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AMP: Next-Generation Sequencing and the Pathologist


At the annual meeting of the Association for Molecular Pathology in Texas this week, the BC Cancer Agency's David Huntsman said that not only is next-generation sequencing changing the paradigm of cancer treatment, but that pathologists can and should use this technology to tease apart cancer's complexity and shed light on the various causes and avenues of treatment. Next-gen sequencing is the first truly disruptive technology for diagnostics since the introduction of the microscope in the 1850s, Huntsman said. It is the source of many cancer biomarkers that can help oncologists with diagnosis, prognosis, and prediction of treatment efficacy for a given patient. Cancer researchers have also had to deal with the challenge of the continuous stratification and sub-typing of different cancers depending on what next-gen sequencing reveals about the diseases' molecular makeup. The technology is changing the cancer care paradigm from generic, as it was many years ago, to stratified, to individualized, and the discovery and validation of biomarkers is driving this paradigm shift, Huntsman said.

Next-gen sequencing is allowing researchers to study many genes at once in a given cancer, instead of one gene or mutation at a time, and it is this plurality of mutations and chromosomal instabilities that drive cancer. Cancer research before the advent of genomics gave "a vague idea of what's going on," Huntsman said. But now that the human draft genome has been published, and sequencing is getting cheaper and faster, use of this technology will become more common.

However, Huntsman said, it's not just enough to sequence a tumor and call it a day. "At that point, you're not just looking for a needle in a haystack," Huntsman said of looking for relevant mutations in genomic data. "It's like looking for a straw-colored needle in a haystack." Collaboration with bioinformaticians is essential to teasing out the relevant data — like base-pair resolution of the germline and tumor genomes and the ability to study intra-tumor heterogeneity — that are really needed for individualized cancer control. In addition, it's not enough to study only DNA abnormalities, Huntsman said. Transcriptomic research has shown that the heterogeneity and complexity of cancer applies to RNA as well.

These factors, and others, may make it seem as though only very large projects like The Cancer Genome Atlas are equipped to study cancer in depth, Huntsman added. But although those projects are certainly integral to our understanding of the disease, smaller projects can also make a very big impact by studying problems like constrained genomes of well-characterized phenotypes, or susceptibility loci, he said. And very exciting discoveries are being made, like change-of-function mutations, or modulators of host response. Next-gen sequencing has opened the door for pathologists to be involved in and make these discoveries, Huntsman said.

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