Inﬂ ammatory Myoﬁ broblastic Tumors Harbor Multiple ...cancerdiscovery.aacrjournals.org/content/candisc/4/8/889.full.pdf · Tumors Harbor Multiple Potentially Actionable Kinase

AUGUST 2014�CANCER DISCOVERY | 889

Infl ammatory Myofi broblastic Tumors Harbor Multiple Potentially Actionable Kinase Fusions Christine M. Lovly 1 , Abha Gupta 2 , Doron Lipson 3 , Geoff Otto 3 , Tina Brennan 3 , Catherine T. Chung 4 , Scott C. Borinstein 5 , Jeffrey S. Ross 3,6 , Philip J. Stephens 3 , Vincent A. Miller 3 ,and Cheryl M. Coffi n 7

RESEARCH BRIEF

ABSTRACT Infl ammatory myofi broblastic tumor (IMT) is a neoplasm that typically occurs in

children. The genetic landscape of this tumor is incompletely understood and thera-

peutic options are limited. Although 50% of IMTs harbor anaplastic lymphoma kinase ( ALK) rearrange-

ments, no therapeutic targets have been identifi ed in ALK-negative tumors. We report for the fi rst time

that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions. We detail the case of

an 8-year-old boy with treatment-refractory ALK-negative IMT. Molecular tumor profi ling revealed

a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor crizotinib. This case prompted

assessment of a larger series of IMTs. Next-generation sequencing revealed that 85% of cases evalu-

ated harbored kinase fusions involving ALK, ROS1, or PDGFRβ. Our study represents the most compre-

hensive genetic analysis of IMTs to date and also provides a rationale for routine molecular profi ling of

these tumors to detect therapeutically actionable kinase fusions.

SIGNIFICANCE: Our study describes the most comprehensive genomics-based evaluation of IMT to

date. Because there is no “standard-of-care” therapy for IMT, the identifi cation of actionable genomic

alterations, in addition to ALK, is expected to redefi ne management strategies for patients with this

disease. Cancer Discov; 4(8); 889–95. ©2014 AACR.

See related commentary by Le and Doebele, p. 870.

1 Department of Medicine, Vanderbilt University, Nashville, Tennessee. 2 Division of Hematology/Oncology, The Hospital for Sick Children, Uni-versity of Toronto, Toronto, Canada. 3 Foundation Medicine, Cambridge, Massachusetts. 4 Division of Pathology, The Hospital for Sick Children, Uni-versity of Toronto, Toronto, Canada. 5 Department of Pediatrics, Vanderbilt University, Nashville, Tennessee. 6 Albany Medical College, Albany, New York. 7 Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.

Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

Corresponding Author: Christine M. Lovly, Vanderbilt University School of Medicine, 2220 Pierce Avenue South, 777 Preston Research Building, Nashville, TN 37232-6307. Phone: 615-936-3457; Fax: 615-343-2973; E-mail: [email protected]

doi: 10.1158/2159-8290.CD-14-0377

©2014 American Association for Cancer Research.

INTRODUCTION

Infl ammatory myofi broblastic tumor (IMT) is a rare mes-

enchymal tumor that can occur at any age, but has a predi-

lection for children, adolescents, and young adults ( 1 ). An

estimated 150 to 200 new cases are diagnosed annually in

the United States ( 2 ). These soft-tissue tumors can occur at

multiple anatomic sites, but most commonly involve the lung,

abdomen/pelvis, and retroperitoneum. The mainstay of

treatment for IMT is surgical resection; however, treatment

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Lovly et al.RESEARCH BRIEF

options are limited for patients with unresectable and/or

advanced disease.

IMTs are diagnosed pathologically using criteria estab-

lished by the World Health Organization (WHO; ref. 3 ).

These tumors are characterized histologically by a spindle

myofi broblastic cell proliferation with a lymphoplasmacytic

infl ammatory infi ltrate ( 4 ). Approximately 50% of IMTs are

positive for anaplastic lymphoma kinase (ALK) expression

by IHC. The most common mechanism of ALK expression

and activation involves structural rearrangements in the ALK

gene, leading to the formation of a chimeric fusion protein.

Several ALK fusion partners have been identifi ed retrospec-

tively ( 5 ), as tumor sequencing is not yet the standard of care

for IMTs. ALK fusions have been validated as a therapeutic

target. A patient with a RANBP2–ALK- positive IMT had a

partial response to the ALK tyrosine kinase inhibitor (TKI)

crizotinib, whereas a patient whose IMT lacked an ALK fusion

did not respond to this agent ( 6 ).

In contrast, actionable genomic alterations have not yet

been described in the 50% of IMT samples that are negative

for ALK by IHC. ALK-negative IMTs may be more aggres-

sive with a higher frequency of metastasis compared with

ALK-positive IMT ( 7 ). Little is known on the genomic level

about potential oncogenic drivers in this subset of IMTs and,

as such, there are no targeted therapies available for these

patients.

Here, we describe the case of an 8-year-old boy with

treatment-refractory ALK-negative IMT. Targeted next-gener-

ation sequencing (NGS)–based genomic profi ling identifi ed

the presence of a ROS1 kinase fusion within his tumor. On

the basis of this fi nding, he was treated with the ROS1/ALK/

MET TKI, crizotinib, and experienced rapid symptomatic

improvement and signifi cant decrease in his tumor burden.

This case prompted us to perform genomic analysis on a

larger series of this rare tumor. Our data show for the fi rst

time that kinase fusions are found in the majority of IMTs.

These data not only offer insight into this disease but also

provide a rationale for routine molecular profi ling to detect

therapeutically actionable kinase fusions and thereby offer

patients rational therapeutic strategies with existing TKIs

based on the genomic profi le of the tumor.

RESULTS Case Report

A 6-year-old boy presented with a 1-year history of cough

and fatigue. Imaging demonstrated the presence of a large

left-sided chest mass. Biopsy of the mass revealed IMT, nega-

tive for ALK expression by standard clinical IHC and for

ALK rearrangement by break-apart FISH. The tumor was

deemed unresectable due to its intimate association with the

pulmonary vein, aorta, and esophagus. At the time of diag-

nosis, his laboratory parameters were indicative of a micro-

cytic anemia and an infl ammatory state. Several treatment

regimens were administered, including anti-infl ammatory

agents (naproxen, corticosteroids, and indomethacin) as well

as cytotoxic chemotherapy (methotrexate–vinorelbine), over

the course of 24 months (Supplementary Fig. S1), with

no antitumor response and minimal improvement of his

anemia. While he was receiving methotrexate–vinorelbine,

we performed targeted NGS-based genomic profi ling of his

tumor using formalin-fi xed and paraffi n-embedded (FFPE)

tissue and surprisingly detected a TFG–ROS1 fusion ( Fig. 1A ).

ROS1 TKIs, such as crizotinib, have proven to be an effec-

tive therapeutic strategy in lung cancers harboring ROS1

kinase fusions ( 8, 9 ). Therefore, he was treated with crizotinib

(250 mg), obtained through a compassionate access program,

twice daily orally. He experienced grade 1 diarrhea and visual

disturbance, both of which resolved with no dose reduction.

Within 3 cycles of crizotinib therapy, he symptomatically

felt better, with decreased cough and signifi cantly increased

energy. Imaging studies revealed, for the fi rst time since diag-

nosis, a decrease in the size of his tumor mass ( Fig. 1B ). Nota-

bly, his hemoglobin (Hgb) and mean corpuscular volume

(MCV) rapidly increased and his erythrocyte sedimentation

rate (ESR) decreased ( Fig. 1C and Supplementary Table S1).

He has now been on crizotinib for 4 months with excellent

tolerance, improved quality of life, and continued decrease in

his tumor burden.

Patient and Tumor Characteristics In an effort to further characterize cases of both ALK-

positive and ALK-negative IMT, we obtained 37 samples from

33 patients with this rare disease ( Table 1 ). Patients ranged

in age from infancy (less than 1 year old) to age 41. As is

typical for IMT, the tumors arose at multiple anatomic loca-

tions, including thorax, mesentery, peritoneum, and bladder.

The pathologic diagnosis was established based on criteria

according to the WHO classifi cation ( 3 ). ALK IHC was com-

pleted on each sample as part of the standard pathologic

evaluation (Supplementary Methods). Eleven of 37 (30%) of

the cases were ALK IHC negative and 26 of 37 (70%) of the

cases were ALK IHC positive.

Targeted NGS Identifi ed ALK, ROS1, and PDGFRb Tyrosine Kinase Fusions in a Collection of IMT Samples

We hypothesized that further insight into the biology of

known fusions as well as discovery of novel kinase fusions

would provide new therapeutic targets to treat patients with

IMT. To address this hypothesis, we analyzed genomic DNA

from all 37 IMT samples using a targeted NGS-based assay

(FoundationOne), which assesses 3,769 exons of 287 cancer

genes and 47 introns of 19 commonly rearranged genes,

Figure 1. Response to crizotinib in an 8-year-old boy with refractory IMT harboring a TFG–ROS1 fusion. A, schematic representation of the TFG–ROS1 fusion. ROS1 is located on chromosome 6q22 and TFG is located on 3q12. The breakpoint occurs in-frame between exon 4 of TFG and exon 36 of ROS1 . B, CT scans before the initiation of crizotinib (left) and after 3 cycles of crizotinib (right) showing dramatic reduction in the tumor mass within the left lung. C, changes in Hgb, MCV, and ESR over the course of the patient’s treatments. Arrows below the graphs, initiation of the indicated therapies. The high (H) and low (L) limits of normal for each measured parameter are indicated on the blue graphs.





Multiple Actionable Kinase Fusions in IMT RESEARCH BRIEF

Pre-crizotinib After 3 cycles of crizotinib

Hemoglobin (g/L)

MCV (fL)

ESR (mm/hr)

TFG (chr3)

ROS1 exons 35-43

ROS1 (chr6)

TFG exons 1-4

TFG–ROS1 fusion

ATG

ATG

ATG

5

35

chr4: 1,808,677

chr6: 117,643,755

A

B

C

g/L

fLm

m/h

162.5

150.0

137.5

125.0

112.5

100.0

87.575.0

100959085807570656055

125

100

75

50

25

0Jul Oct Jan 12 Jul Oct Jan 14Apr Jul Oct Jan 13 Apr

Steroid

pulse

Methotrexate

+ vinorelbine

Crizotinib

(11/20/2013)






Sample ID Age (years) Gender Tumor site Tumor size (cm) ALK IHC Kinase fusion detected Coverage

L1 14 F Mesentery 7 Neg No fusion detected 252

L2 16 F Mesentery 3 Neg No fusion detected 102

L3 22 F Buttock 10 Neg YWHAE–ROS1 a 497

L4 22 F Pelvis Unknown Neg YWHAE–ROS1 a 676

L5 38 F Lung 3 Neg EML4–ALK 607

L6 8 M Mesentery 6 Neg TFG–ROS1 179

L7 12 F Peritoneum >10 Neg NAB2–PDGFRβ 424

L8 5 M Lung 5 Neg No fusion detected 383

L9 41 M Nasopharynx 5 Neg TPM3–ALK 460

L10 12 F Peritoneum Unknown Neg NAB2–PDGFRβ a 147

L11 6 M Omentum 14 Pos RANBP2–ALK 475

L12 7 F Mesentery 11 Pos LMNA–ALK 461

L13 2 F Mesentery 10 Pos TPM3–ALK 121


L15 29 M Mesentery 18 Pos TPM4–ALK 602

L16 36 F Lung 7 Pos No fusion detected 598

L17 13 M Lung 3 Pos Fail

L18 2 M Bladder 5 Pos No fusion detected 341

L19 11 F Lung 2 Pos EML4–ALK 485

L20 7 M Mesentery 14 Pos TPM3–ALK 569


L22 1 M Mesentery 2 Pos Fail

L23 6 F Lung 2 Pos SEC31A–ALK a 1,008


L25 14 M Pelvis 8 Pos TFG–ALK a 844

L26 26 F Bladder 3 Pos FN1–ALK a , b 511

L27 26 F Bladder 7 Pos CLTC–ALK 459

L28 14 M Mesentery 41 Pos CLTC–ALK 326

L29 8 F Bladder 3 Pos FN1–ALK a , b 1,235


L31 9 F Lung Unknown Pos CLTC–ALK 822




L35 <1 F Shoulder Unknown Pos PRKAR1A–ALK 813


L37 6 M Lung 10.1 Neg TFG–ROS1 660

NOTE: A total of 37 FFPE tumor samples from 33 different patients with IMT were included in the analysis. The following samples were obtained from the same patient at different times in his/her disease course: L3/L4, L7/L10, L31/L36, L32/L33/L34. There was 100% concordance in the kinase fusions detected across multiple samples from the same patient. a Suffi cient material was available to verify these kinase fusions with RNA sequencing. b Initial results from the FoundationOne genomic DNA analysis were negative. The FN1–ALK fusion, which harbors an atypical breakpoint within intron 18 of ALK , was detected by RNA sequencing.

Table 1. Summary of clinical characteristics and targeted NGS results for the study cohort






including 8 tyrosine kinases (Supplementary Table S2). This

platform has been previously described and successfully used

in several large genomic studies of various tumor types

( 10–12 ). In each case, tumor DNA was isolated from FFPE

tissue. Average coverage was 543×. Targeted NGS was success-

fully performed in 22 of 26 ALK-positive and 11 of 11 ALK-

negative specimens ( Table 1 and Supplementary Fig. S2). In

cases in which there was suffi cient tumor material available,

the kinase fusions were verifi ed with RNA sequencing.

Among the 11 ALK IHC–negative cases, kinase fusions

were identifi ed in 8 of 11 (73%) of the cases ( Table 1 , Fig. 2A

and B ). Two cases harbored ALK fusions (sample L5, EML4–

ALK ; sample L9, TPM3–ALK ), which were missed by ALK IHC

testing alone. Among the other 9 ALK-negative samples, 4

contained distinct ROS1 fusions (sample L3/L4, YWHAE–

ROS1 ; sample L6, TFG–ROS1 ), including the index patient

(sample L37), and 2 contained a PDGFRβ fusion (samples

L7/L10, NAB2–PDGFRβ ). Notably, neither ROS1 nor PDGFRβ fusions have been described in IMT to date. The genomic

coordinates for each fusion identifi ed are summarized in

Supplementary Table S3. Importantly, all kinase fusions

identifi ed in this study (ALK, ROS1, PDGFRβ) are therapeu-

tically targetable with existing FDA-approved TKIs ( 8 , 13–15 ).

No other recurrent alterations were identifi ed (Supplemen-

tary Table S3). Further analysis of the 3 of 11 samples for

which a kinase fusion was not detected in this targeted NGS

assay is ongoing.

Among the 22 ALK-positive cases analyzed, 20 harbored

ALK gene fusions with various previously described 5′ gene

fusion partners, including TPM3 , TPM4 , SEC31A , TFG ,

RANBP2 , CLTC , and FN1 ( Table 1 ; Fig. 2A and B ). Of note,

the FN1–ALK fusion detected in samples L26 and L29 har-

bors an atypical breakpoint within intron 18 of ALK . This

fusion was initially missed by genomic DNA analysis (which

targeted only intron 19 of ALK ), but later identifi ed with

RNA sequencing. Novel ALK gene fusions were also detected,

including LMNA–ALK (sample L12) and PRKAR1A–ALK

(sample L35). The remaining 2 ALK IHC–positive cases were

also negative for ALK kinase domain mutations and ALK

amplifi cation, suggesting a different mechanism of ALK

expression in these tumor samples.

DISCUSSION IMT is a rare tumor that can arise at multiple anatomic loca-

tions. There are limited systemic therapeutic options available

for patients with surgically unresectable and/or metastatic

disease. Previous data have demonstrated that approximately

50% of IMTs are positive for ALK expression based on results

from IHC. Responses to the TKI crizotinib have been docu-

mented in patients with ALK-positive IMT, demonstrating the

importance of identifying this target ( 6 , 14 ).

In our study, we successfully performed targeted NGS

in 20 of 22 ALK IHC–positive IMT samples and identifi ed

several different ALK gene fusions, with various 5′ gene

fusion partners. Several of these fusion partners have been

previously described, including TPM-3/4 , ATIC , CLTC , CARS ,

and RANBP2 ( 5 ). However, we also identifi ed novel ALK gene

fusions, such as LMNA–ALK and PRKAR1A–ALK , the lat-

ter of which was detected in a congenital IMT. In addition,

Figure 2. Kinase fusions identifi ed in IMT by targeted sequencing. Starting with 37 FFPE IMT samples (26 ALK IHC positive and 11 ALK IHC negative), 33 tumors were evaluable with targeted NGS. A, genomic alterations identifi ed in the 37 IMT tumor samples. Columns, samples; rows, genes. Red bars, ALK fusions; green bars, PDGFRβ fusions; blue bars, ROS1 fusions. The identi-fi ed gene fusions were mutually exclusive. No other recurrent genomic alterations were identifi ed by targeted NGS in these samples. B, schematic representation of the distinct ALK , PDGFRβ , and ROS1 fusions identifi ed. In each case, the exons encompassed within each gene fusion partner are indicated.

A

B

1

ALK

ROS1

PDGFRβ

2 3 4 5 6 7 8 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

Targeted therapy

Crizotinib

Sorafenib

Sunitinib

Regorafenib

Axitinib

Crizotinib

TFGex1 ex4 ex36 ex43

ex36 ex43

ex12 ex23

ex20 ex29

ex20 ex29

ex1 ex4

ex1

ex1

ex1

ex1

ex1

ex1

ex1

ex1

ex1

ex1

ex1 ex31

ex23

ex22

ex18

ex6

ex7

ex2

ex5

ex7

ex2

ex7

ROS1

ROS1

ALK

ALK

ex20 ex29ALK

ex20 ex29ALK

ex20 ex29ALK

ex20 ex29ALK

ex20 ex29ALK

ex20 ex29ALK

ex19 ex29ALK

ex20 ex29ALK

PDGFRβ

YWHAE

NAB2

EML4

LMNA

TPM4

TPM3

TFG

CLTC

FN1

RANBP2

SEC31A

PRKAR1A






we identifi ed ALK fusions with noncanonical fusion break-

points. FN1–ALK , which has previously been described in

ovarian cancer, has a breakpoint in intron 18 of the ALK gene,

whereas most fusions have a breakpoint in ALK intron 19

( 16 ). Because patients with tumors harboring intron 1 (exon

19) ALK fusions can derive clinical benefi t from ALK inhibi-

tor therapy ( 17 ), there is a need to incorporate these atypical

but recurrent fusions into NGS-based diagnostic platforms.

Notably, we also detected ALK fusions in 2 of 11 IMT samples

that tested negative for ALK expression by IHC. Therefore,

the possibility of targeted therapy with an ALK inhibitor

would have been missed for these patients with ALK testing

by IHC alone.

In contrast, there are currently no data about potential

oncogenic “drivers” in the ALK-negative subset of IMTs. We

identifi ed actionable kinase fusions in 8 of 11 ALK-negative

IMT tumors analyzed by targeted NGS, including ROS1 and

PDGFRβ kinase fusions, which have not yet been described in

this disease. PDGFRβ kinase fusions have been described in

myeloproliferative disorders ( 18 ). ROS1 kinase fusions have

been detected in a variety of malignancies, including lung

cancer, glioblastoma, cholangiocarcinoma, and Spitz tumors

(reviewed in ref. 19 ). Crizotinib, which is FDA approved for

the treatment of ALK fusion–positive lung cancer, is also a

potent ROS1 inhibitor. Preliminary results from the phase I

clinical trial of crizotinib in ROS1 fusion–positive lung cancer

demonstrated an objective response rate of 56% ( 9 ). However,

responses in other ROS1 fusion–positive cancers have not

yet been documented. Here, we report that a young boy with

ROS1 fusion–positive IMT responded to crizotinib. This was

the fi rst antitumor response this patient has experienced

since his initial diagnosis more than 2 years before starting

crizotinib; his tumor previously did not respond to four dif-

ferent lines of therapy, including cytotoxic chemotherapy or

anti-infl ammatory agents. His tumor mass decreased in size,

his paraneoplastic anemia improved, and he felt better symp-

tomatically. This case clearly illustrates the need for improved

diagnostic and therapeutic paradigms in this disease.

Overall, our data show for the fi rst time that kinase fusions

are found in the majority of IMTs (85% in our series). To our

knowledge, this study represents the largest genomic analy-

sis of this tumor type to date, and our results redefi ne this

heterogeneous disease as being largely a kinase fusion–driven

neoplasm. These data not only provide insight into this rare

disease but also offer rational targeted therapeutic strate-

gies with existing FDA-approved TKIs based on the genomic

profi le of the tumor. Critical to successful deployment of

this evolving therapeutic paradigm is incorporation of test-

ing with highly sensitive NGS platforms capable of detecting

both known and novel fusions in multiple oncogenes from a

single tumor specimen.

METHODS Patients and Tumor Samples

IMT samples and associated patient characteristics were analyzed

with an Institutional Review Board–approved protocol (#090572).

All clinical data were obtained and maintained according to Health

Insurance Portability and Accountability Act (HIPAA) standards. All

unique identifi ers have been removed before publication.

Genomic DNA Sequencing and Analysis DNA was extracted from FFPE samples. Sequencing was performed

for 3,769 exons of 287 cancer genes and 47 introns of 19 commonly

rearranged genes, including 8 tyrosine kinases (FoundationOne Panel;

Supplementary Table S2) as previously described ( 10 ). Tumor con-

tent was assessed by hematoxylin and eosin staining before analy-

sis; no micro/macro dissection tissue enrichment was performed.

Sequencing was performed on the HiSeq2000 instrument (Illumina)

with 40-bp paired reads to an average depth of 543X. Resultant

sequences were analyzed for base substitutions, insertions, deletions,

copy-number alterations, and select gene fusions ( 10 ). Additional

information about the analytic validation of this assay as well as the

sequencing of RNA is provided in the Supplementary Methods.

Disclosure of Potential Confl icts of Interest C.M. Lovly reports receiving a commercial research grant from

AstraZeneca, has received speakers’ bureau honoraria from Qiagen

and Abbott Molecular, and is a consultant/advisory board mem-

ber for Pfi zer. D. Lipson is director of and has ownership interest

(including patents) in Foundation Medicine. J.S. Ross is medical

director of, reports receiving a commercial research grant from, and

has ownership interest (including patents) in Foundation Medicine.

P.J. Stephens has ownership interest (including patents) in Founda-

tion Medicine, Inc. V.A. Miller is CMO of and has ownership interest

(including patents) in Foundation Medicine. No potential confl icts

of interest were disclosed by the other authors.

Authors’ Contributions Conception and design: C.M. Lovly, D. Lipson, J.S. Ross, C.M. Coffi n

Development of methodology: C.M. Lovly, D. Lipson, G. Otto,

T. Brennan, J.S. Ross, V.A. Miller, C.M. Coffi n

Acquisition of data (provided animals, acquired and managed

patients, provided facilities, etc.): C.M. Lovly, A. Gupta, C.T. Chung,

S.C. Borinstein, J.S. Ross, C.M. Coffi n

Analysis and interpretation of data (e.g., statistical analysis,

biostatistics, computational analysis): C.M. Lovly, D. Lipson,

J.S. Ross, P.J. Stephens, V.A. Miller, C.M. Coffi n

Writing, review, and/or revision of the manuscript: C.M. Lovly,

D. Lipson, C.T. Chung, S.C. Borinstein, J.S. Ross, P.J. Stephens,

V.A. Miller, C.M. Coffi n

Administrative, technical, or material support (i.e., reporting or

organizing data, constructing databases): C.M. Lovly, T. Brennan,

J.S. Ross, C.M. Coffi n

Study supervision: C.M. Lovly, C.M. Coffi n

Acknowledgments The authors thank Drs. Mace Rothenberg and Keith Wilner for

their assistance in obtaining crizotinib for the patient, Drs. William

Pao and Jeff Sosman for their critical review of this article, and Abudi

Nashabi for administrative assistance.

Grant Support This work was supported by the Richard and Valerie Aronsohn

Memorial Research Award from the Sarcoma Foundation of America

and by the Joyce Family Foundation. C.M. Lovly was additionally

supported by an NIH K12 training grant (K12 CA9060625) and a

Damon Runyon Clinical Investigator Award.

The costs of publication of this article were defrayed in part by

the payment of page charges. This article must therefore be hereby

marked advertisement in accordance with 18 U.S.C. Section 1734

solely to indicate this fact.

Received April 9, 2014; revised May 21, 2014; accepted May 21,

2014; published OnlineFirst May 29, 2014.






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2014;4:889-895. Published OnlineFirst May 29, 2014.Cancer Discovery Christine M. Lovly, Abha Gupta, Doron Lipson, et al. Actionable Kinase FusionsInflammatory Myofibroblastic Tumors Harbor Multiple Potentially

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