Sequencing of a tumor and its metastases

In an article just published in Genome Biology, Steven Jones and colleagues at the British Columbia Cancer Agency have used next generation sequencing to monitor the development of a tumor as it metastasized and used the genomic information to inform treatment.

Cancers are known to accumulate mutations as they progress, and there are several mutations characteristic of metastases. However, even the most well-characterised of tumor types show genetic heterogeneity, and there are few data available for rare tumor types. The recent advent of next generation sequencing technology, allowing rapid and inexpensive genome sequencing, has made it possible to explore the genomic landscape of tumors in more detail.

In this study, a man presented with an unusual cancer of the tongue. He received surgery and radiotherapy, but was subsequently found to have metastases in the lungs. The patient was initially treated with the EGFR inhibitor erlotinib, but the lung metastases continued to grow. Sequencing of the metastases uncovered amplification of the RET oncogene, which explained the resistance to erlotinib, and also suggested the use of the RET inhibitor sunitinib. This drug reduced the size of the lung lesions for a few months, before they started to grow again. A skin metastasis was also detected, and sequencing uncovered seven new mutations that were present in neither the lung metastases nor the original tongue tumor. It appeared that the tumor had upregulated the AKT signalling pathway to compensate for the inhibition of the RET pathway.

This eloquent study demonstrates nicely both how tumors respond to treatment with compensatory changes and also how genomics can be used to guide medical treatment.

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