title: Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, 570 West 7th Avenue, Vancouver, BC, V5Z 4S6, Canada. sjones@bcgsc.ca
authors.forename: Steven Jm
authors.initials: SJ
authors.lastname: Jones
authors.forename: Janessa
authors.initials: J
authors.lastname: Laskin
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Li
authors.forename: Obi L
authors.initials: OL
authors.lastname: Griffith
authors.forename: Jianghong
authors.initials: J
authors.lastname: An
authors.forename: Mikhail
authors.initials: M
authors.lastname: Bilenky
authors.forename: Yaron S
authors.initials: YS
authors.lastname: Butterfield
authors.forename: Timothee
authors.initials: T
authors.lastname: Cezard
authors.forename: Eric
authors.initials: E
authors.lastname: Chuah
authors.forename: Richard
authors.initials: R
authors.lastname: Corbett
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Fejes
authors.forename: Malachi
authors.initials: M
authors.lastname: Griffith
authors.forename: John
authors.initials: J
authors.lastname: Yee
authors.forename: Montgomery
authors.initials: M
authors.lastname: Martin
authors.forename: Michael
authors.initials: M
authors.lastname: Mayo
authors.forename: Nataliya
authors.initials: N
authors.lastname: Melnyk
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.forename: Tesa
authors.initials: T
authors.lastname: Severson
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.forename: Margaret
authors.initials: M
authors.lastname: Sutcliffe
authors.forename: Angela
authors.initials: A
authors.lastname: Tam
authors.forename: Jefferson
authors.initials: J
authors.lastname: Terry
authors.forename: Nina
authors.initials: N
authors.lastname: Thiessen
authors.forename: Thomas
authors.initials: T
authors.lastname: Thomson
authors.forename: Richard
authors.initials: R
authors.lastname: Varhol
authors.forename: Thomas
authors.initials: T
authors.lastname: Zeng
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Richard A
authors.initials: RA
authors.lastname: Moore
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Inanc
authors.initials: I
authors.lastname: Birol
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Robert A
authors.initials: RA
authors.lastname: Holt
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use; D018628:Gene Dosage / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D052138:Genes, Neoplasm / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000556:secondary; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D012641:Selection, Genetic; D000077157:Sorafenib; D000077210:Sunitinib; D014062:Tongue Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
chemical_list: D001557:Benzenesulfonates; D007211:Indoles; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D009536:Niacinamide; D000077157:Sorafenib; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000077210:Sunitinib