CRISPR gene editing can favour cells with cancer-linked mutations

Monday, 22 November, 2021

CRISPR gene editing can favour cells with cancer-linked mutations

A comprehensive study, led by researchers at Sanford Burnham Prebys and the US National Cancer Institute (NCI), has shown that gene knockout (KO) with CRISPR-Cas9 can favour cells with mutated forms of genes linked to cancer. The findings, published in the journal Nature Communications, highlight the need to monitor patients undergoing CRISPR-Cas9-based gene therapy for cancer-related mutations.

CRISPR-Cas9 works by creating double-stranded DNA breaks at specific points in a DNA sequence, allowing scientists to target and edit specific genes. However, the p53 gene responds to double-stranded breaks by arresting cell growth, meaning that cells that have undergone CRISPR would grow and divide less effectively. This means that cells with mutations in the p53 gene can continue to grow and divide normally, giving them a competitive advantage.

The p53 gene stops cell division if a genomic error arises and attempts to correct the problem. If the error cannot be fixed, p53 will initiate programmed cell death before the cells can become cancerous. This makes p53 a critical anti-cancer gene and losing its function can make people more susceptible to tumours.

Computational biologists led by Dr Eytan Ruppin, Chief of the Cancer Data Science Laboratory at the NCI Center for Cancer Research and co-leader of the study, analysed p53 responses to double-stranded breaks in nearly 1000 human cell lines. In almost every cell type, they found that after CRISPR-Cas9 KO, cells with normal p53 genes exhibited slower growth, while those with mutated p53 genes were less affected, allowing them to grow faster and outcompete the normal cells. They also found that CRISPR may confer an advantage to cells with other cancer-associated mutations, like those of the KRAS oncogene.

“Our study shows that in many different cell types, CRISPR gene editing can confer a selective advantage to cells harbouring mutations in genes associated with cancer, such as p53 and KRAS,” said co-senior author Dr Ani Deshpande, an assistant professor in the NCI-Designated Cancer Center at Sanford Burnham Prebys. “We have shown that when CRISPR-Cas9 is used to edit the genome, cells with cancer-associated mutations are likely to be selected to survive — and this is more widespread than scientists previously understood.”

“This is not the first time researchers have shown CRISPR may introduce potentially dangerous changes,” added Dr Ruppin. “However, it is the first time these effects have been demonstrated in so many diverse cells.”

The findings point to a need for caution in the use of CRISPR-based gene therapies, particularly when treating individuals with underlying mutations in p53 or KRAS genes. Dr Ruppin noted, “There are CRISPR therapies being developed to correct mutations in many human tissues, but … we need to proceed with caution, because we may be selecting for cells that carry mutations in key cancer driver genes when using CRISPR-Cas9 editing, and that could be potentially dangerous. However, fortunately and importantly, additional new CRISPR editing techniques that have been recently developed are much less likely to carry this risk, if at all.”

“Early CRISPR techniques generated double-stranded breaks, but more modern iterations make simpler edits to target DNA,” Dr Deshpande added. “If we use a non-cutting version of CRISPR we are likely to avoid many of these problems, which could be very good news for patients.”

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