Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors.
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.
Jones
Steven Jm
SJ
Genome Sciences Centre, British Columbia Cancer Agency, 570 West 7th Avenue, Vancouver, BC, V5Z 4S6, Canada. sjones@bcgsc.ca
Laskin
Janessa
J
Li
Yvonne Y
YY
Griffith
Obi L
OL
An
Jianghong
J
Bilenky
Mikhail
M
Butterfield
Yaron S
YS
Cezard
Timothee
T
Chuah
Eric
E
Corbett
Richard
R
Fejes
Anthony P
AP
Griffith
Malachi
M
Yee
John
J
Martin
Montgomery
M
Mayo
Michael
M
Melnyk
Nataliya
N
Morin
Ryan D
RD
Pugh
Trevor J
TJ
Severson
Tesa
T
Shah
Sohrab P
SP
Sutcliffe
Margaret
M
Tam
Angela
A
Terry
Jefferson
J
Thiessen
Nina
N
Thomson
Thomas
T
Varhol
Richard
R
Zeng
Thomas
T
Zhao
Yongjun
Y
Moore
Richard A
RA
Huntsman
David G
DG
Birol
Inanc
I
Hirst
Martin
M
Holt
Robert A
RA
Marra
Marco A
MA
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
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