Up to two thirds of mutations identified in tumors also exist in matched, non-tumor tissues, researchers have found. It is therefore important for oncologists to identify the mutations that actually promote the progression of a patient’s tumor before selecting therapy.
The finding, published in Science Translational Medicine on 15 April, comes as companies have focused on developing drugs that target specific tumor-associated mutations. Demand for tumor sequencing has increased as physicians try to find the best treatments based on specific sets of tumor mutations.
Siân Jones et al. evaluated 815 tumor and matched, non-tumor tissues from patients with 15 different types of cancer. They identified genomic alterations using next-generation sequencing of whole exomes or 111 genes with variants known to increase risk for cancer (cancer-associated).
They found that more than 75% of tumor samples had somatic alterations in genes whose products are targeted by drugs or by agents in drug development.
However, 31% of mutations identified in cancer-associated genes and 65% identified in exomes of tumor tissues were also detected in the matched non-tumor tissues. Many of these were in genes encoding proteins targeted by therapeutic agents.
Jones et al conclude that it is essential to sequence the tumor and matched non-tumor tissue to identify the specific somatic and germline alterations specific to the tumor. These findings have important implications for accurate diagnosis and management of cancer patients.
Nature News reported that many clinics sequence only the tumor DNA and do not compare those sequences to DNA taken from a patient’s normal tissue. Omitting this important control makes it difficult to determine which mutations contributed to tumor formation or progression and should therefore be targeted therapeutically.
“There is a rush to do this clinically and apply it to patient treatment without thinking about what the best control is,” the study’s senior author Victor Velculescu told Nature News. “You could use that information to place patients on inappropriate therapy.”
“The reality is you can’t have precision medicine without having precision genomics,” added Velculescu.
NPR reported that the tumor genome test alone can cost more than $5000, and a second test of non-tumor tissue would increase that price substantially. Velculescu told NPR that insurance often won’t pick up that additional cost.
Nonetheless, some institutions have already begun to sequence tumor and non-tumor tissues of cancer patients. Michael Berger (Memorial Sloan Kettering) told Nature News that his institute’s program has so far analyzed DNA from the tumors and normal tissue of more than 4000 patients, focusing on a set of 400 genes.
Berger explained that in addition to the extra cost, the additional step requires more patient education. Also, because mutations in normal tissue may also be found in reproductive cells, and can therefore be passed on to children, patients have to consider implications for family members and sign separate consent forms.