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Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors

Steven JM Jones1*, Janessa Laskin2, Yvonne Y Li1, Obi L Griffith1, Jianghong An1, Mikhail Bilenky1, Yaron S Butterfield1, Timothee Cezard1, Eric Chuah1, Richard Corbett1, Anthony P Fejes1, Malachi Griffith1, John Yee3, Montgomery Martin2, Michael Mayo1, Nataliya Melnyk4, Ryan D Morin1, Trevor J Pugh1, Tesa Severson1, Sohrab P Shah45, Margaret Sutcliffe2, Angela Tam1, Jefferson Terry4, Nina Thiessen1, Thomas Thomson2, Richard Varhol1, Thomas Zeng1, Yongjun Zhao1, Richard A Moore1, David G Huntsman3, Inanc Birol1, Martin Hirst1, Robert A Holt1 and Marco A Marra1

Author affiliations

1 Genome Sciences Centre, British Columbia Cancer Agency, 570 West 7th Avenue, Vancouver, BC, V5Z 4S6, Canada

2 British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada

3 Vancouver General Hospital, West 12th Avenue, Vancouver, BC, V5Z 1M9, Canada

4 Centre for Translational and Applied Genomics of British Columbia Cancer Agency and the Provincial Health Services Authority Laboratories, 600 West 10th Avenue, Vancouver, V5Z 4E6, BC, Canada

5 Molecular Oncology, BC Cancer Research Centre, 601 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada

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Citation and License

Genome Biology 2010, 11:R82  doi:10.1186/gb-2010-11-8-r82

Published: 9 August 2010



Adenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment.


In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. There were 1,078 genes that exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations, administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumors and 9 new somatic protein coding mutations. The observed mutations and amplifications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways.


We conclude that complete genomic characterization of a rare tumor has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual.