Corresponding Author: JNirmish Singla, MD, MSCS, 1275 York Ave. New York, NY 10065 Phone: (248) 761-2452. Email:email@example.com
Discoveries in one cancer type may hold clues to understanding seemingly unrelated cancers of other types as well. In the case of uveal melanoma (UM), Rodrigues et al. used comparative genomic hybridization assays to demonstrate that partial deletion of chromosome 3 encompassing the BAP1 locus was associated with strikingly worse 5-year metastasis-free and overall survival.1 Their findings resonate with the seminal study by Harbour et al., which originally implicated BAP1 loss in UM metastasis.2
Notably, chromosome 3 plays an integral role in the pathogenesis of the most common type of kidney cancer as well, clear cell renal cell carcinoma (ccRCC). In particular, loss of chromosome 3p occurs in the majority of ccRCC cases, leaving the alleles on the remaining short arm of chromosome 3 susceptible to genetic alterations.3 In line with Knudson’s two-hit hypothesis, the most common driver mutations found in ccRCC involve the tumor suppressor genes found within a short stretch on chromosome 3p, including the histone deubiquitinase gene BAP1 in up to 15% of sporadic cases. As in the case of UM, loss of the BAP1 protein has been consistently associated with more aggressive forms of disease and worse prognostic outcomes in ccRCC patients, leading further to the development of distinct molecular subclassifications of ccRCC. In a similar manner, Rodrigues et al. speculate on different prognostic subtypes of UM defined by the presence of BAP1 alterations and/or chromosome 8q gains.1
This unique genomic similarity between ccRCC and UM—which also extends to include mesothelioma among other malignancies within the spectrum of the BAP1 tumor predisposition syndrome—leads one to question whether there may be a targetable role for BAP1 that can be useful in designing therapeutic basket trials. A possible predictive role for BAP1 in informing response to immune checkpoint inhibitors has been postulated in both ccRCC via human endogenous retroviral expression4 and in malignant mesothelioma.5 Although response to systemic immunotherapy has been traditionally less robust for metastatic UM compared to its cutaneous counterpart, perhaps the molecular landscape may guide a more precise approach to treatment and improve outcomes for these patients.
1. Rodrigues M, Ait Rais K, Salviat F, et al. Association of Partial Chromosome 3 Deletion in Uveal Melanomas With Metastasis-Free Survival. JAMA Ophthalmol. 2020.
2. Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science. 2010;330(6009): 1410-1413.
3. Brugarolas J. Molecular genetics of clear-cell renal cell carcinoma. J Clin Oncol. 2014;32(18):1968-1976.
4. Panda A, de Cubas AA, Stein M, et al. Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma. JCI Insight. 2018;3(16).
5. Ladanyi M, Sanchez Vega F, Zauderer M. Loss of BAP1 as a candidate predictive biomarker for immunotherapy of mesothelioma. Genome Med. 2019;11(1):18.KCJ