iscoveries in one cancer type may hold clues to
understanding seemingly unrelated cancers of
other types as well. In the case of uveal
D
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 metastasisfree
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 tradi-
tionally 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.
References
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
Kidney Cancer Journal 61
Uveal Melanoma and Kidney Cancer:
More Similar than Meets the Eye
Nirmish Singla, MD, MSCS
Urology Service, Department of Surgery
Memorial Sloan Kettering Cancer Center
New York, NY
Keywords: uveal melanoma, clear cell renal cell carcinoma, BAP1,
chromosome 3, prognosis, treatment
Corresponding Author: JNirmish Singla, MD, MSCS, 1275 York Ave.
New York, NY 10065 Phone: (248) 761-2452.
Email: nirmish@gmail.com
link