Expression of the Transcriptional Regulators BAP1 and Cyclin D1 in Malignant Pleural Mesothelioma
Mark J Mentrikoski, Akeesha A Shah, Henry F Frierson, Mark R Wick, Edward B Stelow. University of Virginia, Charlottesville, VA
Background: It has recently been shown that some families with germline mutations of the gene encoding breast cancer associated protein-1 (BAP1) are at risk for developing malignant mesotheliomas (MMs) and other cancers. Furthermore, it has been shown that up to 40% of apparently non-familial cases of MM have mutations of the gene or loss of its protein expression. It has also been shown that more than 40% of MMs have inactivation of the NF2 tumor suppressor gene, which is hypothesized to play a role in the regulation of G1 cell cycle progression through inhibition of Cyclin D1 expression. Here, to help elucidate the molecular changes seen in MM, we investigate the expression of these two regulators of transcription, BAP1 and Cyclin D1, in a large series of MMs.
Design: 53 cases of MM (33 epithelioid, 9 sarcomatoid, and 11 biphasic) were identified and a tissue microarray was constructed. A microarray was constucted of 21 cases of pleuritis. Immunohistochemistry was performed using monoclonal antibodies against Cyclin D1 and BAP1. Tumor cells were assessed for nuclear staining for both antibodies. For Cyclin D1, the percentage of tumor cells showing positive nuclear staining was recorded and the intensity of staining was graded as weak, moderate, or strong. For BAP1, complete absence of nuclear stain was recorded.
Results: 70% of MM showed nuclear staining for Cyclin D1. The majority (29 of 37) were positive in >25% of tumor cells, with 45% (17 of 37) of cases showing staining in in >75% of tumor cells. The staining intensity was strong in most cases. 14% cases of fibrosing pleuritis showed nuclear staining in 10-25% of cells. Loss of BAP1 nuclear staining was seen in 37% of MM cases (figure: left-intact; right-loss).
Conclusions: Cyclin D1 overexpression is detectable in the majority of MM cases, but in a larger percentage of cases than those reported to have inactivation of the NF2 tumor suppressor gene. This suggests that other factors likely play a role in its over-expression. Since Cyclin D1 is rather sensitive and specific for MM, it could be a valuable biomarker in cases with borderline morphology. We confirm a previous report regarding BAP expression in MM and show that nuclear expression of BAP1 is lost in 37% of apparently sporadic cases.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 297, Wednesday Morning