BAP1-defficient breast cancer in a patient with BAP1 cancer syndrome

Abstract

BAP1 cancer syndrome is a rare and highly penetrant hereditary cancer predisposition. Uveal melanoma, mesothelioma, renal cell carcinoma (RCC) and cutaneous melanoma are considered BAP1 cancer syndrome core cancers, whereas association with breast cancer has previously been suggested but not confirmed so far. In view of BAP1 immunomodulatory functions, BAP1 alterations could prove useful as possible biomarkers of response to immunotherapy in patients with BAP1-associated cancers. We present a case of a patient with BAP1 cancer syndrome who developed a metastatic breast cancer with loss of BAP1 demonstrated on immunohistochemistry. She carried a germline BAP1 likely pathogenic variant (c.898_899delAG p.(Arg300Glyfs*6)). In addition, tumor tissue sequencing identified a concurrent somatic variant in BAP1 (partial deletion of exon 12) and a low tumor mutational burden. As her triple negative tumor was shown to be PD-L1 positive, the patient was treated with combination of atezolizumab and nab-paclitaxel. She had a complete and sustained response to immunotherapy even after discontinuation of nab-paclitaxel. This case strengthens the evidence for including breast cancer in the BAP1 cancer syndrome tumor spectrum with implications for future cancer prevention programs. It also indicates immune checkpoint inhibitors might prove to be an effective treatment for BAP1-deficient breast cancer.

Regulation of Med1 protein by overexpression of BAP1 in breast cancer cells

“…However, Med1 protein was increased by the overexpression of BAP1 and decreased by BAP1 C91A overexpression. Various studies have reported that BAP1 acts as a tumor suppressor by binding BRCA1 in breast cancer [13] and BAP1 cancer syndrome, in which metastatic breast cancer develops with loss of BAP1 protein expression [29]. Overexpression of BAP1 in breast cancer is involved in the transcriptional regulation of ER by stabilizing the Med1 protein.…”

Modulation of the ubiquitin‐proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors

“…127,128 Loss of functional BAP1 is associated with tumorigenesis or BAP1 cancer syndrome, which involves uveal melanoma, mesothelioma, renal cell carcinoma (RCC), HCC, cutaneous melanoma, and breast cancer. [129][130][131] Further, the BAP1 expression has been lower in human lung adenocarcinoma samples than in normal samples and is positively correlated with patient survival. Observations in an animal model of lung adenocarcinoma demonstrated the reduction of BAP1 level during tumor growth that was associated with the reduction of KELCH-ECH-associated protein 1 (Keap-1) expression and increased nuclear factor E2-related factor-2 (Nrf-2, a redox-sensitive transcription factor) activity as well as suppression of oxidative stress.…”

“…It also affects cell cycle proteins, mitochondrial function, cell survival, tumor metabolism, and immune responses 127,128 . Loss of functional BAP1 is associated with tumorigenesis or BAP1 cancer syndrome, which involves uveal melanoma, mesothelioma, renal cell carcinoma (RCC), HCC, cutaneous melanoma, and breast cancer 129–131 . Further, the BAP1 expression has been lower in human lung adenocarcinoma samples than in normal samples and is positively correlated with patient survival.…”