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Matched tumor analyses leads to more accurate diagnoses
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Sequencing normal tissue besides tumor tissue resulted in more accurate identification and interpretation of somatic and germline alterations that could inform treatment plans for patients with cancer, according to the results of a retrospective analysis.
Matched tumor-normal sequencing analyses led to the identification of somatic alterations in genes associated with therapies or clinical trials in three-quarters of patients with somatic mutations; however, tumor-only sequencing was associated with a 31% to 65% false-positive rate.
“Inaccurate genetic information can have substantial consequences ranging from serious side effects from inappropriate therapies, to lack of useful targeted therapies, and to increased costs of patient care from misguided medicines,” Victor E. Velculescu, MD, PhD, of the Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University School of Medicine, said during a press conference. “There are currently tens of thousands of cancer patients annually that obtain next-generation sequencing analyses in the United States, largely in a tumor-only fashion. Although there are many factors that physicians take into consideration when deciding therapeutic options, such tests play an increasingly important role.”
If all patients with late-stage cancer eventually undergo sequencing, the number of patients who annually undergo sequencing is likely to reach 1 million annually, according to the researchers.
Velculescu and colleagues evaluated matched tumor and normal DNA samples from 815 patients of 15 cancer types. Researchers conducted next-generation sequencing of whole exomes or 111 clinically relevant genes and compared tumor and normal data.
Researchers identified 105,672 somatic mutations. The mean number of somatic mutations identified through the exome analysis was 140, and the mean number from the targeted analysis was 4.34.
An analysis of 753 patients with somatic mutations demonstrated 77% (n = 580) harbored potentially actionable somatic mutations. Most of the actionable mutations were associated with current clinical trials (67%), whereas 33% were associated with established or investigational therapies.
Actionable mutations were most frequently observed in patients with colorectal cancer and melanoma. Further, 90% of the actionable mutations were mutated in fewer than 5% of cases, suggesting the heterogeneity of the mutations, according to the researchers.
The researchers then examined 85 genes associated with known cancer predisposition syndromes in DNA from blood, saliva or normal tissue samples from the 815 patients. Results showed truncating germline mutations in 27 patients. Although this represents less than 3% of the population, the researchers noted it was a noteworthy finding because all but one of the patients had no previous family history of cancer.
Tumor-only sequencing could not definitely identify germline changes in cancer-predisposition genes, according to the researchers. Further, tumor-only sequencing was associated with a 31% false-positive rate in targeted analyses and a 65% false-positive rate in the exome analyses.
This inaccurate data could potentially misguide treatment plans, the researchers wrote.
“When focusing on those genes that are likely to be actionable, we found that one-third of the changes in tumor-only analyses were false positive,” Velculescu said. “Because each patient on average had multiple such alterations, these false-positive changes affected roughly one in every two patients analyzed. In other words, a tumor-only genetic analyses for identifying correct sequence changes was the equivalent of flipping a coin.” – by Cameron Kelsall
Disclosure: Velculescu reports a co-founder, scientific advisory board and board of directors role with and stock ownership in Personal Genome Diagnostics. Please see the full study for a list of all other authors’ relevant financial disclosures.
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