Voltar
Artigo Acesso aberto Revisado por pares
BIBTEX RIS

Single-Cell Genetic Analysis Reveals Insights into Clonal Development of Prostate Cancers and Indicates Loss of PTEN as a Marker of Poor Prognosis

2014; Elsevier BV; Volume: 184; Issue: 10 Linguagem: Inglês

10.1016/j.ajpath.2014.06.030

ISSN

1525-2191

Autores

Kerstin Heselmeyer‐Haddad, Lissa Y. Berroa Garcia, Allan Bradley, Leanora S. Hernandez, Yue Hu, Jens K. Habermann, Christoph Dumke, Christoph Thorns, Sven Perner, Ekaterina Pestova, Catherine Burke, Salim A. Chowdhury, Russell Schwartz, Alejandro A. Schäffer, Pamela L. Paris, Thomas Ried,

Tópico(s)

Cancer-related molecular mechanisms research

Resumo

Gauging the risk of developing progressive disease is a major challenge in prostate cancer patient management. We used genetic markers to understand genomic alteration dynamics during disease progression. By using a novel, advanced, multicolor fluorescence in situ hybridization approach, we enumerated copy numbers of six genes previously identified by array comparative genomic hybridization to be involved in aggressive prostate cancer [TBL1XR1, CTTNBP2, MYC (alias c-myc), PTEN, MEN1, and PDGFB] in six nonrecurrent and seven recurrent radical prostatectomy cases. An ERG break-apart probe to detect TMPRSS2-ERG fusions was included. Subsequent hybridization of probe panels and cell relocation resulted in signal counts for all probes in each individual cell analyzed. Differences in the degree of chromosomal and genomic instability (ie, tumor heterogeneity) or the percentage of cells with TMPRSS2-ERG fusion between samples with or without progression were not observed. Tumors from patients that progressed had more chromosomal gains and losses, and showed a higher degree of selection for a predominant clonal pattern. PTEN loss was the most frequent aberration in progressers (57%), followed by TBL1XR1 gain (29%). MYC gain was observed in one progresser, which was the only lesion with an ERG gain, but no TMPRSS2-ERG fusion. According to our results, a probe set consisting of PTEN, MYC, and TBL1XR1 would detect progressers with 86% sensitivity and 100% specificity. This will be evaluated further in larger studies. Gauging the risk of developing progressive disease is a major challenge in prostate cancer patient management. We used genetic markers to understand genomic alteration dynamics during disease progression. By using a novel, advanced, multicolor fluorescence in situ hybridization approach, we enumerated copy numbers of six genes previously identified by array comparative genomic hybridization to be involved in aggressive prostate cancer [TBL1XR1, CTTNBP2, MYC (alias c-myc), PTEN, MEN1, and PDGFB] in six nonrecurrent and seven recurrent radical prostatectomy cases. An ERG break-apart probe to detect TMPRSS2-ERG fusions was included. Subsequent hybridization of probe panels and cell relocation resulted in signal counts for all probes in each individual cell analyzed. Differences in the degree of chromosomal and genomic instability (ie, tumor heterogeneity) or the percentage of cells with TMPRSS2-ERG fusion between samples with or without progression were not observed. Tumors from patients that progressed had more chromosomal gains and losses, and showed a higher degree of selection for a predominant clonal pattern. PTEN loss was the most frequent aberration in progressers (57%), followed by TBL1XR1 gain (29%). MYC gain was observed in one progresser, which was the only lesion with an ERG gain, but no TMPRSS2-ERG fusion. According to our results, a probe set consisting of PTEN, MYC, and TBL1XR1 would detect progressers with 86% sensitivity and 100% specificity. This will be evaluated further in larger studies. Prostate cancer is the most commonly diagnosed noncutaneous neoplasm among US males (238,590 estimated cases in 2013) and is the second leading cause of cancer-related deaths (29,720 estimated deaths).1Siegel R. Naishadham D. Jemal A. Cancer statistics, 2013.CA Cancer J Clin. 2013; 63: 11-30Crossref PubMed Scopus (11579) Google Scholar Disease incidence exceeds mortality by a factor of 8; this suggests that many prostate cancers do not result in disease-associated death. This observation is attributable to the fact that many prostate cancers do not progress to metastatic disease. Patients with more indolent tumors would benefit from an active surveillance approach. Men with aggressive disease, however, need immediate and often adjuvant therapy after radical prostatectomy (RP) to improve survival. Although serum-level screening for prostate-specific antigen (PSA) has increased detection of prostate cancer at earlier stages,2Brawley O.W. Prostate cancer epidemiology in the United States.World J Urol. 2012; 30: 195-200Crossref PubMed Scopus (245) Google Scholar sensitive and specific tests to distinguish men with indolent disease from men with aggressive prostate cancers are still lacking, which generates a dilemma in how to adapt risk-associated treatments.3Logothetis C.J. Gallick G.E. Maity S.N. Kim J. Aparicio A. Efstathiou E. Lin S.H. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer.Cancer Discov. 2013; 3: 849-861Crossref PubMed Scopus (106) Google Scholar Numerous studies have identified genomic changes as potential predictors of progression.3Logothetis C.J. Gallick G.E. Maity S.N. Kim J. Aparicio A. Efstathiou E. Lin S.H. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer.Cancer Discov. 2013; 3: 849-861Crossref PubMed Scopus (106) Google Scholar, 4Mousses S. Bubendorf L. Wagner U. Hostetter G. Kononen J. Cornelison R. Goldberger N. Elkahloun A.G. Willi N. Koivisto P. Ferhle W. Raffeld M. Sauter G. Kallioniemi O.P. Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays.Cancer Res. 2002; 62: 1256-1260PubMed Google Scholar, 5Malhotra S. Lapointe J. Salari K. Higgins J.P. Ferrari M. Montgomery K. van de Rijn M. Brooks J.D. Pollack J.R. A tri-marker proliferation index predicts biochemical recurrence after surgery for prostate cancer.PLoS One. 2011; 6: e20293Crossref PubMed Scopus (35) Google Scholar, 6Vainio P. Mpindi J.P. Kohonen P. Fey V. Mirtti T. Alanen K.A. Perala M. Kallioniemi O. Iljin K. High-throughput transcriptomic and RNAi analysis identifies AIM1, ERGIC1, TMED3 and TPX2 as potential drug targets in prostate cancer.PLoS One. 2012; 7: e39801Crossref PubMed Scopus (51) Google Scholar, 7Roychowdhury S. Chinnaiyan A.M. Advancing precision medicine for prostate cancer through genomics.J Clin Oncol. 2013; 31: 1866-1873Crossref PubMed Scopus (77) Google Scholar, 8Zellweger T. Sturm S. Rey S. Zlobec I. Gsponer J.R. Rentsch C.A. Terracciano L.M. Bachmann A. Bubendorf L. Ruiz C. Estrogen receptor beta expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naive prostate cancer and are elevated in castration-resistant disease.Endocr Relat Cancer. 2013; 20: 403-413Crossref PubMed Scopus (38) Google Scholar Perhaps the best-known tumor marker specific to prostate cancer is the fusion of TMPRSS2 and ERG on chromosome 21.9Tomlins S.A. Rhodes D.R. Perner S. Dhanasekaran S.M. Mehra R. Sun X.W. Varambally S. Cao X. Tchinda J. Kuefer R. Lee C. Montie J.E. Shah R.B. Pienta K.J. Rubin M.A. Chinnaiyan A.M. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer.Science. 2005; 310: 644-648Crossref PubMed Scopus (3147) Google Scholar Fusions of these two genes have been observed in approximately 30% to 60% of prostate cancers,9Tomlins S.A. Rhodes D.R. Perner S. Dhanasekaran S.M. Mehra R. Sun X.W. Varambally S. Cao X. Tchinda J. Kuefer R. Lee C. Montie J.E. Shah R.B. Pienta K.J. Rubin M.A. Chinnaiyan A.M. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer.Science. 2005; 310: 644-648Crossref PubMed Scopus (3147) Google Scholar, 10Perner S. Demichelis F. Beroukhim R. Schmidt F.H. Mosquera J.M. Setlur S. Tchinda J. Tomlins S.A. Hofer M.D. Pienta K.G. Kuefer R. Vessella R. Sun X.W. Meyerson M. Lee C. Sellers W.R. Chinnaiyan A.M. Rubin M.A. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer.Cancer Res. 2006; 66: 8337-8341Crossref PubMed Scopus (432) Google Scholar, 11Soller M.J. Isaksson M. Elfving P. Soller W. Lundgren R. Panagopoulos I. Confirmation of the high frequency of the TMPRSS2/ERG fusion gene in prostate cancer.Genes Chromosomes Cancer. 2006; 45: 717-719Crossref PubMed Scopus (168) Google Scholar, 12Wang J. Cai Y. Ren C. Ittmann M. Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer.Cancer Res. 2006; 66: 8347-8351Crossref PubMed Scopus (326) Google Scholar, 13Tu J.J. Rohan S. Kao J. Kitabayashi N. Mathew S. Chen Y.T. Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues.Mod Pathol. 2007; 20: 921-928Crossref PubMed Scopus (147) Google Scholar, 14Mehra R. Tomlins S.A. Shen R. Nadeem O. Wang L. Wei J.T. Pienta K.J. Ghosh D. Rubin M.A. Chinnaiyan A.M. Shah R.B. Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer.Mod Pathol. 2007; 20: 538-544Crossref PubMed Scopus (248) Google Scholar, 15Attard G. Clark J. Ambroisine L. Fisher G. Kovacs G. Flohr P. Berney D. Foster C.S. Fletcher A. Gerald W.L. Moller H. Reuter V. De Bono J.S. Scardino P. Cuzick J. Cooper C.S. Group T.P. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer.Oncogene. 2008; 27: 253-263Crossref PubMed Scopus (382) Google Scholar, 16Gopalan A. Leversha M.A. Satagopan J.M. Zhou Q. Al-Ahmadie H.A. Fine S.W. Eastham J.A. Scardino P.T. Scher H.I. Tickoo S.K. Reuter V.E. Gerald W.L. TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy.Cancer Res. 2009; 69: 1400-1406Crossref PubMed Scopus (221) Google Scholar, 17Park K. Tomlins S.A. Mudaliar K.M. Chiu Y.L. Esgueva R. Mehra R. Suleman K. Varambally S. Brenner J.C. MacDonald T. Srivastava A. Tewari A.K. Sathyanarayana U. Nagy D. Pestano G. Kunju L.P. Demichelis F. Chinnaiyan A.M. Rubin M.A. Antibody-based detection of ERG rearrangement-positive prostate cancer.Neoplasia. 2010; 12: 590-598Abstract Full Text PDF PubMed Scopus (294) Google Scholar but whether the gene fusion predicts tumor progression is controversial.12Wang J. Cai Y. Ren C. Ittmann M. Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer.Cancer Res. 2006; 66: 8347-8351Crossref PubMed Scopus (326) Google Scholar, 18FitzGerald L.M. Agalliu I. Johnson K. Miller M.A. Kwon E.M. Hurtado-Coll A. Fazli L. Rajput A.B. Gleave M.E. Cox M.E. Ostrander E.A. Stanford J.L. Huntsman D.G. Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer.BMC Cancer. 2008; 8: 230Crossref PubMed Scopus (133) Google Scholar, 19Barwick B.G. Abramovitz M. Kodani M. Moreno C.S. Nam R. Tang W. Bouzyk M. Seth A. Leyland-Jones B. Prostate cancer genes associated with TMPRSS2-ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts.Br J Cancer. 2010; 102: 570-576Crossref PubMed Scopus (52) Google Scholar One explanation might be that many possible TMPRSS2-ERG fusions exist, which result in transcripts with different consequences for disease prognostication.13Tu J.J. Rohan S. Kao J. Kitabayashi N. Mathew S. Chen Y.T. Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues.Mod Pathol. 2007; 20: 921-928Crossref PubMed Scopus (147) Google Scholar, 20Clark J. Merson S. Jhavar S. Flohr P. Edwards S. Foster C.S. Eeles R. Martin F.L. Phillips D.H. Crundwell M. Christmas T. Thompson A. Fisher C. Kovacs G. Cooper C.S. Diversity of TMPRSS2-ERG fusion transcripts in the human prostate.Oncogene. 2007; 26: 2667-2673Crossref PubMed Scopus (208) Google Scholar, 21Liu W. Ewing C.M. Chang B.L. Li T. Sun J. Turner A.R. Dimitrov L. Zhu Y. Sun J. Kim J.W. Zheng S.L. Isaacs W.B. Xu J. Multiple genomic alterations on 21q22 predict various TMPRSS2/ERG fusion transcripts in human prostate cancers.Genes Chromosomes Cancer. 2007; 46: 972-980Crossref PubMed Scopus (41) Google Scholar, 22Zammarchi F. Boutsalis G. Cartegni L. 5′ UTR control of native ERG and of Tmprss2:ERG variants activity in prostate cancer.PLoS One. 2013; 8: e49721Crossref PubMed Scopus (25) Google Scholar An additional problem in elucidating the role of TMPRSS2-ERG in tumor progression might be intratumor heterogeneity.23Furusato B. Tan S.H. Young D. Dobi A. Sun C. Mohamed A.A. Thangapazham R. Chen Y. McMaster G. Sreenath T. Petrovics G. McLeod D.G. Srivastava S. Sesterhenn I.A. ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification.Prostate Cancer Prostatic Dis. 2010; 13: 228-237Crossref PubMed Scopus (201) Google Scholar, 24Mertz K.D. Horcic M. Hailemariam S. D'Antonio A. Dirnhofer S. Hartmann A. Agaimy A. Eppenberger-Castori S. Obermann E. Cathomas G. Bubendorf L. Heterogeneity of ERG expression in core needle biopsies of patients with early prostate cancer.Hum Pathol. 2013; 44: 2727-2735Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 25Yoshimoto M. Ding K. Sweet J.M. Ludkovski O. Trottier G. Song K.S. Joshua A.M. Fleshner N.E. Squire J.A. Evans A.J. PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade.Mod Pathol. 2013; 26: 435-447Crossref PubMed Scopus (64) Google Scholar Deep sequencing of somatic mutations26Tao Y. Ruan J. Yeh S.H. Lu X. Wang Y. Zhai W. et al.Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data.Proc Natl Acad Sci U S A. 2011; 108: 12042-12047Crossref PubMed Scopus (112) Google Scholar, 27Navin N. Kendall J. Troge J. Andrews P. Rodgers L. McIndoo J. Cook K. Stepansky A. Levy D. Esposito D. Muthuswamy L. Krasnitz A. McCombie W.R. Hicks J. Wigler M. Tumour evolution inferred by single-cell sequencing.Nature. 2011; 472: 90-94Crossref PubMed Scopus (1867) Google Scholar, 28Hou Y. Song L. Zhu P. Zhang B. Tao Y. Xu X. et al.Single-cell exome sequencing and monoclonal evolution of a JAK2-negative myeloproliferative neoplasm.Cell. 2012; 148: 873-885Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar and approaches to enumerate copy number variation on the level of single cells29Snuderl M. Fazlollahi L. Le L.P. Nitta M. Zhelyazkova B.H. Davidson C.J. Akhavanfard S. Cahill D.P. Aldape K.D. Betensky R.A. Louis D.N. Iafrate A.J. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.Cancer Cell. 2011; 20: 810-817Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 30Szerlip N.J. Pedraza A. Chakravarty D. Azim M. McGuire J. Fang Y. Ozawa T. Holland E.C. Huse J.T. Jhanwar S. Leversha M.A. Mikkelsen T. Brennan C.W. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response.Proc Natl Acad Sci U S A. 2012; 109: 3041-3046Crossref PubMed Scopus (382) Google Scholar, 31Heselmeyer-Haddad K. Berroa Garcia L.Y. Bradley A. Ortiz-Melendez C. Lee W.J. Christensen R. Prindiville S.A. Calzone K.A. Soballe P.W. Hu Y. Chowdhury S.A. Schwartz R. Schäffer A.A. Ried T. Single-cell genetic analysis of ductal carcinoma in situ and invasive breast cancer reveals enormous tumor heterogeneity yet conserved genomic imbalances and gain of MYC during progression.Am J Pathol. 2012; 181: 1807-1822Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar in cancer have led to increasing recognition of the importance of such intratumor heterogeneity in cancer progression. Herein, we explore intratumor heterogeneity of prostate tumors using a special break-apart probe for the TMPRSS2-ERG fusion10Perner S. Demichelis F. Beroukhim R. Schmidt F.H. Mosquera J.M. Setlur S. Tchinda J. Tomlins S.A. Hofer M.D. Pienta K.G. Kuefer R. Vessella R. Sun X.W. Meyerson M. Lee C. Sellers W.R. Chinnaiyan A.M. Rubin M.A. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer.Cancer Res. 2006; 66: 8337-8341Crossref PubMed Scopus (432) Google Scholar and six single-gene probes selected on the basis of a prior array comparative genome hybridization (aCGH) study.32Paris P.L. Andaya A. Fridlyand J. Jain A.N. Weinberg V. Kowbel D. Brebner J.H. Simko J. Watson J.E.V. Volik S. Albertson D.G. Pinkel D. Alers J.C. van der Kwast T.H. Vissers K.J. Schroder F.H. Wildhagen M.F. Febbo P.G. Chinnaiyan A.M. Pienta K.J. Carroll P.R. Rubin M.A. Collins C. van Dekken H. Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors.Hum Mol Genet. 2004; 13: 1303-1313Crossref PubMed Scopus (163) Google Scholar Paris et al32Paris P.L. Andaya A. Fridlyand J. Jain A.N. Weinberg V. Kowbel D. Brebner J.H. Simko J. Watson J.E.V. Volik S. Albertson D.G. Pinkel D. Alers J.C. van der Kwast T.H. Vissers K.J. Schroder F.H. Wildhagen M.F. Febbo P.G. Chinnaiyan A.M. Pienta K.J. Carroll P.R. Rubin M.A. Collins C. van Dekken H. Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors.Hum Mol Genet. 2004; 13: 1303-1313Crossref PubMed Scopus (163) Google Scholar screened prostate cancers treated with RP from patients with similar high recurrence risk, but different clinical outcomes, for chromosomal aberrations with aCGH. Comparison with an independent set of metastases revealed approximately 40 candidate markers associated with metastatic potential. For the current study, we chose six of these markers (listed herein in chromosome order)—TBL1XR1 (3q26.23), CTTNBP2 (7q31.2), MYC (alias c-myc; 8q24.21), PTEN (10q23.1), MEN1 (11q13), and PDGFB (22q13.1)—to be tested for their potential use as indicators of progressive disease. The markers and two centromeric control/enumerator probes (CEP8 and CEP10) were applied as fluorescence in situ hybridization (FISH) probes to single-cell suspensions prepared from archived formalin-fixed, paraffin-embedded (FFPE) material for a subset of cases from the original study32Paris P.L. Andaya A. Fridlyand J. Jain A.N. Weinberg V. Kowbel D. Brebner J.H. Simko J. Watson J.E.V. Volik S. Albertson D.G. Pinkel D. Alers J.C. van der Kwast T.H. Vissers K.J. Schroder F.H. Wildhagen M.F. Febbo P.G. Chinnaiyan A.M. Pienta K.J. Carroll P.R. Rubin M.A. Collins C. van Dekken H. Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors.Hum Mol Genet. 2004; 13: 1303-1313Crossref PubMed Scopus (163) Google Scholar (ie, seven prostate cancers from patients with recurrence and six tumors from patients without recurrence after RP). Our novel approach of multiplexing FISH probes31Heselmeyer-Haddad K. Berroa Garcia L.Y. Bradley A. Ortiz-Melendez C. Lee W.J. Christensen R. Prindiville S.A. Calzone K.A. Soballe P.W. Hu Y. Chowdhury S.A. Schwartz R. Schäffer A.A. Ried T. Single-cell genetic analysis of ductal carcinoma in situ and invasive breast cancer reveals enormous tumor heterogeneity yet conserved genomic imbalances and gain of MYC during progression.Am J Pathol. 2012; 181: 1807-1822Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar allowed signal enumeration in the same cells. Probes were selected on the basis of the aCGH loci mapping to a gene. Two of the gene probes represent genes with well-known roles in prostate cancers, MYC33Jenkins R.B. Qian J. Lieber M.M. Bostwick D.G. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization.Cancer Res. 1997; 57: 524-531PubMed Google Scholar, 34Sato H. Minei S. Hachiya T. Yoshida T. Takimoto Y. Fluorescence in situ hybridization analysis of c-myc amplification in stage TNM prostate cancer in Japanese patients.Int J Urol. 2006; 13: 761-766Crossref PubMed Scopus (33) Google Scholar and PTEN.35Cairns P. Okami K. Halachmi S. Halachmi N. Esteller M. Herman J.G. Jen J. Isaacs W.B. Bova G.S. Sidransky D. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer.Cancer Res. 1997; 57: 4997-5000PubMed Google Scholar, 36Steck P.A. Pershouse M.A. Jasser S.A. Yung W.K. Lin H. Ligon A.H. Langford L.A. Baumgard M.L. Hattier T. Davis T. Frye C. Hu R. Swedlund B. Teng D.H.R. Tavtigian S.V. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.Nat Genet. 1997; 15: 356-362Crossref PubMed Scopus (2526) Google Scholar Many prostate cancer studies have reported the co-occurrence of TMPRSS2-ERG fusion and loss of PTEN37Phin S. Moore M.W. Cotter P.D. Genomic rearrangements of PTEN in prostate cancer.Front Oncol. 2013; 3: 240Crossref PubMed Scopus (90) Google Scholar, 38Leinonen K.A. Saramaki O.R. Furusato B. Kimura T. Takahashi H. Egawa S. Suzuki H. Keiger K. Ho Hahm S. Isaacs W.B. Tolonen T.T. Stenman U.H. Tammela T.L. Nykter M. Bova G.S. Visakorpi T. Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer.Cancer Epidemiol Biomarkers Prev. 2013; 22: 2333-2344Crossref PubMed Scopus (109) Google Scholar; others have reported the co-occurrence of gain of MYC and loss of PTEN.39Lapointe J. Li C. Giacomini C.P. Salari K. Huang S. Wang P. Ferrari M. Hernandez-Boussard T. Brooks J.D. Pollack J.R. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis.Cancer Res. 2007; 67: 8504-8510Crossref PubMed Scopus (226) Google Scholar, 40Zafarana G. Ishkanian A.S. Malloff C.A. Locke J.A. Sykes J. Thoms J. Lam W.L. Squire J.A. Yoshimoto M. Ramnarine V.R. Meng A. Ahmed O. Jurisca I. Milosevic M. Pintilie M. van der Kwast T. Bristow R.G. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy.Cancer. 2012; 118: 4053-4062Crossref PubMed Scopus (98) Google Scholar A third gene in our probe set, MEN1, is a known cancer-associated gene, but with few studies in prostate cancer. TBL1XR1, CTTNBP2, and PDGFB have rarely been the objects of targeted studies in prostate cancer, but there is evidence supporting their potential relevance to prostate cancer. Biallelic inactivation of MEN1 results in multiple endocrine neoplasia, type 1,41Chandrasekharappa S.C. Guru S.C. Manickam P. Olufemi S.-E. Collins F.S. Emmert-Buck M.R. Debelenko L.V. Zhuang Z. Lubensky I.A. Liotta L.A. Crabtree J.S. Wang Y. Roe B.A. Weisemann J. Boguski M.S. Agarwal S.K. Kester M.B. Kim Y.S. Heppner C. Dong Q. Spiegel A.M. Burns A.L. Marx S.J. Positional cloning of the gene for multiple endocrine neoplasia-type 1.Science. 1997; 276: 404-407Crossref PubMed Scopus (1700) Google Scholar leading to hormone-related tumors, and MEN1 is considered to function as a classic tumor suppressor. Men1+/− mice are susceptible to prostate cancer.42Seigne C. Fontanière S. Carreira C. Lu J. Tong W.-M. Fontanière B. Wang Z.-Q. Zhang C.X. Frappart L. Characterisation of prostate cancer lesions in heterozygous Men1 mutant mice.BMC Cancer. 2010; 10: 395Crossref PubMed Scopus (18) Google Scholar In human prostate cancer, however, MEN1 has copy number gains and is usually overexpressed, making it an oncogene.43Paris P.L. Sridharan S. Hittelman A.B. Kobayashi Y. Perner S. Huang G. Simko J. Carroll P. Rubin M.A. Collins C. An oncogenic role for the multiple endocrine neoplasia type 1 gene in prostate cancer.Prostate Cancer Prostatic Dis. 2009; 12: 184-191Crossref PubMed Scopus (15) Google Scholar, 44Lapointe J. Li C. Higgins J.P. van de Rijn M. Bair E. Montgomery K. Ferrari M. Egevad L. Rayford W. Bergerheim U. Ekman P. DeMarzo A.M. Tibshirani R. Botstein D. Brown P.O. Brooks J.D. Pollack J.R. Gene expression profiling identifies clinically relevant subtypes of prostate cancer.Proc Natl Acad Sci U S A. 2004; 101: 811-816Crossref PubMed Scopus (1064) Google Scholar TBL1XR1 is an E3 ubiquitin ligase, which is expressed in the prostate.45Zhang X.M. Chang Q. Zeng L. Gu J. Brown S. Basch R.S. TBLR1 regulates the expression of nuclear hormone receptor co-repressors.BMC Cell Biol. 2006; 7: 31Crossref PubMed Scopus (34) Google Scholar One of its principal functions is to recruit β-catenin to the promoters of Wnt target genes.46Li J. Wang C.Y. TBL1-TBLR1 and beta-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis.Nat Cell Biol. 2008; 10: 160-169Crossref PubMed Scopus (137) Google Scholar The β-catenin binding leads to increased transcription of lymphoid enhancer-binding factor 1 target genes by displacing proteins of the transcriptional repressor family called transducing-like enhancers from lymphoid enhancer-binding factor 1.47Daniels D.L. Weis W.I. Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation.Nat Struct Mol Biol. 2005; 12: 364-371Crossref PubMed Scopus (435) Google Scholar Evidence implicating increased nuclear location of β-catenin in prostate cancer and its progression includes the following: i) various associations between increased Wnt signaling and prostate cancer metastasis to the bone, ii) somatic mutations in specific regions of CTNNB1, the gene encoding β-catenin, in 5% of prostate cancers, iii) significantly increased frequency of positive nuclear staining for β-catenin in prostate cancers, and iv) both direct and indirect regulatory effects of β-catenin binding to the AR gene, which encodes the androgen receptor.48Robinson D.R. Zylstra C.R. Williams B.O. Wnt signaling and prostate cancer.Curr Drug Targets. 2008; 9: 571-580Crossref PubMed Scopus (86) Google Scholar As for MEN1, whether TBL1XR1 functions as an oncogene or as a tumor suppressor varies by tumor type. TBL1XR1 is overexpressed and in a region of recurrent copy number gains in lung cancer49Liu Y. Sun W. Zhang K. Zheng H. Ma Y. Lin D. Zhang X. Feng L. Lei W. Zhang Z. Guo S. Han N. Tong W. Feng X. Gao Y. Cheng S. Identification of genes differentially expressed in human primary lung squamous cell carcinoma.Lung Cancer. 2007; 56: 307-317Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar and in breast cancer.50Gonzalez-Aguilar A. Idbaih A. Boisselier B. Habbita N. Rossetto M. Laurenge A. Bruno A. Jouvet A. Polivka M. Adam C. Figarella-Branger D. Miquel C. Vital A. Ghesquières H. Gressin R. Delwail V. Taillandier L. Chinot O. Soubeyran P. Gyan E. Choquet S. Houillier C. Soussain C. Tanguy M.L. Marie Y. Mokhtari K. Hoang-Xuan K. Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas.Clin Cancer Res. 2012; 18: 5203-5211Crossref PubMed Scopus (180) Google Scholar However, TBL1XR1 is recurrently mutated or deleted in hematological malignancies,50Gonzalez-Aguilar A. Idbaih A. Boisselier B. Habbita N. Rossetto M. Laurenge A. Bruno A. Jouvet A. Polivka M. Adam C. Figarella-Branger D. Miquel C. Vital A. Ghesquières H. Gressin R. Delwail V. Taillandier L. Chinot O. Soubeyran P. Gyan E. Choquet S. Houillier C. Soussain C. Tanguy M.L. Marie Y. Mokhtari K. Hoang-Xuan K. Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas.Clin Cancer Res. 2012; 18: 5203-5211Crossref PubMed Scopus (180) Google Scholar and its expression inhibits the growth of head and neck cancer cells.45Zhang X.M. Chang Q. Zeng L. Gu J. Brown S. Basch R.S. TBLR1 regulates the expression of nuclear hormone receptor co-repressors.BMC Cell Biol. 2006; 7: 31Crossref PubMed Scopus (34) Google Scholar Platelet-derived growth factor (PDGF) comprises a set of four ligands (PDGFs A, B, C, and D) that bind to two receptors (PDGFRA and PDGFRB) to deliver signals that affect cell growth, cell shape, and chemotaxis.51Heldin C.H. Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor.Physiol Rev. 1999; 79: 1283-1316Crossref PubMed Scopus (1996) Google Scholar PDGFRA and PDGFRB, which encode the receptor units, are overexpressed in bone marrow metastases of prostate cancer,52Chott A. Sun Z. Morganstern D. Pan J. Li T. Susani M. Mosberger I. Upton M.P. Bubley G.J. Balk S.P. Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor.Am J Pathol. 1999; 155: 1271-1279Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar and higher PDGFRB expression is part of a five-gene expression-based predictor for prostate cancer recurrence.53Singh D. Febbo P.G. Ross K. Jackson D.G. Manola J. Ladd C. Tamayo P. Renshaw A.A. D'Amico A.V. Richie J.P. Lander E.S. Loda M. Kantoff P.W. Golub T.R. Sellers W.R. Gene expression correlates of clinical prostate cancer behavior.Cancer Cell. 2002; 1: 203-209Abstract Full Text Full Text PDF PubMed Scopus (2035) Google Scholar There is a competition between two of its ligands, PDGFB and PDGFD, in prostate cancer, such that when PTEN is lost, PDGFD is preferred.54Conley-LaComb M.K. Huang W. Wang S. Shi D. Jung Y.S. Najy A. Fridman R. Bonfil R.D. Cher M.L. Chen Y.Q. Kim H.R. PTEN regulates PDGF ligand switch for beta-PDGFR signaling in prostate cancer.Am J Pathol. 2012; 180: 1017-1027Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar CTTNBP2 influences the size and number of dendritic spines.55Chen Y.K. Hsueh Y.P. Cortactin-binding protein 2 modulates the mobility of cortactin and regulates dendritic spine formation and maintenance.J Neurosci. 2012; 32: 1043-1055Crossref PubMed Scopus (59) Google Scholar CTTNBP2 has roles in other tissues, including binding of the RAD21-cohesin complex.56Panigrahi A.K. Zhang N. Otta S.K. Pati D. A cohesin-RAD21 interactome.Biochem J. 2012; 442: 661-670Crossref PubMed Scopus (15) Google Scholar More specific to prostate cancer, CTTNBP2 is in a block of genes on chromosome 7 that is differentially methylated in prostate cancer cell lines.57Coolen M.W. Stirzaker C. Song J.Z. Statham A.L. Kassir Z. Moreno C.S. Young A.N. Varma V. Speed T.P. Cowley M. Lacaze P. Kaplan W. Robinson M.D. Clark S.J. Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plastic

Referência(s)