Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors.

Testicular germ cell tumors (TGCTs) are the most common cancers in men aged 15-39 years, and are divided into two major groups, seminomas and non-seminomas. Novel treatment options are required for these patients, to limit side effects of chemotherapy. We hypothesized that promoter methylation of relevant homologous recombination (HR) genes might be predictive of response to poly-ADP ribose polymerase inhibitors (PARPis) in TGCTs. We report a study pipeline combining in silico, in vitro and clinical steps. By using several databases and in silico tools, we identified BRCA1, RAD51C, PALB2, RAD54B and SYCP3 as the most relevant genes for further investigation, and pinpointed specific CpG sites with pronounced negative correlation to gene expression. Non-seminomas displayed significantly higher methylation levels for all target genes, where increased methylation was observed in patients with more differentiated subtypes and higher disease burden. We independently performed second-line targeted validation in tissue series from TGCT patients. A moderate and/or strong anti-correlation between gene expression (assessed by RNA-sequencing) and promoter methylation (assessed by 450k array) was found, for all of the targets. As a proof of concept, we demonstrated the sensitivity of TGCT cell lines to Olaparib, which associated with differential methylation levels of a subset of targets, namely BRCA1 and RAD51C. Our findings support the use of HR genes promoter methylation as a predictor of the therapeutic response to PARPis in patients with TGCT.

Molecular oncology. 2021 Jan 29 [Epub ahead of print]

João Lobo, Vera Constâncio, Catarina Guimarães-Teixeira, Pedro Leite-Silva, Vera Miranda-Gonçalves, José Pedro Sequeira, Laura Pistoni, Rita Guimarães, Mariana Cantante, Isaac Braga, Joaquina Maurício, Leendert Hj Looijenga, Rui Henrique, Carmen Jerónimo

Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto) & Porto Comprehensive Cancer Center (P.CCC), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal., Department of Urology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal., Department of Medical Oncology, Portuguese Oncology Institute of Porto (IPOP), R. Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal., Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, The Netherlands.

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