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of specific type 2 pRCC alterations, including FH mutations
(13%) that account for Warburg-like metabolic shifts, NF2
mutations (13%) that are involved in Hippo pathway
activation, and SWI/SNF chromatin remodeling complex
alterations (28%) that might induce genome-wide repro-
gramming. More comprehensive molecular profiling,
including detection of MITF family fusion transcripts,
will be needed to further assess the prevalence of MITF
family translocations , present in 12% of type 2 pRCCs
in the TCGA dataset . The overlap of pRCC tumors
harboring FH mutations with HLRCC and collecting duct
carcinomas also represents a gray zone that must be
explored.
The work by Pal et al is of major importance, notably
because their large collection is enriched in cases considered
as advanced papillary RCC. Thus, their findings may lead to
rational therapies and benefit patients with metastatic
disease. Clinical trials targeting MET in type 1 pRCCwithMET
alterations (NCT01524926, NCT02761057) are ongoing.
Given the wide range of genomic alterations reported in
this cohort of diverse pRCCs, the integration of molecular
profiling into clinical routine is of utmost importance.
However, advanced models are needed to identify the most
important oncogenic drivers, as various putative oncogenic
mutations might co-occur in the same tumor. We should
keep in mind that previous developments of targeted
therapies such as MTOR inhibition in pRCC ended up in
disappointment without proper selection of patients . It
will also be necessary to closely study tumor heterogeneity
between the primary tumor and metastatic localizations to
understand the shift from indolent local tumors to extensive
disease. Taking the next step in the fight against advanced
pRCCs will require an understanding of the influence of the
coding and noncoding genome of metastatic pRCCs via
analysis of whole-genome sequencing. In the era of
immunotherapy, definition of the tumor microenvironment
and intratumor immunity is also urgently needed. Therefore,
new integrative models for histological and molecular
analysis of pRCCs will be needed in the near future to
define distinct phenotypic and molecular portraits of pRCC
subgroups.
Conflicts of interest: The authors have nothing to disclose.
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