Researchers Uncover New Potential Driver Mutations in Advanced Cancer

March 26, 2018
Researchers Uncover New Potential Driver Mutations in Advanced Cancer
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Scientists report that they have found new genetic mutations that promote the survival of cancer cells. Their study also provided a clearer understanding of how some cancer cells are able to resist treatment.

The findings (“Novel Putative Drivers Revealed by Targeted Exome Sequencing of Advanced Solid Tumors”) are published in PLOS ONE.

Next generation sequencing (NGS) is becoming increasingly integrated into oncological practice and clinical research. NGS methods have also provided evidence for clonal evolution of cancers during disease progression and treatment. The number of variants associated with response to specific therapeutic agents keeps increasing. However, the identification of novel driver mutations as opposed to passenger (phenotypically silent or clinically irrelevant) mutations remains a major challenge,” write the investigators.

“We conducted targeted exome sequencing of advanced solid tumors from 44 pre-treated patients with solid tumors including breast, colorectal and lung carcinomas, neuroendocrine tumors, sarcomas and others. We catalogued established driver mutations and putative new drivers as predicted by two distinct algorithms. The established drivers we detected were consistent with published observations. However, we also detected a significant number of mutations with driver potential never described before in each tumor type we studied. These putative drivers belong to key cell fate regulatory networks, including potentially druggable pathways. Should our observations be confirmed, they would support the hypothesis that new driver mutations are selected by treatment in clinically aggressive tumors, and indicate a need for longitudinal genomic testing of solid tumors to inform second line cancer treatment.”

"All cancers are caused by genetic damage, mutations to key genes that control the lives of cells," notes Lucio Miele, M.D., Ph.D., professor and chair of genetics at LSU Health New Orleans School of Medicine. He led the team along with Justin Stebbing, Ph.D., professor of cancer medicine and medical oncology at Imperial College of Medicine in London. "Mutant genes that cancers depend upon for survival are called 'driver' mutations."

No two cancers were genetically identical, even cancers of the same organs that looked the same under a microscope. In some cases, the researchers found evidence that an individual cancer had evolved two or even three drivers in the same gene, a sign that multiple cancer cell clones had evolved in the same tumor that had found different ways of mutating a particularly important gene. Many of these new genetic mutations are in functional pathways that can be targeted with existing drugs.

"These findings imply that genomic testing should be performed as early as possible to optimize therapy, before cancers evolve new mutations, and that recurrent cancers should be tested again, because their driver mutation may be different from those that existed at diagnosis," says Miele. 

With this information, therapy could be tailored to the evolving genomic picture of each individual cancer—the hallmark of precision medicine.

"We are working toward a day when we won't have to give a patient the devastating news that a cancer has come back and isn't responding to chemotherapy," says Miele.