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Treatment Clues Gleaned From Molecular Features in Rare Kidney Cancer Type

NEW YORK – Rare renal medullary carcinoma kidney cancers are marked by frequent focal chromosomal changes and other mutations that may inform future treatment strategies, according to a new study from investigators at the University of Texas MD Anderson Cancer Center, the Baylor College of Medicine, and other centers in the US and France.

"[O]ur study has revealed several insights into the molecular foundations of [renal medullary carcinoma]," first and co-corresponding author Pavlos Msaouel, a genitourinary medical oncology and precision environmental health researcher affiliated with MD Anderson and Baylor, and his colleagues wrote in a paper published in Cancer Cell on Thursday.

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.

Using a combination of exome sequencing, RNA sequencing, fluorescence in situ hybridization (FISH), and multiplex ligation-dependent probe amplification (MLPA) analyses, the researchers 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 contrast to the low number of focal 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 copy number alterations.

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 bump up activity by the MYC signaling pathway, producing tumors predicted to be more apt to respond to DNA-damage repair-targeting drugs.

"[W]e 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," the authors explained. "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."

By digging into these and other findings in more detail using renal medullary carcinoma cell lines and in mice carrying patient-derived xenograft tumors, the investigators found that at least some drugs targeting DNA damage repair may have an impact on the kidney cancer subtype.

In their cell line experiments, for example, the authors saw hints that renal cell carcinoma cells missing SMARCB1were sensitive to PARP inhibitor drugs and drugs that inhibit the ATR kinase. Meanwhile, in mouse xenograft models treated with the PARP inhibitor niraparib or the kinase inhibitor AZD6738, alone or in combination, they saw significant tumor shrinkage in a group of five niraparib-treated mice.

Such findings "suggest the potential therapeutic value of targeting the PARP pathway alone or in combination with platinum chemotherapy in [renal medullary carcinoma]," they wrote.

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