Genomic structural variant may drive development of rare kidney cancer

Investigators have identified rearrangements of the NOTCH1 gene that may contribute to the development of reninoma, a rare form of renal cancer.^1,2

The investigators examined 2 cases of reninoma–one in a pediatric patient with a localized tumor and another in a young adult with metastatic reninoma.

The data were published in Nature Communications.¹

For the study, the investigators examined 2 cases of reninoma–one in a pediatric patient with a localized tumor and another in a young adult with metastatic reninoma. Somatic changes were assessed via whole genome and bulk RNA sequencing. The first patient was enrolled in the UMBRELLA study, and the second patient was enrolled in the Characterisation of the immunological and biological markers or Renal cancer progression study.

The investigators identified a 0.8 MB deletion on chromosome 9q that was present in both patient tumors. The pediatric patient’s deletion was determined to be from a single deletion event, whereas the young adult patient’s deletion was determined to be the cause of a more complex configuration that included intragenic NOTCH1 inversion between intron 27 and intron 28.

Further, both tumors showed truncation of the NOTCH1 gene within the regulatory region of the extracellular domain, which activated NOTCH1 while removing NRARP, one copy of the NOTCH1 inhibitor that negatively regulates NOTCH1 signaling.

The data were then validated through RNA sequencing and corroborated with published reninoma transcriptomes. The NOTCH1 gene was found to be overexpressed in reninoma compared with mesoblastic nephroma, Wilms tumor, renal cell carcinoma, and normal kidney (P < .05). Overexpression of NOTCH1 was further found when compared with normal human mesangial-like cells using single-cell data (P < .05).Excessive renin was also observed upon immunofluorescence of reninoma, which also confirmed the overexpression of NOTCH1.

“Rare cancers are exceedingly challenging to study, and patients with such tumors may therefore not benefit from cancer research. Here, we have a powerful example of cutting-edge science rewriting our understanding of an ultra-rare tumor type, reninoma, whilst delivering a finding that potentially has immediate clinical benefits for patients,” said Sam Behjati, BMBCh, PhD, MRCPCH, in a news release on the findings.² Behjati is a senior research fellow at the Wellcome Sanger Institute and honorary consultant in pediatric oncology at Addenbrooke’s Hospital in Cambridge, England.

According to the authors, the findings suggest that drug therapies targeting this gene may serve as an alternative treatment option for patients in whom surgery is not recommended.

“Rare kidney cancers known as reninomas do not respond to conventional anti-cancer therapies. The only known treatment at the moment is surgery. Our study shows that, actually, there is a specific and well-studied gene that drives this rare cancer. If we use already known drugs that affect this gene, we might be able to treat it without the need for an invasive technique such as surgery,” commented Tanzina Chowdhury, MD, in the news release.² Chowdhury is a consultant pediatric oncologist at Great Ormond Street Hospital in London, England.

References

1. Treger TD, Lawrence JEG, Anderson ND, et al. Targetable NOTCH1 rearrangements in reninoma. Nat Commun. 2023;14(1):5826. doi:10.1038/s41467-023-41118-8

2. Genetic code of rare kidney cancer cracked. News release. Wellcome Trust Sanger Institute. September 25, 2023. Accessed September 27, 2023. https://www.newswise.com/articles/rare-kidney-cancer-code-cracked