Abstract
iStock/Evgeny Terentev
Many of the mutations that are found with tumor-only genetic sequencing are not actually tumor-related. Instead, they are just germline mutations, which are inherited changes that differ from person to person. They are common in normal tissues, and they are not necessarily related to cancer.
Tumor-only genetic sequencing, then, may lead personalized cancer therapies astray—unless genomic information from a patient's tumor is compared with genomic information from the patient's normal tissue. Without this check, innocuous genetic changes may be thought “actionable” and therapies thought “targeted” may stray wide of the mark.
Essentially, the problem is a failure to distinguish between positive results and false-positive results. The scale of the problem, warn scientists from Johns Hopkins University and Personal Genome Diagnostics, is considerable.
The scientists compared the genomes of tumor and normal tissue from 815 patients who had a variety of cancers, including breast, brain, renal, gastric, lung, pancreatic, blood cancers, and melanoma. When the researchers looked at the genetic changes found in a patient's tumor and filtered out the most well-known germline changes, they counted 382 possible tumor-related changes. But after comparing a patient's full germline genome to his or her tumor genomes, they determined that, on average, 249 of these changes were part of the patient's normal, inherited genetic variation and were not tumor-specific.
The researchers also looked at the alterations in actionable genes, which were defined as genes which have been identified as potential targets for cancer drugs or investigational cancer therapies. In the study, 48%, or almost half of the tumor samples, had at least one false-positive mutation in an actionable gene. These findings are noteworthy because use of false-positive findings to guide personalized treatment decisions could result in a substantial number of patients receiving therapies that are not optimized for their cancer.
These results appeared April 15 in Science Translational Medicine, in an article entitled, “Personalized genomic analyses for cancer mutation discovery and interpretation.”
“Analyses of matched normal DNA identified germline alterations in cancer-predisposing genes in 3% of patients with apparently sporadic cancers,” the authors wrote. “In contrast, a tumor-only sequencing approach could not definitively identify germline changes in cancer-predis-posing genes and led to additional false-positive findings comprising 31% and 65% of alterations identified in targeted and exome analyses, respectively, including in potentially actionable genes.”
The Johns Hopkins scientists acknowledged that implementing tumor-normal analyses in a clinical setting could bring additional challenges. These include the additional work and costs of sequencing and analyzing a patient's normal tissue along with his or her tumor tissue. However, according to Victor Velculescu, M.D., Ph.D., a professor of oncology and pathology and co-director of the Cancer Biology Program at Johns Hopkins, some efficiencies could be realized by using the patient's saliva, blood, or normal tissue recovered during a biopsy or tumor removal.
Dr. Velculescu also noted that health insurance may not fully cover normal-tissue genetic sequencing. Addressing concerns about patient privacy when normal genomes are sequenced, Dr. Velculescu said that comparisons of tumor and normal sequences can be designed to use germline changes as a filter without identifying what those germline changes are and what their potential health implications might be.
Study co-author Siân Jones, Ph.D., vice president of genome sciences at PGDx, noted that accurately identifying tumor-specific alterations is essential to realizing the potential of personalized medicine to achieve better treatment outcomes. “As a result of this work,” he continued, “we decided to include the option to analyze both normal and tumor tissue DNA when we launched our CancerSelect™ targeted gene panel, which is designed to detect those genetic alterations in the individual's cancer that are most relevant to optimizing treatment. The study [we conducted] with our colleagues at Johns Hopkins University is a powerful validation of that decision.”
In addition to selecting personalized therapies for patients with cancer, sequencing the normal tissue genome can also increase the overall understanding of cancer, including finding cancer predisposition due to germline genome changes. “These analyses,” suggested Dr. Velculescu, “can help us find alterations in cancer-predisposing genes in ways that weren't previously appreciated.”