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.

Cardiac angiosarcoma: histopathologic, immunohistochemical, and cytogenetic analysis of 10 cases.

Angiosarcoma (AS) is the most common cardiac sarcoma with differentiation, and is poorly characterized from a molecular genetic standpoint. Prognosis remains poor, owing to several factors including aggressive tumor biology, poor response to adjuvant therapy, and lack of targeted therapy. The clinical, pathologic and molecular cytogenetic features were studied in ten cardiac AS surgically resected at Mayo Clinic (1994-2015) using a whole-genome, single-nucleotide polymorphism-based platform (OncoScan). Mean patient age was 47.8 years, male/female ratio was 1:1.5, and overall median survival was 5.2 months. The most common location was the right atrium (n=7), with one case each occurring in the epicardium, pericardium, and right ventricle. No patients had received thoracic irradiation. The most common morphology was spindle cell (n=8), with one case each of epithelioid and biphasic. ERG was the most sensitive vascular marker, with diffuse immunoreactivity in all cases. Several recurrent (present in at least 3 cases) aberrations were identified, including trisomies in chromosomes 4, 8, 11, 17, 20, as well as 1q+, and homozygous deletion of CDKN2. Patients who received adjuvant therapy had longer overall survival than those who did not (median 13.4 vs 3.2 months; P=.0283). There were no significant associations between tumor location, histology, immunohistochemical findings, cytogenetic profile, and clinical outcome; however, there was a trend towards improved overall survival in patients with tumors harboring 1q+(median 31.8 vs 3.7 months, P=.06). This study confirms recurrent cytogenetic aberrations in cardiac AS, some of which may have prognostic or predictive implications.