Genetic signature predicts tumor metastasis and patient survival in clear cell kidney cancer

Genetic signature predicts tumor metastasis and patient survival in clear cell kidney cancer

In patients with kidney cancer, the activity of four specific genes in the cancer cells appears to be able to predict the risk of tumor spread and the patient's chances of survival. This is what researchers from the Karolinska Institutet in Sweden show in a preclinical study published in Nature Communications.

This could potentially be a tool to better understand the disease progression 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 tumor growth.”

Ninib Baryawno, senior researcher, Department of Women and Children's Health, Karolinska Institutet, and final author of the study

Clear cell kidney cancer is the most common form of kidney cancer in adults. If the tumor is limited to the kidney, the prognosis is often favorable, but if it has spread to the skeleton, which occurs in around a third of patients, the five-year survival rate is only around ten percent.

Immunotherapies called checkpoint inhibitors have become an important treatment for patients with clear cell kidney cancer in recent years. However, it is common for cancer cells to develop resistance to treatment, in part due to factors in the cancer cells' environment, called the tumor microenvironment.

In the current study, 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 computer scientists at Harvard Medical School in Boston, USA.

Both tumor tissue and nearby normal kidney tissue were collected from the same patient to allow appropriate comparisons and to control for interindividual differences. The cells were examined using single-cell analysis; a sequencing technique that makes it possible to examine every single cell in the tissue and gene expression, i.e. which genes are active in individual cells.

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

The study shows that a genetic signature consisting of four specific genes is predictive of whether the tumor will spread to the skeleton and whether it will survive. The simultaneous overexpression of these genes (SAA1, SAA2, APOL1 and MET) suggests that the patient has a higher risk of developing a spreading tumor and a worse survival outcome.

The link between the gene signature and risk of spread was also confirmed when researchers examined tumor cells from bone metastases in seven patients with metastatic clear cell kidney cancer.

In addition, the study shows that the tumor microenvironment inhibits the immune system, and the researchers suggest several possible drug targets that could be interesting to study further. These were identified using computer simulations of cell interactions.

The study provides important biological insights into the interaction between tumor cells and their microenvironment in clear cell kidney cancer, the researchers say.

"We hope that our results will contribute to further investigations of factors that influence the tumor microenvironment, which may ultimately provide new opportunities to treat relapse and the spread of cancer. For us, the next step is to study how metastases in the bone marrow are different from the local tumor in the kidney, but also how the bone marrow develops in patients with kidney cancer metastases in the skeleton The skeleton differs from the healthy bone marrow. We hope it can help us answer the question of why immunotherapy doesn’t work for some kidney cancer patients,” says Adele Alchahin, a doctoral candidate in the Department of Women and Children’s Health at Karolinska Institutet and one of the first authors of the study.

The AI ​​researchers involved in the publication declare that they have no potential conflicts of interest. Other authors have connections to various pharmaceutical and biotechnology companies, including in the form of founding and consulting engagements. For more information, see the scientific article.

The research was funded by philanthropic donations from Bill and Cheryl Swanson, Gunther and Maggie Buerman, and Robert Higginbotham. The research in Sweden was funded by the Swedish Cancer Society.

Source:

Karolinska Institute

Reference:

Alkhahin, AM, et al. (2022) A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma. Nature communication. doi.org/10.1038/s41467-022-33375-w.

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