Rare Kidney Cancer Marked by Molecular Features

Rare renal medullary carcinoma kidney cancers are marked by frequent focal chromosomal changes and other mutations that may inform future treatment strategies and renal medullary carcinoma (RMC) is a highly lethal malignancy. Men are twice as likely to be affected by RMC as women, and about 70% of RMC cases start from the right kidney.

A large team of medical scientists from the University of Texas MD Anderson Cancer Center (Houston, TX, USA), and other centers in the USA and France used a combination of exome sequencing, RNA sequencing, fluorescence in situ hybridization (FISH), and multiplex ligation-dependent probe amplification (MLPA) analyses, and assessed 31 untreated renal medullary carcinoma tumors and 15 matched normal samples, identifying several recurrent copy number changes in the kidney cancers, from chromosome 8 gains and chromosome 22 losses to upregulated Notch signaling- and innate immune-related pathways.

In general, the team's results revealed recurrent copy number changes falling at focal chromosomal sites, and chromosome sites prone to structural changes in individuals with sickle cell blood traits. Such findings might help to explain why renal medullary carcinoma diagnoses are more frequent in individuals with the sickle cell trait, the authors noted. The kidney cancer is also over-represented in younger individuals with African ancestry.

In contrast to the low number of focal copy number alterations (CNAs) found in malignant rhabdoid tumors (MRT) and atypical teratoid/rhabdoid tumors (ATRT), the authors said they found that renal medullary carcinoma harbors a much more complex genome with high levels of focal CNAs. They also found that the tumors tended to have enhanced DNA replication stress related to SMARCB1 mutations. The replication stress not only contributed to the focal copy number changes, the investigators suggested, but also seemed to increase activity by the MYC signaling pathway, producing tumors predicted to be more apt to respond to DNA-damage repair-targeting drugs.

The authors concluded that they had identified the importance of SMARCB1 loss as a major recurrent genetic alteration in renal medullary carcinoma and found that it confers replication stress-induced vulnerabilities that can be therapeutically targeted. These results highlight a potential opportunity to utilize agents targeting replication stress pathways alone or in combination with other therapies to yield deep and durable therapeutic responses. The study was published on April 30, 2020 in the journal Cancer Cell.

Related Links:
University of Texas MD Anderson Cancer Center