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Integrative Genomic Analyses Identify as a Novel Lineage-Specific Oncogene in Lung Squamous Cell Carcinoma


Background:
Traditionally, non-small cell lung cancer is treated as a single disease entity in terms of systemic therapy. Emerging evidence suggests the major subtypes—adenocarcinoma (AC) and squamous cell carcinoma (SqCC)—respond differently to therapy. Identification of the molecular differences between these tumor types will have a significant impact in designing novel therapies that can improve the treatment outcome.

Methods and Findings:
We used an integrative genomics approach, combing high-resolution comparative genomic hybridization and gene expression microarray profiles, to compare AC and SqCC tumors in order to uncover alterations at the DNA level, with corresponding gene transcription changes, which are selected for during development of lung cancer subtypes. Through the analysis of multiple independent cohorts of clinical tumor samples (>330), normal lung tissues and bronchial epithelial cells obtained by bronchial brushing in smokers without lung cancer, we identified the overexpression of BRF2, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of BRF2, which encodes a RNA polymerase III (Pol III) transcription initiation factor, was found to be associated with increased expression of small nuclear RNAs (snRNAs) that are involved in processes essential for cell growth, such as RNA splicing. Ectopic expression of BRF2 in human bronchial epithelial cells induced a transformed phenotype and demonstrates downstream oncogenic effects, whereas RNA interference (RNAi)-mediated knockdown suppressed growth and colony formation of SqCC cells overexpressing BRF2, but not AC cells. Frequent activation of BRF2 in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that BRF2 expression is an early event in cancer development of this cell lineage.

Conclusions:
This is the first study, to our knowledge, to show that the focal amplification of a gene in Chromosome 8p12, plays a key role in squamous cell lineage specificity of the disease. Our data suggest that genetic activation of BRF2 represents a unique mechanism of SqCC lung tumorigenesis through the increase of Pol III-mediated transcription. It can serve as a marker for lung SqCC and may provide a novel target for therapy.

: Please see later in the article for the Editors' Summary


Vyšlo v časopise: Integrative Genomic Analyses Identify as a Novel Lineage-Specific Oncogene in Lung Squamous Cell Carcinoma. PLoS Med 7(7): e32767. doi:10.1371/journal.pmed.1000315
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1000315

Souhrn

Background:
Traditionally, non-small cell lung cancer is treated as a single disease entity in terms of systemic therapy. Emerging evidence suggests the major subtypes—adenocarcinoma (AC) and squamous cell carcinoma (SqCC)—respond differently to therapy. Identification of the molecular differences between these tumor types will have a significant impact in designing novel therapies that can improve the treatment outcome.

Methods and Findings:
We used an integrative genomics approach, combing high-resolution comparative genomic hybridization and gene expression microarray profiles, to compare AC and SqCC tumors in order to uncover alterations at the DNA level, with corresponding gene transcription changes, which are selected for during development of lung cancer subtypes. Through the analysis of multiple independent cohorts of clinical tumor samples (>330), normal lung tissues and bronchial epithelial cells obtained by bronchial brushing in smokers without lung cancer, we identified the overexpression of BRF2, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of BRF2, which encodes a RNA polymerase III (Pol III) transcription initiation factor, was found to be associated with increased expression of small nuclear RNAs (snRNAs) that are involved in processes essential for cell growth, such as RNA splicing. Ectopic expression of BRF2 in human bronchial epithelial cells induced a transformed phenotype and demonstrates downstream oncogenic effects, whereas RNA interference (RNAi)-mediated knockdown suppressed growth and colony formation of SqCC cells overexpressing BRF2, but not AC cells. Frequent activation of BRF2 in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that BRF2 expression is an early event in cancer development of this cell lineage.

Conclusions:
This is the first study, to our knowledge, to show that the focal amplification of a gene in Chromosome 8p12, plays a key role in squamous cell lineage specificity of the disease. Our data suggest that genetic activation of BRF2 represents a unique mechanism of SqCC lung tumorigenesis through the increase of Pol III-mediated transcription. It can serve as a marker for lung SqCC and may provide a novel target for therapy.

: Please see later in the article for the Editors' Summary


Zdroje

1. ParkinDM

BrayF

FerlayJ

PisaniP

2005

Global cancer statistics, 2002.

CA Cancer J Clin

55

74

108

2. JemalA

SiegelR

WardE

HaoY

XuJ

2008

Cancer statistics, 2008.

CA Cancer J Clin

58

71

96

3. MurrayCJ

LopezAD

1997

Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study.

Lancet

349

1498

1504

4. TravisWD

2002

Pathology of lung cancer.

Clin Chest Med

23

65

81, viii

5. KimHS

ParkK

JunHJ

YiSY

LeeJ

2009

Comparison of survival in advanced non-small cell lung cancer patients in the pre- and post-gefitinib eras.

Oncology

76

239

246

6. ScagliottiG

HannaN

FossellaF

SugarmanK

BlatterJ

2009

The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies.

Oncologist

14

253

263

7. GarrawayLA

SellersWR

2006

Lineage dependency and lineage-survival oncogenes in human cancer.

Nat Rev Cancer

6

593

602

8. GiangrecoA

GrootKR

JanesSM

2007

Lung cancer and lung stem cells: strange bedfellows?

Am J Respir Crit Care Med

175

547

553

9. FisherGH

WellenSL

KlimstraD

LenczowskiJM

TichelaarJW

2001

Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes.

Genes Dev

15

3249

3262

10. GuerraC

MijimolleN

DhawahirA

DubusP

BarradasM

2003

Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context.

Cancer Cell

4

111

120

11. MeuwissenR

LinnSC

van der ValkM

MooiWJ

BernsA

2001

Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene.

Oncogene

20

6551

6558

12. JohnsonL

MercerK

GreenbaumD

BronsonRT

CrowleyD

2001

Somatic activation of the K-ras oncogene causes early onset lung cancer in mice.

Nature

410

1111

1116

13. GarrawayLA

WeirBA

ZhaoX

WidlundH

BeroukhimR

2005

“Lineage addiction” in human cancer: lessons from integrated genomics.

Cold Spring Harb Symp Quant Biol

70

25

34

14. AlbertsonDG

2006

Gene amplification in cancer.

Trends Genet

22

447

455

15. LockwoodWW

ChariR

CoeBP

GirardL

MacaulayC

2008

DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers.

Oncogene

27

4615

4624

16. KendallJ

LiuQ

BaklehA

KrasnitzA

NguyenKC

2007

Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer.

Proc Natl Acad Sci U S A

104

16663

16668

17. TononG

WongKK

MaulikG

BrennanC

FengB

2005

High-resolution genomic profiles of human lung cancer.

Proc Natl Acad Sci U S A

102

9625

9630

18. GarnisC

DaviesJJ

BuysTP

TsaoMS

MacAulayC

2005

Chromosome 5p aberrations are early events in lung cancer: implication of glial cell line-derived neurotrophic factor in disease progression.

Oncogene

24

4806

4812

19. LockwoodWW

CoeBP

WilliamsAC

MacAulayC

LamWL

2007

Whole genome tiling path array CGH analysis of segmental copy number alterations in cervical cancer cell lines.

Int J Cancer

120

436

443

20. BaldwinC

GarnisC

ZhangL

RosinMP

LamWL

2005

Multiple microalterations detected at high frequency in oral cancer.

Cancer Res

65

7561

7567

21. CoeBP

LockwoodWW

GirardL

ChariR

MacaulayC

2006

Differential disruption of cell cycle pathways in small cell and non-small cell lung cancer.

Br J Cancer

94

1927

1935

22. IshkanianAS

MalloffCA

WatsonSK

DeLeeuwRJ

ChiB

2004

A tiling resolution DNA microarray with complete coverage of the human genome.

Nat Genet

36

299

303

23. WatsonSK

deLeeuwRJ

HorsmanDE

SquireJA

LamWL

2007

Cytogenetically balanced translocations are associated with focal copy number alterations.

Hum Genet

120

795

805

24. KhojastehM

LamWL

WardRK

MacAulayC

2005

A stepwise framework for the normalization of array CGH data.

BMC Bioinformatics

6

274

25. ChiB

DeLeeuwRJ

CoeBP

MacAulayC

LamWL

2004

SeeGH–a software tool for visualization of whole genome array comparative genomic hybridization data.

BMC Bioinformatics

5

13

26. ChiB

deLeeuwRJ

CoeBP

NgRT

MacAulayC

2008

MD-SeeGH: a platform for integrative analysis of multi-dimensional genomic data.

BMC Bioinformatics

9

243

27. JongK

MarchioriE

MeijerG

VaartAV

YlstraB

2004

Breakpoint identification and smoothing of array comparative genomic hybridization data.

Bioinformatics

20

3636

3637

28. BildAH

YaoG

ChangJT

WangQ

PottiA

2006

Oncogenic pathway signatures in human cancers as a guide to targeted therapies.

Nature

439

353

357

29. ChariR

LonerganKM

NgRT

MacAulayC

LamWL

2007

Effect of active smoking on the human bronchial epithelium transcriptome.

BMC Genomics

8

297

30. RamirezRD

SheridanS

GirardL

SatoM

KimY

2004

Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins.

Cancer Res

64

9027

9034

31. SatoM

VaughanMB

GirardL

PeytonM

LeeW

2006

Multiple oncogenic changes (K-RAS(V12), p53 knockdown, mutant EGFRs, p16 bypass, telomerase) are not sufficient to confer a full malignant phenotype on human bronchial epithelial cells.

Cancer Res

66

2116

2128

32. SambrookJ

RussellDW

2001

Molecular cloning: a laboratory manual

New York

Cold Spring Harbor Laboratory Press

33. TusherVG

TibshiraniR

ChuG

2001

Significance analysis of microarrays applied to the ionizing radiation response.

Proc Natl Acad Sci U S A

98

5116

5121

34. LukC

TsaoMS

BayaniJ

ShepherdF

SquireJA

2001

Molecular cytogenetic analysis of non-small cell lung carcinoma by spectral karyotyping and comparative genomic hybridization.

Cancer Genet Cytogenet

125

87

99

35. SySM

WongN

LeeTW

TseG

MokTS

2004

Distinct patterns of genetic alterations in adenocarcinoma and squamous cell carcinoma of the lung.

Eur J Cancer

40

1082

1094

36. CroceCM

2008

Oncogenes and cancer.

N Engl J Med

358

502

511

37. ZhaoX

WeirBA

LaFramboiseT

LinM

BeroukhimR

2005

Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis.

Cancer Res

65

5561

5570

38. SchrammL

PendergrastPS

SunY

HernandezN

2000

Different human TFIIIB activities direct RNA polymerase III transcription from TATA-containing and TATA-less promoters.

Genes Dev

14

2650

2663

39. CabartP

MurphyS

2001

BRFU, a TFIIB-like factor, is directly recruited to the TATA-box of polymerase III small nuclear RNA gene promoters through its interaction with TATA-binding protein.

J Biol Chem

276

43056

43064

40. WhiteRJ

2004

RNA polymerase III transcription and cancer.

Oncogene

23

3208

3216

41. WhiteRJ

2005

RNA polymerases I and III, growth control and cancer.

Nat Rev Mol Cell Biol

6

69

78

42. GoodfellowSJ

WhiteRJ

2007

Regulation of RNA polymerase III transcription during mammalian cell growth.

Cell Cycle

6

2323

2326

43. WoiwodeA

JohnsonSA

ZhongS

ZhangC

RoederRG

2008

PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex.

Mol Cell Biol

28

4204

4214

44. Felton-EdkinsZA

KennethNS

BrownTR

DalyNL

Gomez-RomanN

2003

Direct regulation of RNA polymerase III transcription by RB, p53 and c-Myc.

Cell Cycle

2

181

184

45. Gomez-RomanN

Felton-EdkinsZA

KennethNS

GoodfellowSJ

AthineosD

2006

Activation by c-Myc of transcription by RNA polymerases I, II and III.

Biochem Soc Symp

141

154

46. MarshallL

KennethNS

WhiteRJ

2008

Elevated tRNA(iMet) synthesis can drive cell proliferation and oncogenic transformation.

Cell

133

78

89

47. JohnsonSA

DubeauL

JohnsonDL

2008

Enhanced RNA polymerase III-dependent transcription is required for oncogenic transformation.

J Biol Chem

283

19184

19191

48. SchrammL

HernandezN

2002

Recruitment of RNA polymerase III to its target promoters.

Genes Dev

16

2593

2620

49. SaxenaA

MaB

SchrammL

HernandezN

2005

Structure-function analysis of the human TFIIB-related factor II protein reveals an essential role for the C-terminal domain in RNA polymerase III transcription.

Mol Cell Biol

25

9406

9418

50. DieciG

FiorinoG

CastelnuovoM

TeichmannM

PaganoA

2007

The expanding RNA polymerase III transcriptome.

Trends Genet

23

614

622

51. CabarcasS

JacobJ

VerasI

SchrammL

2008

Differential expression of the TFIIIB subunits Brf1 and Brf2 in cancer cells.

BMC Mol Biol

9

74

52. WistubaII

GazdarAF

2006

Lung cancer preneoplasia.

Annu Rev Pathol

1

331

348

53. SatoM

ShamesDS

GazdarAF

MinnaJD

2007

A translational view of the molecular pathogenesis of lung cancer.

J Thorac Oncol

2

327

343

54. RewDA

2003

Small RNAs: a new class of genome regulators and their significance.

Eur J Surg Oncol

29

764

765

55. ButcherSE

BrowDA

2005

Towards understanding the catalytic core structure of the spliceosome.

Biochem Soc Trans

33

447

449

56. FaustinoNA

CooperTA

2003

Pre-mRNA splicing and human disease.

Genes Dev

17

419

437

57. HenryRW

MittalV

MaB

KobayashiR

HernandezN

1998

SNAP19 mediates the assembly of a functional core promoter complex (SNAPc) shared by RNA polymerases II and III.

Genes Dev

12

2664

2672

58. KweiKA

KimYH

GirardL

KaoJ

Pacyna-GengelbachM

2008

Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer.

Oncogene

27

3635

3640

59. TanakaH

YanagisawaK

ShinjoK

TaguchiA

MaenoK

2007

Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1.

Cancer Res

67

6007

6011

60. WeirBA

WooMS

GetzG

PernerS

DingL

2007

Characterizing the cancer genome in lung adenocarcinoma.

Nature

450

893

898

61. PernerS

WagnerPL

SoltermannA

LaFargueC

TischlerV

2009

TTF1 expression in non-small cell lung carcinoma: association with TTF1 gene amplification and improved survival.

J Pathol

217

65

72

62. HerbstRS

HeymachJV

LippmanSM

2008

Lung cancer.

N Engl J Med

359

1367

1380

63. BassAJ

2009

SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas.

Nat Genet

41

1238

1242

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Interné lekárstvo

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PLOS Medicine


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