Abstract
BackgroundBAP1 and PBRM1 are frequently mutated in primary clear cell renal cell carcinoma (ccRCC) tumors; however, the frequency and clinical relevance of these mutations in metastatic ccRCC tumors is unknown. Additionally, while intra-tumor heterogeneity has been shown to be common in primary ccRCC, little is known regarding heterogeneity in metastatic ccRCC tumors.Materials and methodsWe analyzed BAP1 and PBRM1 loss of protein expression in patient-matched primary and metastatic tumors from 97 patients. Expression was determined using a validated immunohistochemistry assay, which has been shown to be correlated with mutation status.ResultsOf the 97 patients evaluated, 20 and 57% showed loss of BAP1 and PBRM1 in their primary tumors, respectively. Comparing expression across patient-matched primary-metastatic tumor pairs, 98 and 90% had concordant BAP1 and PBRM1 expression, respectively. Both patients who demonstrated discordant BAP1 expression showed loss of BAP1 expression during progression to metastatic ccRCC. Similarly, seven of the ten patients that demonstrated discordant PBRM1 expression showed loss of PBRM1 expression during progression to metastatic ccRCC. We evaluated intra-metastatic tumor heterogeneity using 12 patients who had multiple blocks available from the same tumor with representative pathology; 100 and 92% showed concordant BAP1 and PBRM1 expression, respectively. Amongst 32 patients who had serial metastatic tumors available, both BAP1 and PBRM1 had 97% concordant expression.ConclusionsWe observed minimal intra- and inter- tumor heterogeneity in metastatic ccRCC tumors. Patients with discordant BAP1 or PBRM1 expression across their matched primary and metastatic tumors usually showed loss of expression during progression to metastatic ccRCC.
Highlights
BAP1 and PBRM1 are frequently mutated in primary clear cell renal cell carcinoma tumors; the frequency and clinical relevance of these mutations in metastatic ccRCC tumors is unknown
We evaluated intra-metastatic tumor heterogeneity using 12 patients who had multiple blocks available from the same tumor with representative pathology; 100 and 92% showed concordant BAP1 and PBRM1 expression, respectively
Concordance across patient-matched primary and metastatic ccRCC tumors BAP1 Of the available 111 patients, 97 (87%) primary ccRCC tumors successfully stained for BAP1 (Table 1) and 20% showed loss of BAP1 expression (IHC negative)
Summary
BAP1 and PBRM1 are frequently mutated in primary clear cell renal cell carcinoma (ccRCC) tumors; the frequency and clinical relevance of these mutations in metastatic ccRCC tumors is unknown. Mutations that cause loss of expression of BAP1 and PBRM1 are two of the most frequently occurring molecular events in primary clear cell renal cell carcinoma (ccRCC) with a prevalence of approximately 10 and 40%, respectively [1,2,3]. Both of these genes are located on chromosome arm 3p, which is deleted in approximately 90% of ccRCC patients. The value of this initial exploration notwithstanding, investigations focused on larger cohorts of patients with matched primary and metastatic ccRCC tumors are necessary to obtain estimates of the prevalence of BAP1 and PBRM1 mutations in metastatic ccRCC tumors and to better inform the potential value of these alterations as potential biomarkers for response to therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
