xenograft) RNA-sequencing data, an empirical approach,
DisHet, was able to dissect the tumor microenvironment
(eTME). Using eTME, genomics, pathology, and medical
record data involving >1,000 patients, the study established
an inflamed pan-RCC subtype (IS) enriched for
regulatory T cells, natural killer cells, TH1 cells, neutrophils,
macrophages, B cells, and CD8+ T cells. IS is
enriched for aggressive RCCs, including BAP1-deficient
clear-cell and type 2 papillary tumors. The IS subtype correlated
with systemic manifestations of inflammation such
as thrombocytosis and anemia, which are enigmatic
predictors of poor prognosis. Furthermore, IS was a strong
predictor of poor survival. The analyses suggest that tumor
cells drive the stromal immune response. These data
provide a missing link between tumor cells, the TME,
and systemic factors.
Conclusion: the authors undertook a novel empirical approach
to dissect the RCC TME by leveraging tumorgrafts.
The dissection and downstream analyses uncovered
missing links between tumor cells, the TME, systemic
manifestations of inflammation, and poor prognosis.
The classification of pediatric and young adult renal
cell carcinomas registered on the children’s oncology
group (COG) protocol AREN03B2 after focused genetic
testing. Cajaiba MM, Dyer LM, Geller JI, et al. Cancer. 2018
Aug;124(16):3381-3389.
Summary: Renal cell carcinomas (RCCs) are rare in young
patients. Knowledge of their pathologic and molecular
spectrum remains limited, and no prospective studies have
been performed to date in this population. This study
analyzed patients diagnosed with RCC who were prospectively
enrolled in the AREN03B2 Children’s Oncology
Group (COG). The objective was to classify these tumors
with the aid of focused genetic testing and to characterize
their features. All tumors registered as RCC by central
review were retrospectively re-reviewed and underwent
additional ancillary studies. Tumors were classified according
to the 2016 World Health Organization classification
system when possible. In total, 212 tumors were identified,
and these were classified as microphthalmia transcription
factor (MiT) translocation RCC (MiT-RCC) (41.5%), papillary
RCC (16.5%), renal medullary carcinoma (12.3%),
chromophobe RCC (6.6%), clear cell RCC (3.3%), fumarate
hydratase-deficient RCC (1.4%), and succinate dehydrogenase
deficient RCC (0.5%). Other subtypes included
tuberous sclerosis-associated RCC (4.2%), anaplastic
lymphoma kinase (ALK)-rearranged RCC (3.8%), thyroidlike
RCC (1.4%), myoepithelial carcinoma (0.9%), and
unclassified (7.5%). MiT-RCCs were classified as either
transcription factor E3 (TFE3) (93.2%) or EB (TFEB) (6.8%)
translocations, and characterization of fusion partners was
possible in most tumors.
Conclusion: The current study delineates the frequency of
distinct RCC subtypes in a large prospective series of
94 Kidney Cancer Journal
young patients and contributes knowledge to the diagnostic,
clinical, and genetic features of MiT-RCC, the most
common subtype among this age group. The identification
of rare subtypes expands the spectrum of RCC in young
patients, supporting the need for a thorough diagnostic
workup. These studies may aid in the introduction of
specific therapies for different RCC subtypes in the future.
Prevalence of germline mutations in cancer susceptibility
genes in patients with advanced renal cell
carcinoma. Carlo MI, Mukherjee S, Mandelker D, et al.
JAMA Oncol. 2018 Sep 1;4(9):1228-1235.
Summary: The prevalence of cancer-related germline
mutations in patients with advanced RCC and the phenotypes
associated with some rare mutations are unknown.
This study examined the prevalence of germline mutations
in both known RCC predisposition genes and other
cancer-associated genes and to identify clinical and pathologic
factors associated with germline mutations. In this
2-year cohort study, 254 of 267 patients with advanced
(American Joint Committee on Cancer stage III or IV) RCC
who were seen in medical oncology or urology clinics
agreed to germline sequencing and disclosure of results.
Mutation prevalence and spectrum in patients with advanced
RCC were determined. Clinical characteristics were
assessed by mutation status. Of the 254 patients (median
age range, 56 13-79 years; 179 70.5% male; 211
83.1% non-Hispanic white), germline mutations were
identified in 41 (16.1%); 14 (5.5%) had mutations in
syndromic RCC-associated genes (7 in FH, 3 in BAP1, and
1 each in VHL, MET, SDHA, and SDHB). The most frequent
mutations were CHEK2 (n = 9) and FH (n = 7). Of genes not
previously associated with RCC risk, CHEK2 was overrepresented
in patients compared with the general population,
with an odds ratio of RCC of 3.0 ( P= .003). Patients with
non-clear cell RCC were significantly more likely to have
an RCC-associated gene mutation (9 11.7% of 74 vs 3
1.7% of 177), and 8 (10.0%) had a mutation in a gene
that could guide therapy. Of patients with mutations in
RCC-associated genes, 5 (35.7%) failed to meet current
clinical guidelines for genetic testing.
Conclusion: Of patients with non-clear cell RCC, more
than 20% had a germline mutation, of which half had the
potential to direct systemic therapy. Current referral criteria
for genetic testing did not identify a substantial portion
of patients with mutations, supporting the role of a more
inclusive sequencing approach.
KIM-1 as a blood-based marker for early detection of
kidney cancer: a prospective nested case-control study.
Scelo G, Muller DC, Riboli E, et al. Clin Cancer Res. 2018
Jul 23. doi: 10.1158/1078-0432.CCR-18-1496.
Summary: Kidney injury molecule-1 (KIM-1) has been
shown to be elevated in the plasma of RCC patients. This
study tested whether plasma KIM-1 could represent a
means of detecting RCC prior to clinical diagnosis. KIM-1
concentrations were measured in prediagnostic plasma
from 190 RCC cases and 190 controls nested within a
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