TFEB-VEGFA (6p21.1) co-amplified renal cell carcinoma: a distinct entity with potential implications for clinical management.
A subset of renal cell carcinomas shows TFEB overexpression secondary to MALAT1-TFEB gene fusion. As alternate mechanisms of TFEB overexpression are likely to have the same effect, we sought to determine the frequency of amplification of TFEB and the adjacent VEGFA gene at 6p21.1. As patients with metastatic renal cell carcinomas are managed with anti-VEGF therapies, we retrospectively assessed therapeutic response in patients with amplified tumors. Amplification status was analyzed for 875 renal cell carcinomas from our institution, a consultative case and 794 cases from The Cancer Genome Atlas. Cases were classified as having low level (5-10 copies), and high-level amplification (>10 copies), and were further analyzed for adjacent oncogene copy number status (n=6; 3 single-nucleotide polymorphism genomic microarray, 3 The Cancer Genome Atlas) and structural rearrangements (n=1; mate-pair sequencing). These were then reviewed for histopathology, immunophenotype, and response to VEGF-targeted therapy on follow-up. In all, 10/875 (1.1%) institutional cases, 1 consultative case, and 3/794 (0.4%) of The Cancer Genome Atlas cases showed TFEB high-level amplification, while 14/875 (1.6%) cases showed TFEB low-level amplification. All cases had associated VEGFA amplification. This was confirmed with evaluation for copy number changes (n=6). The 6p21.1 high and low-level amplified tumors occurred in adults (mean age: 66), with over half being ≥pT3 (13/25, 52%), and most showed oncocytic, tubulopapillary features and high grade (≥grade 3: 20/22, 91%). These were aggressive tumors with metastasis and death from renal cell carcinoma in 11 (of 24, 46%) cases. Four patients received targeted therapy and had a mean survival of 31 months (range: 17-50) post nephrectomy. In summary, a group of aggressive renal cell carcinomas show genomic amplification of the 6p21.1 region including TFEB and VEGFA genes and share morphologic features. Additional studies are warranted to determine whether these patients respond to anti-VEGF therapy.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Sounak
S
Gupta
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Sarah H
SH
Johnson
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
George
G
Vasmatzis
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Binu
B
Porath
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Jeannette G
JG
Rustin
Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA.
Priya
P
Rao
Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
Brian A
BA
Costello
Department of Urology, Mayo Clinic, Rochester, MN, USA.
Bradley C
BC
Leibovich
Department of Urology, Mayo Clinic, Rochester, MN, USA.
R Houston
RH
Thompson
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
John C
JC
Cheville
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
William R
WR
Sukov
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C064972:TFEB protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A