Abstract
The introduction of next-generation sequencing technologies has dramatically impacted the life sciences, perhaps most profoundly in the area of cancer genomics. Clinical applications of next-generation sequencing and associated methods are emerging from ongoing large-scale discovery projects that have catalogued hundreds of genes as having a role in cancer susceptibility, onset and progression. For example, discovery cancer genomics has confirmed that many of the same genes are altered by mutation, copy number gain or loss, or structural variation across multiple tumor types, resulting in a gain or loss of function that likely contributes to cancer development in these tissues. Beyond these frequently mutated genes, we now know there is a ‘long tail’ of less frequently mutated, but probably important, genes that play roles in cancer onset or progression. Here, I discuss some of the remaining barriers to clinical translation, and look forward to new applications of these technologies in cancer care.
Highlights
In 2004, following the completion of the Human Genome Project [1], a correlation was described between a specific set of mutations and patients whose lung cancers had dramatically responded to a new class of therapeutics called tyrosine kinase inhibitors (TKIs) [2]
Our group and two others [2,3,4] found that about 80% of patients with a response to a TKI carried somatic mutations in the gene encoding the epidermal growth factor receptor (EGFR) resulting in changes to the amino acid sequence
A large number of driver alterations have been identified in lung adenocarcinoma, a significant proportion of which can be treated with specific drug-gene combinations, and there are many more drivers to be identified [5]
Summary
In 2004, following the completion of the Human Genome Project [1], a correlation was described between a specific set of mutations and patients whose lung cancers had dramatically responded to a new class of therapeutics called tyrosine kinase inhibitors (TKIs) [2]. Further complications arise from the broad scope of MPS inquiries because novel mutations in cancer genes are identified (not just the hotspots), often with no clear indication of their pathogenicity (that is, gain or loss of function) or their likely drug response Another issue involves a second data type that is proving to be critically informative but is not presently being utilized by most diagnostic testing assays: RNA sequencing of the tumor. The larger number of practicing physicians who want to use genomicsbased diagnostics but feel alienated because they do not understand the approach and how best to interpret the results of data analysis will need effective continuing medical education (CME)-based training and user-friendly decision support tools to feel sufficiently educated and confident to order and interpret these tests They will need evidence that specific gene-mutationtargeted therapy combinations will provide clinical benefits, which may be challenging to demonstrate with the current paradigm of one-size-fits-all clinical trials. The astounding sequencing capacity of NGS instruments makes monitoring changes in a patient’s T- and B-cell repertoires quite straightforward within a single experiment [40], and could provide a critically important component of patient monitoring during immunotherapy or other therapeutic interventions
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