%) and IV (22.3%), followed by II (6.0%), and I (4.1%). Among ovarian cancer cases with PALB2 sequencing data available, 0.4% demonstrated a germline pathogenic variant in the PALB2 gene and the pooled odds ratio (OR) for having a PALB2 mutation was 2.31 (95% CI 0.89- 5.98). Among 94 patients with a germline PALB2 pathogenic variant, the pooled odds ratio (OR) for developing ovarian cancer was 2.85 (95% CI 1.58-5.15) relative to 33,855 patients without PALB2 mutations. Conclusions: Our meta-analysis demonstrates that the pooled OR for developing ovarian cancer with an underlying PALB2 germline pathogenic variant was 2.85 (95% CI 1.58-5.15). While this risk is lower than many of the well-established hereditary ovarian cancer genes, it does exceed the baseline population risk of 1-2%. Whether this meets the threshold to consider risk-reducing salpingo-oophorectomy is up for debate. Large population-based studies and evaluation of the combination of PALB2 mutations and cancer family history are needed to improve management recommendations for patients harboring pathogenic mutations in this gene.