NEW YORK — Researchers in the UK have found that aberrations in the NOTCH1 gene are the drivers of a rare kidney cancer called reninoma, suggesting that it might be treatable with existing NOTCH1 inhibitors.
The cancer, of which only about 100 cases have been reported to date, emerges from juxtaglomerular cells of the kidney. It causes the overproduction of renin, also called angiotensinogenase, an enzyme that regulates blood pressure. Although it can usually be cured with surgery, it can cause severe hypertension and metastasize, and no therapies currently exist to treat the condition.
A study published in Nature Communications on Monday, led by groups at the Wellcome Sanger Institute, Great Ormond Street Hospital, and the Royal Free Hospital, found how specific rearrangements in the NOTCH1 gene were key drivers of reninomas.
According to the authors, even though previous gene expression studies in reninoma have noted several dysregulated pathways, the leading genetic drivers of this rare cancer remained unknown. Meanwhile, prior investigations had found that NOTCH1 signaling was central to regulating renin secretion by juxtaglomerular cells; however, it hadn't been implicated in reninomas.
The researchers procured samples from two reninoma patients, a young adult with lung metastasis and a child. Next, they conducted whole-genome sequencing on the two primary tumors, a metastasis sample from the adult, blood cell-derived DNA from the child, and normal kidney samples from both cases, and noted the somatic changes.
One of the major findings was a 0.8 Mb deletion on chromosome 9q in the tumors of both patients. In the sample from the child, this was caused by a single deletion event, whereas in the adult cancer sample, in addition to the deletion, there was an intragenic NOTCH1 inversion between intron 27 and intron 28. "Annotation of breakpoints at the 5’ end revealed that NOTCH1 was truncated within the regulatory region of the extracellular domain in both cases, akin to activating rearrangements described in T-cell leukemia," they wrote.
Next, to study transcriptional changes due to the NOTCH1 inversion, the researchers generated single nuclei mRNA data from fresh frozen tissues of both primary tumors. They compared these with the expression profiles of normal mesangial-like kidney cells and found that the tumors expressed a high level of renin suggesting that the excess renin production in patients may result not only from an increased number of renin-producing cells but also from elevated renin transcription within each cell.
Subsequently, they reanalyzed the bulk transcriptomes of four previously published reninomas and found evidence of NOTCH1 signaling dysregulation, corroborating the new findings.
"As reninomas do not respond to conventional anticancer therapies, it may be reasonable to consider NOTCH1 inhibitors in patients with otherwise incurable reninoma," the authors concluded, adding that a child with a NOTCH1 rearranged metastatic glomus tumor was already successfully treated with NOTCH1 inhibitor.
Highlighting a limitation of the study, the authors noted that they could not access additional fresh frozen samples of reninoma, since the cancer is so exceedingly rare.