Research reveals how genetic mutations cause kidney cancer

Researchers at the University of Cambridge have shown that genetic mutations associated with kidney cancer rely on factors that regulate normal kidney cells in order to develop into cancer cells.

The study suggests that similar mechanisms could explain why cancer mutations cause specific types of cancer to develop.

Inherited genetic variants and mutations that are randomly acquired during the lifetime of an individual can lead to the development of cancer. But different mutations tend to cause different types of cancer.

While this cancer-specificity of mutations has been clear for decades, exactly why mutations can lead to the formation of tumours in some tissues but not others has remained poorly understood.

All tissues have specific functions that are ultimately dependent on the instructions encoded by the genome. These instructions are read by a group of proteins called transcription factors that recognise specific DNA sequences and ensure that the right regions of the genome are active in each cell. This mechanism allows the same genome to control the functions of diverse cell types with vastly different characteristics.

In this study, published in the journal Nature, the researchers tested whether the transcription factors that control tissue-specific functions of normal kidney cells were also required for the growth of kidney cancers.

They used a combination of advanced genomic tools, experimental cancer models and analysis of large human data sets.

The results show that the ability of kidney cancer-associated genetic alterations to promote tumour formation was dependent on transcription factors that are specifically active in normal kidney cells.

When kidney-specific transcription factors were inactivated experimentally, the cancer mutations were no longer capable of activating genes that are important for tumour growth.

Senior author Dr Sakari Vanharanta said: “Our results provide some insight into the molecular mechanisms that dictate the cancer type-specificity of mutations.

“Genetic alterations that cause kidney cancer rely on factors that under normal conditions regulate specific functions of healthy kidney cells. If these factors are not present, as they are not in most other cell types, the process that eventually leads to cancer formation does not proceed.”

Large genetic alterations commonly observed in advanced, metastatic kidney cancer cells also relied on kidney-specific transcription factors for their cancer-promoting effect.

The common genetic variant characterised in this study is carried by the majority of individuals of European descent and it increases the risk of kidney cancer. Overall, the molecular mechanisms described in this work are likely to be important for a large proportion of kidney cancers.

Professor Grant Stewart, study co-author and co-lead of the CRUK Cambridge Centre Urological Malignancies Programme, said: “[This] paves the way to new thinking on how to develop new treatments for kidney cancer and even prevent it from developing in the first place.

“These same mechanisms might also be at play in other cancer types, making this study highly relevant across all cancers”.