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Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer


Background:
The identification of prognostic tumor biomarkers that also would have potential as therapeutic targets, particularly in patients with early stage disease, has been a long sought-after goal in the management and treatment of lung cancer. The nuclear receptor (NR) superfamily, which is composed of 48 transcription factors that govern complex physiologic and pathophysiologic processes, could represent a unique subset of these biomarkers. In fact, many members of this family are the targets of already identified selective receptor modulators, providing a direct link between individual tumor NR quantitation and selection of therapy. The goal of this study, which begins this overall strategy, was to investigate the association between mRNA expression of the NR superfamily and the clinical outcome for patients with lung cancer, and to test whether a tumor NR gene signature provided useful information (over available clinical data) for patients with lung cancer.

Methods and Findings:
Using quantitative real-time PCR to study NR expression in 30 microdissected non-small-cell lung cancers (NSCLCs) and their pair-matched normal lung epithelium, we found great variability in NR expression among patients' tumor and non-involved lung epithelium, found a strong association between NR expression and clinical outcome, and identified an NR gene signature from both normal and tumor tissues that predicted patient survival time and disease recurrence. The NR signature derived from the initial 30 NSCLC samples was validated in two independent microarray datasets derived from 442 and 117 resected lung adenocarcinomas. The NR gene signature was also validated in 130 squamous cell carcinomas. The prognostic signature in tumors could be distilled to expression of two NRs, short heterodimer partner and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease. Of equal interest, the studies of microdissected histologically normal epithelium and matched tumors identified expression in normal (but not tumor) epithelium of NGFIB3 and mineralocorticoid receptor as single gene predictors of good prognosis.

Conclusions:
NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease. This study highlights the potential use of NRs as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer.

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


Vyšlo v časopise: Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer. PLoS Med 7(12): e32767. doi:10.1371/journal.pmed.1000378
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pmed.1000378

Souhrn

Background:
The identification of prognostic tumor biomarkers that also would have potential as therapeutic targets, particularly in patients with early stage disease, has been a long sought-after goal in the management and treatment of lung cancer. The nuclear receptor (NR) superfamily, which is composed of 48 transcription factors that govern complex physiologic and pathophysiologic processes, could represent a unique subset of these biomarkers. In fact, many members of this family are the targets of already identified selective receptor modulators, providing a direct link between individual tumor NR quantitation and selection of therapy. The goal of this study, which begins this overall strategy, was to investigate the association between mRNA expression of the NR superfamily and the clinical outcome for patients with lung cancer, and to test whether a tumor NR gene signature provided useful information (over available clinical data) for patients with lung cancer.

Methods and Findings:
Using quantitative real-time PCR to study NR expression in 30 microdissected non-small-cell lung cancers (NSCLCs) and their pair-matched normal lung epithelium, we found great variability in NR expression among patients' tumor and non-involved lung epithelium, found a strong association between NR expression and clinical outcome, and identified an NR gene signature from both normal and tumor tissues that predicted patient survival time and disease recurrence. The NR signature derived from the initial 30 NSCLC samples was validated in two independent microarray datasets derived from 442 and 117 resected lung adenocarcinomas. The NR gene signature was also validated in 130 squamous cell carcinomas. The prognostic signature in tumors could be distilled to expression of two NRs, short heterodimer partner and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease. Of equal interest, the studies of microdissected histologically normal epithelium and matched tumors identified expression in normal (but not tumor) epithelium of NGFIB3 and mineralocorticoid receptor as single gene predictors of good prognosis.

Conclusions:
NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease. This study highlights the potential use of NRs as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer.

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


Zdroje

1. JemalA

SiegelR

WardE

HaoY

XuJ

2009 Cancer statistics, 2009. CA Cancer J Clin 59 225 249

2. SunS

SchillerJH

SpinolaM

MinnaJD

2007 New molecularly targeted therapies for lung cancer. J Clin Invest 117 2740 2750

3. XieY

MinnaJD

2008 Predicting the future for people with lung cancer. Nat Med 14 812 813

4. ChenHY

YuSL

ChenCH

ChangGC

ChenCY

2007 A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med 356 11 20

5. PottiA

MukherjeeS

PetersenR

DressmanHK

BildA

2006 A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. N Engl J Med 355 570 580

6. SheddenK

TaylorJM

EnkemannSA

TsaoMS

YeatmanTJ

2008 Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med 14 822 827

7. ChawlaA

RepaJJ

EvansRM

MangelsdorfDJ

2001 Nuclear receptors and lipid physiology: opening the X-files. Science 294 1866 1870

8. ShulmanAI

MangelsdorfDJ

2005 Retinoid x receptor heterodimers in the metabolic syndrome. N Engl J Med 353 604 615

9. BarishGD

DownesM

AlaynickWA

YuRT

OcampoCB

2005 A Nuclear Receptor Atlas: macrophage activation. Mol Endocrinol 19 2466 2477

10. BookoutAL

JeongY

DownesM

YuRT

EvansRM

2006 Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126 789 799

11. FuM

SunT

BookoutAL

DownesM

YuRT

2005 A Nuclear Receptor Atlas: 3T3-L1 adipogenesis. Mol Endocrinol 19 2437 2450

12. XieCQ

JeongY

FuM

BookoutAL

Garcia-BarrioMT

2009 Expression profiling of nuclear receptors in human and mouse embryonic stem cells. Mol Endocrinol 23 724 733

13. YangX

DownesM

YuRT

BookoutAL

HeW

2006 Nuclear receptor expression links the circadian clock to metabolism. Cell 126 801 810

14. CoombesKR

WangJ

BaggerlyKA

2007 Microarrays: retracing steps. Nat Med 13 1276 1277; author reply 1277–1278

15. GentlemanR

2005 Reproducible research: a bioinformatics case study. Stat Appl Genet Mol Biol 4 Article2

16. LamportL

1994 LaTeX: A document preparation system. Boston Addison Wesley

17. MaitraA

GazdarAF

WistubaII 2001 Microdissection and the study of cancer pathways. Curr Mol Med 1 153 162

18. TomidaS

TakeuchiT

ShimadaY

ArimaC

MatsuoK

2009 Relapse-related molecular signature in lung adenocarcinomas identifies patients with dismal prognosis. J Clin Oncol 27 2793 2799

19. RaponiM

ZhangY

YuJ

ChenG

LeeG

2006 Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung. Cancer Res 66 7466 7472

20. BolstadBM

IrizarryRA

AstrandM

SpeedTP

2003 A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19 185 193

21. EisenMB

SpellmanPT

BrownPO

BotsteinD

1998 Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 95 14863 14868

22. GarzottoM

BeerTM

HudsonRG

PetersL

HsiehYC

2005 Improved detection of prostate cancer using classification and regression tree analysis. J Clin Oncol 23 4322 4329

23. HessKR

AbbruzzeseMC

LenziR

RaberMN

AbbruzzeseJL

1999 Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res 5 3403 3410

24. KoziolJA

ZhangJY

CasianoCA

PengXX

ShiFD

2003 Recursive partitioning as an approach to selection of immune markers for tumor diagnosis. Clin Cancer Res 9 5120 5126

25. ValeraVA

WalterBA

YokoyamaN

KoyamaY

IiaiT

2007 Prognostic groups in colorectal carcinoma patients based on tumor cell proliferation and classification and regression tree (CART) survival analysis. Ann Surg Oncol 14 34 40

26. KaplanEL

MeierP

1958 Nonparametric estimation from incomplete observations. J Am Stat Assoc 53 457 481

27. CollettD

2003 Modelling survival data in medical research, 2nd edition. Boca Raton Chapman & Hall/CRC

28. LandiMT

DrachevaT

RotunnoM

FigueroaJD

LiuH

2008 Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival. PLoS ONE 3 e1651 doi:10.1371/journal.pone.0001651

29. BeerDG

KardiaSL

HuangCC

GiordanoTJ

LevinAM

2002 Gene-expression profiles predict survival of patients with lung adenocarcinoma. Nat Med 8 816 824

30. EndohH

TomidaS

YatabeY

KonishiH

OsadaH

2004 Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction. J Clin Oncol 22 811 819

31. LuY

LemonW

LiuPY

YiY

MorrisonC

2006 A gene expression signature predicts survival of patients with stage I non-small cell lung cancer. PLoS Med 3 e467 doi:10.1371/journal.pmed.0030467

32. JordanVC

2009 A century of deciphering the control mechanisms of sex steroid action in breast and prostate cancer: the origins of targeted therapy and chemoprevention. Cancer Res 69 1243 1254

33. MilesSA

DezubeBJ

LeeJY

KrownSE

FletcherMA

2002 Antitumor activity of oral 9-cis-retinoic acid in HIV-associated Kaposi's sarcoma. AIDS 16 421 429

34. MiyamotoH

MessingEM

ChangC

2004 Androgen deprivation therapy for prostate cancer: current status and future prospects. Prostate 61 332 353

35. RealPJ

FerrandoAA

2009 NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 23 1374 1377

36. IshibashiH

SuzukiT

SuzukiS

NiikawaH

LuL

2005 Progesterone receptor in non-small cell lung cancer—a potent prognostic factor and possible target for endocrine therapy. Cancer Res 65 6450 6458

37. SiegfriedJM

2006 Hormone replacement therapy and decreased lung cancer survival. J Clin Oncol 24 9 10

38. StabileLP

DavisAL

GubishCT

HopkinsTM

LuketichJD

2002 Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res 62 2141 2150

39. StabileLP

LykerJS

GubishCT

ZhangW

GrandisJR

2005 Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects. Cancer Res 65 1459 1470

40. TraynorAM

SchillerJH

StabileLP

KolesarJM

EickhoffJC

2008 Pilot study of gefitinib and fulvestrant in the treatment of post-menopausal women with advanced non-small cell lung cancer. Lung Cancer 64 51 59

41. GirnunGD

NaseriE

VafaiSB

QuL

SzwayaJD

2007 Synergy between PPARgamma ligands and platinum-based drugs in cancer. Cancer Cell 11 395 406

42. ChlebowskiRT

SchwartzAG

WakeleeH

AndersonGL

StefanickML

2009 Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet 374 1243 1251

43. GoodwinB

JonesSA

PriceRR

WatsonMA

McKeeDD

2000 A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6 517 526

44. LuTT

MakishimaM

RepaJJ

SchoonjansK

KerrTA

2000 Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6 507 515

45. NishizawaH

YamagataK

ShimomuraI

TakahashiM

KuriyamaH

2002 Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation. J Biol Chem 277 1586 1592

46. ZhangY

XuP

ParkK

ChoiY

MooreDD

2008 Orphan receptor small heterodimer partner suppresses tumorigenesis by modulating cyclin D1 expression and cellular proliferation. Hepatology 48 289 298

47. ChandaD

ParkJH

ChoiHS

2008 Molecular basis of endocrine regulation by orphan nuclear receptor Small Heterodimer Partner. Endocr J 55 253 268

48. MullicanSE

ZhangS

KonoplevaM

RuvoloV

AndreeffM

2007 Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med 13 730 735

49. Di FabioF

AlvaradoC

MajdanA

GologanA

VodaL

2007 Underexpression of mineralocorticoid receptor in colorectal carcinomas and association with VEGFR-2 overexpression. J Gastrointest Surg 11 1521 1528

Štítky
Interné lekárstvo

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PLOS Medicine


2010 Číslo 12
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Autori: MUDr. Tomáš Ürge, PhD.

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