Gene signature points to prognosis in kidney cancer

“This could potentially become a tool to gain a better understanding of the course of the disease at an early stage. Patients with a cancer profile with a high probability of spreading could then be monitored more closely, to quickly detect and treat any growth of the tumour,” says Ninib Baryawno, senior researcher at the Department of Women’s and Children’s Health, Karolinska Institutet, and the study’s last author.

Clear cell kidney cancer is the most common form of kidney cancer in adults. If the tumour is confined to the kidneys, the prognosis is often favourable, but if it has spread to the skeleton, which occurs in about a third of patients, the five-year survival rate is only about ten per cent.

Can develop resistance to the treatment

Immunotherapy known as checkpoint inhibitors have in recent years become an important treatment for patients with clear cell kidney cancer. But it is common for the cancer cells to develop resistance to the treatment, which may partly be attributed to factors in the environment around the cancer cells, the so-called tumour microenvironment.

In the current study, the researchers examined samples from nine patients with clear cell kidney cancer. The study is a collaboration between researchers at Karolinska Institutet, clinicians at Massachusetts General Hospital, where the patients were recruited, and computational scientists from Harvard Medical School in Boston, USA.

Both tumour tissue and nearby normal kidney tissue were collected from the same patient to be able to make matched comparisons and control for inter-individual variation. The cells were studied by single-cell analysis; a sequencing technique that makes it possible to investigate each single cell in the tissue and the gene expression, that is, which genes are active, in individual cells.

In two patients, the researchers also compared primary tumour tissue from the kidney with tissue from skeletal metastases.

Gene signature predicted risk of spreading

The study demonstrates that a genetic signature consisting of four specific genes is predictive of whether the tumour will spread to the skeleton and of survival. Simultaneous overexpression of these genes (SAA1, SAA2, APOL1 and MET) suggests that the patient has a greater risk of developing a tumour that spreads and a poorer survival outcome.

The association of the gene signature to the risk of spreading was also confirmed when the researchers examined tumour cells from bone metastases in seven patients with metastatic clear cell kidney cancer.

Moreover, the study shows that the microenvironment of the tumour inhibits the immune system, and the researchers suggest several possible targets for drugs that may be interesting to investigate further. These were identified with computer simulations of cell interactions.

The study provides important biological knowledge about the interaction between tumour cells and their microenvironment in clear cell kidney cancer, the researchers say.

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