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Mechanism and vulnerability of BAP1 loss in tumor metastasis

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Understanding renal cancer molecular mechanisms

Mutations in a particular gene can lead to more aggressive tumours and distant metastasis, but there are no specific treatments for it. A crucial discovery by EU funded researchers will lead to better precision medicine in cancers with these mutations.

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Renal cancer is among the 10 most prevalent cancers arising in Western countries, with clear-cell renal cell carcinoma (ccRCC) being the most frequent subtype (75%). About 30% of patients with ccRCC present metastatic disease at diagnosis and another 30 % develop metastases after surgery. When metastatic, ccRCC remains largely incurable. Researchers from the German Cancer Consortium (DKTK) at the Essen University Hospital, previously discovered that the tumour suppressor BRCA1-associated protein 1 (BAP1) is inactivated in 15% of ccRCCs. They found that mutations in BAP1 are mutually exclusive with mutations of the tumour suppressor gene PBRM1. Furthermore, loss of BAP1 was associated with higher tumour grade, activation of the protein complex mTORC1, and poorer overall patient survival. However, tumours with PBRM1 loss were associated with a lower tumour grade and better overall survival. This initial molecular genetic classification of ccRCC may have tangible clinical implications since tumours with BAP1 loss display in general more aggressive pathological features and are more prone to metastasise. However, the molecular mechanism through which BAP1 loss induces metastasis and tumour aggressiveness remains elusive.

Regulation region identified

The EU-funded VulneraBAP1 project addressed this challenge with the support of the Marie Skłodowska-Curie programme. By investigating the molecular mechanism behind the repression of a miRNA cluster involved in metastasis by BAP1, researchers identified opportunities for therapies. A miRNA is a small non-coding RNA molecule that functions in RNA silencing and post-transcriptional regulation of gene expression. One of the Europe-wide initiative’s main objectives involved the identification and characterisation of the BAP1 protein complex that binds at the microRNA (miRNA) cluster promoter. According to Samuel Peña-Llopis, Junior Group Leader at DKTK: “We identified the minimal region of regulation of BAP1 to the promoter region and several interesting proteins by using mass spectrometry in collaboration with a proteomics group from the German Cancer Research Center.” Another important goal was identifying genetic vulnerabilities of BAP1 loss by a synthetic lethality strategy. Synthetic lethality occurs when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. Scientists validated several candidate ‘hits’ in vitro and are currently in the process of validating them in vivo using mouse models of metastasis. “We used the immunohistochemistry of BAP1 as a biomarker of BAP1 mutation, as well as a methodology to simultaneously extract genomic DNA, RNA, small RNA (including miRNA) and proteins from tissues for genomic analyses, which we previously developed. Our main finding was the identification of vulnerabilities of BAP1 loss that might be exploited therapeutically,” Peña-Llopis explains.

New treatments for patients

VulneraBAP1’s most exciting development is the translational potential for classifying patients with loss of BAP1, who are generally associated with more aggressive tumours, higher incidence of metastases and poor survival. VulneraBAP1 can use the loss of BAP1 in immunohistochemistry to identify patients with renal cancer or other tumors with mutations in BAP1 who would benefit from novel treatments developed by the project. “The project’s results will be used by doctors, clinical scientists and researchers to eventually benefit patients with cancer with mutations in BAP1, such as renal cell carcinoma, uveal melanoma, mesothelioma and cholangiocarcinoma,” concludes Peña Llopis.

Keywords

VulneraBAP1, BAP1, ccRCC, BAP1 loss, renal cancer, miRNA, mutations, metastases, synthetic lethality, clear-cell renal cell carcinoma

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9 October 2020