Introduction:

While renal AML is generally a benign tumor, malignant eAML is a rare form of renal malignancy of uncertain histogenesis and variable prognosis. This CGP-based study was designed to identify genomic alterations (GA) associated with potential therapeutic targets in this uncommon tumor.

Methods:

Hybrid capture based CGP was performed on 38 cases of clinically advanced/metastatic renal eAML for all classes of GA. MSI status, gLOH, genomic ancestry, and gene signatures were determined by CGP. TMB was measured in mutations/Megabase (mut/Mb) of sequenced DNA. PD-L1 was measured by IHC using the DAKO 22C3 tumor cell proportional score (0%: negative; 1-49%: low positive).

Results:

The primary tumor was used for CGP in 16/38 (42.1%) and a metastatic tissue in 22/38 (57.9%) cases (12 liver, 3 lung, 4 retroperitoneum, 2 peritoneum; 1 psoas muscle). In a subset when either MART1 or HMB45 IHC staining was performed all (100%) cases were positive for either biomarker. There were 21 (55.2%) female and 17 (44.8%) male patients with mean age of 50.5 years (median 53 years). There were no MSI-high cases. The mean (1.54 mut/Mb) and median (1.3 mut/Mb) TMB were uniformly low. Of 5 malignant eAML cases tested, 4 (80%) were negative and 1 (20%) case was low PD-L1 expression. Short variant mutations were found in TSC2 in 27 (71.1%) cases, the other 8 (28.9%) were TSC2-wild type. Germline mutations in the malignant eAML cases included 2 (5.3%) TSC2 GA and 1 (2.6%) each in the TP53, ARID1A, BRCA2, CHEK2, EGFR, MUTYH, CD36, FLCN and FANCC genes, all of uncertain roles in the pathogenesis of these tumors. In addition to the TSC2 mutatations, other GA potentially implicating MTOR pathway based targeted therapies included GA in PTEN (5.2%) and NF2  (2.6%). Other identified GA currently considered as “non-targetable” included TP53 (34.2%) and CDKN2A/B, ATRX and RB1 all at 13.2%. GA potentially impacting PARPi use included BRCA2 (2.6%). In 28 evaluable cases, the mean gLOH was 6.3% (0-37.9%) with 3/28 malignant eAML (10.7%) featuring gLOH of >16%. In 34 evaluable cases, 26 (76.5%) patients were of EUR ancestry, 5 (14.7%) of AMR ancestry, 3 (8.8%) of AFR ancestry. No specific genomic signature characterized these cases.

Conclusion:

Renal malignant eAML also known as malignant PEComa of the kidney is an exceedingly rare tumor with propensity for malignant behavior that frequently displays a variety of germline mutations as well as GA indicative of potential efficacy of MTOR pathway inhibitors.

Funding: N/A