- Genomics offers the promise of personalized medicine in oncology.
- In the ideal clinical situation, the chemical and genetic weaknesses of a patient’s disease would be revealed and the optimal treatment would be applied.
- In some cases, however, the genomic data can confuse or mislead the clinician.
- Researchers are racing to eliminate the mystery areas in targeted therapy.
- Today, questions remain and all genomic data must be corroborated.
“Despite the numerous prognostic biomarkers reported in the literature, only seven biomarkers have been approved by the FDA Center for Devices and Radiological Health. One of the major reasons is that prognostic prediction itself often does not directly change clinical decision making unless coupled to specific therapeutic options,” argued the authors of an paper in Translational Cancer Research.
Figure 1. Mutation: A covalent adduct between benzo[a]pyrene, the major mutagen in tobacco smoke, and DNA.
BMC Genomics
An article published recently in BMC Genomics was titled “Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis.”
The researchers reported the following:
While analysing whole genome paired-end sequencing of oesophageal adenocarcinomas to find genomic rearrangements, we identified three ways in which new mobile element insertions appear in the data, resembling translocation or insertion junctions: inserts where unique sequence has been transduced by an L1 (Long interspersed element 1) mobile element; novel inserts that are confidently, but often incorrectly, mapped by alignment software to L1s or polyA tracts in the reference sequence; and a combination of these two ways, where different sequences within one insert are mapped to different loci. We identified nine unique sequences that were transduced by neighbouring L1s, both L1s in the reference genome and L1s not present in the reference.
Somatic mobile elements insertions are abundant in these tumours, with over 75 % of cases having a number of novel inserts detected. The inserts create a variety of problems for the interpretation of paired-end sequencing data,” the researchers concluded.
“Flawed” Comparison Study
More recently, readers wrote to the editors of OncoTargets and Therapy explaining that a paper called “Evaluation and comparison of two commercially available targeted next-generation sequencing platforms to assist oncology decision-making” was so flawed methodologically that it should be retracted. The original article is available here.
The readers wrote that “The study directly compared results for the Paradigm Cancer Diagnostic test to the FoundationOne test for formalin-fixed, paraffin-embedded specimen pairs from 21 advanced cancer cases. We believe this study is fundamentally flawed, misleading, and potentially dangerous for patient care, for the reasons outlined herein.”
The reasons described therein included “a remarkable lack of concordance between the genomic alterations detected on each platform, even in genes common to both assays.” The two assays were returning markedly different results upon examining the same samples.
Oncologists increasingly rely upon results of comprehensive genomic profiling in making important treatment decisions. For this reason, rigorous peer-reviewed validation of genomic tests offered for use in clinical applications is essential. We believe the Paradigm study does not meet this standard and is sufficiently flawed such that we encourage the authors to consider retracting the paper.
This conclusion reinforces the notion that genomic testing is still not foolproof. Clinicians should compare results gained through other types of testing before accepting the results of genomic tests.
The Time Will Come
Despite decades of excitement about the promise of personalized oncology resulting from genomic research, important questions about this approach will still take years to answer. A 2015 article in The Journal of Thoracic Disease is called “The challenge of using biomarkers and molecularly targeted drugs to improve cure rate in early stage non-small cell lung cancer."
The paper goes on conclude exactly what one might expect: “For lung cancer, there is considerable excitement with emerging results of immunotherapy with checkpoint inhibiting antibodies in advanced disease. There is an intriguing possibility that the high antigenic load from many mutations in NSCLC may be an asset for adjuvant immunotherapy studies where the burden of residual disease is low,” but it will take years for reliable clinical trials to effectively test this hypothesis.
