Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma

Molecular hallmarks of renal medullary carcinoma: more to c-MYC than meets the eye

“… 1 , 4 Our transcriptomic analysis suggested that both RMC and CDC originate from the collecting ducts, in contrast to kidney MRTs. 3 Furthermore, the gene expression signature of RMC clearly distinguished this disease from UTUC and kidney MRT, whereas it shared similar core metabolic and hypoxia-associated gene expression patterns with CDC. 3 Conversely, pathways associated with MYC-induced replication stress were significantly upregulated in RMC compared with CDC tumors.…”

“…We accordingly investigated the molecular landscape of RMC by performing comprehensive genomic and transcriptomic profiling of untreated primary RMC tisses. 3 To determine features unique to RMC, we compared our data to that of other closely related malignancies including collecting duct carcinoma (CDC), upper tract urothelial carcinoma (UTUC) and kidney malignant rhabdoid tumors (MRT). This integrative strategy produced new insights into the immune microenvironment of RMC, and identified a complex RMC genome harboring recurrent focal copy number alterations (CNAs).…”

“…We further established a tumor-derived cell line and patient-derived xenograft (PDX) model of RMC, which allowed us to investigate a new treatment approach that exploits the therapeutic vulnerability to DNA damage repair (DDR) inhibition that we discovered characterizes this highly malignant tumor. 3 …”

“…However, RMC is characterized by an abundance of larger structural alterations such as recurrent focal copy number alterations (often in chromosomal fragile sites), gain of chromosome 8q (where c-MYC is located), as well as deletions and inactivating translocations of the SMARCB1 gene. 3 Notably, we previously postulated that red blood cell sickling in the hypoxic renal medulla of individuals with sickle cell trait can induce such chromosomal structural alterations, particularly in known hotspots for genomic rearrangements. 2 …”

“…CDC arises from the same anatomical epicenter within the renal medulla and is morphologically very similar to RMC but expresses SMARCB1 by immunohistochemistry and is not associated with sickle hemoglobinopathies. 1 – 3 UTUC originates anatomically close to the renal medulla and is treated with similar platinum-based cytotoxic chemotherapy regimens to those used for RMC. 1 MRT is negative for SMARCB1 by immunohistochemistry and can often arise from the kidney but morphologically appears like an undifferentiated rhabdoid malignancy, whereas RMC manifests as a high grade adenocarcinoma.…”