MTAP
loss in primary kidney tumors: A comprehensive genomic profiling study.
Authors: Goodman Alexandra , Desai Devashish , Spiess Philippe E. , Li Roger , Grivas Petros , Kamat Ashish M. , Gupta Shilpa , Agarwal Neeraj , Singer Adam E. , Cheng Liang , Necchi Andrea , Jacob Joseph M , Mollapour Mehdi , Bratslavsky Gennady , Lin Douglas I , Pavlick Dean , Gjoerup Ole , Jamaspishvili Tamara , Ross Jeffrey S. , Basnet Alina 
Published: February 2025

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Background:
Kidney tumors (KT) comprises approximately 4% of all new cancer cases in US per year, with about a third being
de-novo
metastatic. 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway & has emerged as a putative biomarker for synthetic lethality-based trials testing Protein Arginine Methyltransferase 5 (PTMT5) & Metastasis-associated protein 2 (MTA2) inhibitors. We compared the genomic landscape in KT with vs without
MTAP
loss (del).
Methods:
From 541,919 consecutive cases of clinically advanced cancers, 5,467 consecutive cases of recurrent & metastatic KT underwent hybrid-capture based Comprehensive Genomic Profiling (CGP) to identify all classes of genomic alterations (GA), Microsatellite Instability (MSI) status, & tumor mutation burden (TMB). Programmed Cell Death Ligand 1 (PD-L1) expression was determined by IHC (Dako 22C3). Results were evaluated using the Fisher Exact method.
Results:
The overall
MTAP
del frequency in all KT was 10.9%. At 26.3%
MTAP
del frequency was highest in urothelial carcinoma (uCA) followed by not otherwise specified renal cell carcinoma (nosRCC) (13.3%), collecting duct (cdRCC) (12.5%), sarcomatoid (srcRCC) (11.7%), papillary (papRCC) (7.3%) & clear cell (ccRCC) (4.0%). Chromophobe & medullary RCC were devoid of
MTAP
del cases. Tendencies for patients with
MTAP
del KT to be slightly older & more often of male gender were noted. Across uCA & the RCC subtypes, the frequencies of driver GA were higher in
MTAP
del vs
MTAP
intact cases (Table).
CDKN2A
was co-deleted in 99.6% &
CDKN2B
in 92.8% cases of KT. For ccRCC the Von Hippel-Lindau (
VHL)
GA was higher in
MTAP
intact than
MTAP
del (76.4% vs 67.0%; p=.029). Biomarkers that may correlate with immune-checkpoint inhibitor efficacy, including MSI-high status (0-4%) & median TMB level (2.5-5 mutations/Mb), as well as PD-L1 low-high expression (29-69%), did not differ significantly by
MTAP
del status in all KT types.
Conclusions:
At 11% overall,
MTAP
del is a relatively common GA in advanced KT including uCA & RCC cases. MTAPdel was more frequent in non-clear cell RCC, collecting duct carcinomas, & sarcomatoid histology, generating hypotheses for targeted therapy clinical trials. Limitations include retrospective nature, lack of clinical data annotation, selection & confounding biases. Further evaluation of KT, including uCA & RCC, for
MTAP
del-enabled PTMT5 & MTA2 inhibitor trials seem warranted.

MTAPdel

Top GA in
MTAP
del

Top GA in
MTAPi
ntact

uCA
26.3%

FGFR3
34.7%,
PIK3CA
20.4%,
ERBB2
7.4%

FGFR3
25.4%,
PIK3CA
19.8%,
ERBB2
13.0%

nosRCC
13.3%

NF2
25.6%,
VHL
17.9%,
PTEN
12.8%

NF2
13.0%,
VHL
27.6%,
PTEN
5.1%

ccRCC
4.0%

VHL
67.0%,
PBRM1
33.0%,
BAP1
23.9%

VHL
76.4%,
PBRM1
45.9%,
BAP1
14.6%

papRCC
7.3%

ERBB2
8.3%,
MET
16.7%,
NF2
5.6%

ERBB2
1.7%,
MET
11.5%,
NF2
11.1%

srcRCC
11.7%

VHL
50.0%,
NF2
30.8%,
TP53
19.2%

VHL
39.8%,
NF2
18.9%,
TP53
37.8%

cdRCC
12.5%

NF2
33.3%,
SMARCB1
0%,
TERT
44.4%

NF2
25.4%,
SMARCB1
17.5%,
TERT
1.8%