Oncology
Screening a larger gene panel for earlier intervention Beyond looking for immediately druggable mutations, there is substantial value in screening a larger gene panel to simply discover the presence of disease. In this case, early detection is the goal and uncovering any cancer-causing mutation (whether treatable or not) highlights disease for clinical follow- up while it is easier to treat, since for some cancers, early detection has a significantly better prognosis. From a technical perspective, there are three critical factors to the development of diagnostic solutions that screen larger gene panels.
1. Establish a clinically actionable or early- detection gene panel
Gene panels for molecular diagnosis must strike a balance between the need for efficiency and access to the greatest spread of mutated genes. To fully characterise a tumour, all mutations associated with it need to be considered. However, this can be unwieldy and won’t necessarily aid actionability. Instead, it can be preferrable to focus on the sequencing of carefully curated target gene mutations with druggable or prognostic consequences. For instance, a gene panel for lung cancer might prioritise the genes defined by ASCO guidelines on actionable targets. A skeleton lung cancer panel might include very few actionable genes (EGFR, BRAF, KRAS and NRAS) to minimise costs (using DNA sequencing only and minimising coverage) while still offering disease detection for roughly half of cases. For early detection rather than actionable reporting, covering a broader range of genes, such as TP53, ALK, PIK3CA, RBM10, substantially raises sensitivity. This is desirable but it comes with additional cost and complexity which may need to be balanced differently across patient groups (by age, lifestyle, etc).
2. Understand target genes The four actionable genes mentioned above encompass the most frequent mutations in lung cancer, and they also provide the greatest levels of actionability. Each has different patterns of mutation, so to maximise the efficiency and sensitivity of tests it’s best to focus on exons that include frequent mutations. Looking at the entire gene would bring additional cost and complexity, vastly increasing the amount of data to be handled with little extra value. By selecting small portions of target genes for sequencing, the number of base pairs is reduced, enabling greater depth of analysis (and hence sensitivity) while lowering the interpretation
complexity. It’s about prioritising genetic regions that have the greatest diagnostic potential.
3. Balance key aspects of accessible design Managing complexity is a top priority in the development of accessible molecular diagnosis technologies. Controlling coverage (the amount of DNA to be sequenced) is just one part of this. Test sensitivity also needs to be considered. This is especially important when it comes to the improvement of early diagnosis as small or encapsulated tumours shed less DNA and therefore require greater depth of analysis. It may be necessary to assess the same DNA sequence many times looking for rare mutations. Test price and speed also need to be factored in, and ultimately may dictate what can be achieved in terms of depth and coverage of analysis.
More technical considerations Unfortunately, standard sequencing of genomic DNA doesn’t always go far enough to deliver the clinically actionable insights needed for precision oncology For instance, gene fusions caused by
chromosomal breaks and rearrangement complicate matters, and they have been identified as common drivers in a number of cancers. It can be useful to detect these genomic translocations (and they are included in ASCO’s actionable lung panel list), but this inevitably introduces further complexity and cost. Adding gene fusion testing capability to a liquid biopsy genetic test requires the sequencing of RNA as well as DNA, increasing sensitivity by more than 10%, but also increasing the cost. Similarly, DNA methylation can be an important biomarker for disease at
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