Scientists in the U.K. report that cancer manipulates a natural cell process to promote its survival. Controlling this mechanism may halt progress of the disease, the investigators say.

Their study (“A Pan-Cancer Genome-Wide Analysis Reveals Tumour Dependencies by Induction of Nonsense-Mediated Decay”) is published in Nature Communications.

“We discover cancer-specific NMD [nonsense mediated decay]-elicit signatures in TSGs [tumor suppressor genes] and cancer-associated genes,” write the researchers. “Our analysis reveals a previously unrecognized dependence of hypermutated tumors on hypofunction of genes that are involved in chromatin remodeling and translation.”

NMD is a natural physiological process that allows cells to detect nonsense mutations. It also enables these cells to remove the mutated message (decay) that comes from these faulty genes before they can be translated into proteins that can cause disease formation.

NMD is known for the role it plays in the development of genetic diseases, such as cystic fibrosis, and some hereditary forms of cancer. But not all nonsense mutations can elicit NMD; so until now, its wider impact on cancer was largely unknown, point out the researchers.

A team from the University of Oxford Medical Sciences Division and the University of Birmingham developed a computer algorithm to mine DNA sequences from cancer to accurately predict whether or not an NMD would eliminate genes that had nonsense mutations. The work originally focused on ovarian cancer and found that about a fifth of these cancers use NMD to become stronger. This is because NMD ensures that the message from a gene called TP53, which ordinarily protects cells from developing cancer, is almost completely eliminated.

Without NMD, a mutated TP53 might still retain some activity, but NMD ensures that this is not the case.

The team predicts that because cancers essentially feed on NMD, they become dependent on it in some cases. If scientists were therefore able to inhibit or control the process, it is possible that they could also control cancer and prevent the progression of the disease.

“Our first observations of evidence of the role of NMD in ovarian cancer were tantalizing,” said Ahmed Ashour Ahmed, M.D., Ph.D., co-author and professor of gynecology oncology at the Nuffield department of obstetrics & gynecology and the head of the Ovarian Cancer Cell Laboratory at the Weatherall Institute of Molecular Medicine at the University of Oxford.

“We found that NMD precisely explained why there was almost no expression of TP53 in certain ovarian cancers. We went on to test the role of NMD in other cancer types and the evidence of the role of NMD was compelling. This opens the door for exciting possibilities for customized treatments, including individualized immunotherapies for patients in the future.”

The team has expanded the study to include other cancer types. They analyzed about a million different cell mutations in more than 7000 tumors from the Cancer Genome Atlas covering 24 types of cancer. The scientists were able to map how each cancer type used NMD, showing how NMD helps cancer to survive.

According to Katherine Taylor, CEO of Ovarian Cancer Action, which partially funded the research, the “discovery could help clinicians identify and inhibit the process, giving them much better control of a person's cancer.”

She calls ovarian cancer “a very complicated disease” with low survival rates (about 46% of women live beyond five years after diagnosis). ”So understanding how we can prevent the disease from thriving is imperative if we are to improve the outcome for more women.”

The investigators will now focus on testing their theory and understanding to what degree stopping the NMD process allows them to control tumors.








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