Single-cell genetic analysis reveals insights into clonal development of prostate cancers and indicates loss of PTEN as a marker of poor prognosis

American Journal of Pathology

Volumn 184, Issue 10, 2014, Pages 2671-2686

  Heselmeyer Haddad, Kerstin M ^a   Garcia, Lissa Y Berroa ^a   Bradley, Amanda ^a   Hernandez, Leanora ^a   Hu, Yue ^a   Habermann, Jens K ^c   Dumke, Christoph ^c   Thorns, Christoph ^c   Perner, Sven ^d   Pestova, Ekaterina ^e   Burke, Catherine ^f   Chowdhury, Salim A ^g,h   Schwartz, Russell ^g,h   Schäffer, Alejandro A ^b   Paris, Pamela L ^f   Ried, Thomas ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

^b NATIONAL INSTITUTES OF HEALTH   (United States)

^c UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

^d UNIVERSITY HOSPITAL BONN   (Germany)

^e Abbott Molecular Inc   (United States)

^f UNIVERSITY OF CALIFORNIA   (United States)

^g CARNEGIE MELLON UNIVERSITY   (United States)

^h Carnegie Mellon University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; ONCOPROTEIN; PTEN PROTEIN, HUMAN; TUMOR MARKER;

ADULT; AGED; ARTICLE; CANCER GROWTH; CANCER PROGNOSIS; CHROMOSOMAL INSTABILITY; CLINICAL ARTICLE; CLINICAL FEATURE; CLONAL EVOLUTION; COMPARATIVE GENOMIC HYBRIDIZATION; CONTROLLED STUDY; CTTNBP2 GENE; FLUORESCENCE IN SITU HYBRIDIZATION; FUSION GENE; GENE DOSAGE; GENETIC ANALYSIS; GENETIC MARKER; GENOMIC INSTABILITY; GENOMICS; HUMAN; HUMAN CELL; MALE; MEN1 GENE; MIDDLE AGED; ONCOGENE C MYC; ONCOGENE MYC; PDGFB GENE; PLOIDY; PRIORITY JOURNAL; PROSTATE CANCER; PROSTATECTOMY; PROTEIN DEPLETION; SINGLE CELL ANALYSIS; TBL1XR1 GENE; TUMOR GENE; ADENOCARCINOMA; DISEASE COURSE; GENETICS; METABOLISM; PATHOLOGY; PROGNOSIS; PROSTATE; PROSTATE TUMOR;

ADENOCARCINOMA; AGED; BIOMARKERS, TUMOR; CHROMOSOMAL INSTABILITY; COMPARATIVE GENOMIC HYBRIDIZATION; DISEASE PROGRESSION; HUMANS; IN SITU HYBRIDIZATION, FLUORESCENCE; MALE; MIDDLE AGED; ONCOGENE PROTEINS, FUSION; PLOIDIES; PROGNOSIS; PROSTATE; PROSTATECTOMY; PROSTATIC NEOPLASMS; PTEN PHOSPHOHYDROLASE; SINGLE-CELL ANALYSIS;

EID: 84922438928     PISSN: 00029440     EISSN: 15252191     Source Type: Journal    
DOI: 10.1016/j.ajpath.2014.06.030     Document Type: Article

References (70)

1. Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 2013, 63:11-30.
2. Brawley OW: Prostate cancer epidemiology in the United States. World J Urol 2012, 30:195-200.
3. Logothetis CJ, Gallick GE, Maity SN, Kim J, Aparicio A, Efstathiou E, Lin SH: Molecular classification of prostate cancer progression: Foundation for marker-driven treatment of prostate cancer. Cancer Discov 2013, 3:847-861.
4. Mousses S, Bubendorf L, Wagner U, Hostetter G, Kononen J, Cornelison R, Goldberger N, Elkahloun AG, Willi N, Koivisto P, Ferhle W, Raffeld M, Sauter G, Kallioniemi OP: Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays. Cancer Res 2002, 62:1256-1260.
5. Malhotra S, Lapointe J, Salari K, Higgins JP, Ferrari M, Montgomery K, van de Rijn M, Brooks JD, Pollack JR: A tri-marker proliferation index predicts biochemical recurrence after surgery for prostate cancer. PLoS One 2011, 6:e20293.
6. Vainio P, Mpindi JP, Kohonen P, Fey V, Mirtti T, Alanen KA, 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: e39801.
7. Roychowdhury S, Chinnaiyan AM: Advancing precision medicine for prostate cancer through genomics. J Clin Oncol 2013, 31: 1866-1873.
8. Zellweger T, Sturm S, Rey S, Zlobec I, Gsponer JR, Rentsch CA, Terracciano LM, 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, 20:403-413.
9. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005, 310:644-648.
10. Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera JM, Setlur S, Tchinda J, Tomlins SA, Hofer MD, Pienta KG, Kuefer R, Vessella R, Sun XW, Meyerson M, Lee C, Sellers WR, Chinnaiyan AM, Rubin MA: TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res 2006, 66:8337-8341.
11. Soller MJ, 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, 45:717-719.
12. Wang J, Cai Y, Ren C, Ittmann M: Expression of variant TMPRSS2/ERG fusion messenger RNAs is associated with aggressive prostate cancer. Cancer Res 2006, 66:8347-8351.
13. Tu JJ, Rohan S, Kao J, Kitabayashi N, Mathew S, Chen YT: 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, 20:921-928.
14. Mehra R, Tomlins SA, Shen R, Nadeem O, Wang L, Wei JT, Pienta KJ, Ghosh D, Rubin MA, Chinnaiyan AM, Shah RB: Comprehensive assessment of TMPRSS2 and ETS family gene aberrations in clinically localized prostate cancer. Mod Pathol 2007, 20: 538-544.
15. Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P, Berney D, Foster CS, Fletcher A, Gerald WL, Moller H, Reuter V, De Bono JS, Scardino P, Cuzick J, Cooper CS, Group TP: Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 2008, 27:253-263.
16. Gopalan A, Leversha MA, Satagopan JM, Zhou Q, Al-Ahmadie HA, Fine SW, Eastham JA, Scardino PT, Scher HI, Tickoo SK, Reuter VE, Gerald WL: TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. Cancer Res 2009, 69:1400-1406.
17. Park K, Tomlins SA, Mudaliar KM, Chiu YL, Esgueva R, Mehra R, Suleman K, Varambally S, Brenner JC, MacDonald T, Srivastava A, Tewari AK, Sathyanarayana U, Nagy D, Pestano G, Kunju LP, Demichelis F, Chinnaiyan AM, Rubin MA: Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia 2010, 12: 590-598.
18. FitzGerald LM, Agalliu I, Johnson K, Miller MA, Kwon EM, Hurtado- Coll A, Fazli L, Rajput AB, Gleave ME, Cox ME, Ostrander EA, Stanford JL, Huntsman DG: Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer 2008, 8:230.
19. Barwick BG, Abramovitz M, Kodani M, Moreno CS, 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: 570-576.
20. Clark J, Merson S, Jhavar S, Flohr P, Edwards S, Foster CS, Eeles R, Martin FL, Phillips DH, Crundwell M, Christmas T, Thompson A, Fisher C, Kovacs G, Cooper CS: Diversity of TMPRSS2-ERG fusion transcripts in the human prostate. Oncogene 2007, 26:2667-2673.
21. Liu W, Ewing CM, Chang BL, Li T, Sun J, Turner AR, Dimitrov L, Zhu Y, Sun J, Kim JW, Zheng SL, Isaacs WB, Xu J: Multiple genomic alterations on 21q22 predict various TMPRSS2/ERG fusion transcripts in human prostate cancers. Genes Chromosomes Cancer 2007, 46:972-980.
22. Zammarchi F, Boutsalis G, Cartegni L: 50 UTR control of native ERG and of Tmprss2:ERG variants activity in prostate cancer. PLoS One 2013, 8:e49721.
23. Furusato B, Tan SH, Young D, Dobi A, Sun C, Mohamed AA, Thangapazham R, Chen Y, McMaster G, Sreenath T, Petrovics G, McLeod DG, Srivastava S, Sesterhenn IA: ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification. Prostate Cancer Prostatic Dis 2010, 13:228-237.
24. Mertz KD, 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, 44:2727-2735.
25. Yoshimoto M, Ding K, Sweet JM, Ludkovski O, Trottier G, Song KS, Joshua AM, Fleshner NE, Squire JA, Evans AJ: PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade. Mod Pathol 2013, 26: 435-447.
26. Tao Y, Ruan J, Yeh SH, 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, 108:12042-12047.
27. Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M: Tumour evolution inferred by single-cell sequencing. Nature 2011, 472:90-94.
28. Hou 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, 148:873-885.
29. Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, Akhavanfard S, Cahill DP, Aldape KD, Betensky RA, Louis DN, Iafrate AJ: Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 2011, 20:810-817.
30. Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, Ozawa T, Holland EC, Huse JT, Jhanwar S, Leversha MA, Mikkelsen T, Brennan CW: 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, 109:3041-3046.
31. Heselmeyer-Haddad K, Berroa Garcia LY, Bradley A, Ortiz- Melendez C, Lee WJ, Christensen R, Prindiville SA, Calzone KA, Soballe PW, Hu Y, Chowdhury SA, Schwartz R, Schäffer AA, 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, 181:1807-1822.
32. Paris PL, Andaya A, Fridlyand J, Jain AN, Weinberg V, Kowbel D, Brebner JH, Simko J, Watson JEV, Volik S, Albertson DG, Pinkel D, Alers JC, van der Kwast TH, Vissers KJ, Schroder FH, Wildhagen MF, Febbo PG, Chinnaiyan AM, Pienta KJ, Carroll PR, Rubin MA, Collins C, van Dekken H: Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors. Hum Mol Genet 2004, 13:1303-1313.
33. Jenkins RB, Qian J, Lieber MM, Bostwick DG: Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res 1997, 57:524-531.
34. Sato 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, 13:761-766.
35. Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG, Jen J, Isaacs WB, Bova GS, Sidransky D: Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 1997, 57:4997-5000.
36. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DHR, Tavtigian SV: Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997, 15:356-362.
37. Phin S, Moore MW, Cotter PD: Genomic rearrangements of PTEN in prostate cancer. Front Oncol 2013, 3:240.
38. Leinonen KA, Saramaki OR, Furusato B, Kimura T, Takahashi H, Egawa S, Suzuki H, Keiger K, Ho Hahm S, Isaacs WB, Tolonen TT, Stenman UH, Tammela TL, Nykter M, Bova GS, Visakorpi T: Loss of PTEN is associated with aggressive behavior in ERG-positive prostate cancer. Cancer Epidemiol Biomarkers Prev 2013, 22: 2333-2344.
39. Lapointe J, Li C, Giacomini CP, Salari K, Huang S, Wang P, Ferrari M, Hernandez-Boussard T, Brooks JD, Pollack JR: Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res 2007, 67:8504-8510.
40. Zafarana G, Ishkanian AS, Malloff CA, Locke JA, Sykes J, Thoms J, Lam WL, Squire JA, Yoshimoto M, Ramnarine VR, Meng A, Ahmed O, Jurisca I, Milosevic M, Pintilie M, van der Kwast T, Bristow RG: Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer 2012, 118:4053-4062.
41. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi S-E, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ: Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997, 276:404-407.
42. Seigne C, Fontanière S, Carreira C, Lu J, Tong W-M, Fontanière B, Wang Z-Q, Zhang CX, Frappart L: Characterisation of prostate cancer lesions in heterozygous Men1 mutant mice. BMC Cancer 2010, 10:395.
43. Paris PL, Sridharan S, Hittelman AB, Kobayashi Y, Perner S, Huang G, Simko J, Carroll P, Rubin MA, Collins C: An oncogenic role for the multiple endocrine neoplasia type 1 gene in prostate cancer. Prostate Cancer Prostatic Dis 2009, 12:184-191.
44. Lapointe J, Li C, Higgins JP, van de Rijn M, Bair E, Montgomery K, Ferrari M, Egevad L, Rayford W, Bergerheim U, Ekman P, De Marzo AM, Tibshirani R, Botstein D, Brown PO, Brooks JD, Pollack JR: Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci U S A 2004, 101: 811-816.
45. Zhang XM, Chang Q, Zeng L, Gu J, Brown S, Basch RS: TBLR1 regulates the expression of nuclear hormone receptor co-repressors. BMC Cell Biol 2006, 7:31.
46. Li J, Wang CY: TBL1-TBLR1 and beta-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis. Nat Cell Biol 2008, 10:160-169.
47. Daniels DL, Weis WI: Beta-catenin directly displaces Groucho/TLE repressors from Tcf/Lef in Wnt-mediated transcription activation. Nat Struct Mol Biol 2005, 12:364-371.
48. Robinson DR, Zylstra CR, Williams BO: Wnt signaling and prostate cancer. Curr Drug Targets 2008, 9:571-580.
49. Liu 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: 307-317.
50. Gonzalez-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 ML, Marie Y, Mokhtari K, Hoang- Xuan K: Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res 2012, 18: 5203-5211.
51. Heldin CH, Westermark B: Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 1999, 79:1283-1316.
52. Chott A, Sun Z, Morganstern D, Pan J, Li T, Susani M, Mosberger I, Upton MP, Bubley GJ, Balk SP: 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: 1271-1279.
53. Singh D, Febbo PG, Ross K, Jackson DG, Manola J, Ladd C, Tamayo P, Renshaw AA, D'Amico AV, Richie JP, Lander ES, Loda M, Kantoff PW, Golub TR, Sellers WR: Gene expression correlates of clinical prostate cancer behavior. Cancer Cell 2002, 1: 203-209.
54. Conley-LaComb MK, Huang W, Wang S, Shi D, Jung YS, Najy A, Fridman R, Bonfil RD, Cher ML, Chen YQ, Kim HR: PTEN regulates PDGF ligand switch for beta-PDGFR signaling in prostate cancer. Am J Pathol 2012, 180:1017-1027.
55. Chen YK, Hsueh YP: Cortactin-binding protein 2 modulates the mobility of cortactin and regulates dendritic spine formation and maintenance. J Neurosci 2012, 32:1043-1055.
56. Panigrahi AK, Zhang N, Otta SK, Pati D: A cohesin-RAD21 interactome. Biochem J 2012, 442:661-670.
57. Coolen MW, Stirzaker C, Song JZ, Statham AL, Kassir Z, Moreno CS, Young AN, Varma V, Speed TP, Cowley M, Lacaze P, Kaplan W, Robinson MD, Clark SJ: Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity. Nat Cell Biol 2010, 12:235-246.
58. Chowdhury SA, Shackney SE, Heselmeyer-Haddad K, Ried T, Schäffer AA, Schwartz R: Phylogenetic analysis of multiprobe fluorescence in situ hybridization data from tumor cell populations. Bioinformatics 2013, 29:i187-i198.
59. Wangsa D, Heselmeyer-Haddad K, Ried P, Eriksson E, Schäffer AA, Morrison LE, Luo J, Auer G, Munck-Wikland E, Ried T, Lundqvist EÅ: Fluorescence in situ hybridization markers for prediction of cervical lymph node metastases. Am J Pathol 2009, 175: 2637-2645.
60. Auer GU, Caspersson TO, Wallgren AS: DNA content and survival in mammary carcinoma. Anal Quant Cytol 1980, 2:161-164.
61. Paris PL, Weinberg V, Albo G, Roy R, Burke C, Simko J, Carroll P, Collins C: A group of genome-based biomarkers that add to a Kattan nomogram for predicting progression in men with high-risk prostate cancer. Clin Cancer Res 2010, 16:195-202.
62. Park SY, Gonen M, Kim HJ, Michor F, Polyak K: Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. J Clin Invest 2010, 120: 636-644.
63. D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A: Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998, 280:967-974.
64. Perner S, Mosquera JM, Demichelis F, Hofer MD, Paris PL, Simko J, Collins C, Bismar TA, Chinnaiyan AM, De Marzo AM, Rubin MA: TMPRSS2-ERG fusion prostate cancer: An early molecular event associated with invasion. Am J Surg Pathol 2007, 31:882-888.
65. Mosquera JM, Perner S, Genega EM, Sanda M, Hofer MD, Mertz KD, Paris PL, Simko J, Bismar TA, Ayala G, Shah RB, Loda M, Rubin MA: Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res 2008, 14:3380-3385.
66. Steineck G, Helgesen F, Adolfsson J, Dickman PW, Johansson JE, Norlén BJ, Holmberg L; Scandinavian Prostatic Cancer Group Study Number 4: Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 2002, 347:790-796.
67. Toubaji A, Albadine R, Meeker AK, Isaacs WB, Lotan T, Haffner MC, Chaux A, Epstein JI, Han M, Walsh PC, Partin AW, De Marzo AM, Platz EA, Netto GJ: Increased gene copy number of ERG on chromosome 21 but not TMPRSS2-ERG fusion predicts outcome in prostatic adenocarcinomas. Mod Pathol 2011, 24:1511-1520.
68. Chaux A, Peskoe SB, Gonzalez-Roibon N, Schultz L, Albadine R, Hicks J, De Marzo AM, Platz EA, Netto GJ: Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer. Mod Pathol 2012, 25:1543-1549.
69. Krohn A, Diedler T, Burkhardt L, Mayer PS, De Silva C, Meyer- Kornblum M, Kötschau D, Tennstedt P, Huang J, Gerhauser C, Mader M, Kurtz S, Sirma H, Saad F, Steuber T, Graefen M, Plass C, Sauter G, Simon R, Minner S, Schlomm T: Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. Am J Pathol 2012, 181:401-412.
70. Punnoose E, Tucker E, Marrinucci D, Amler LC, Koeppen H, Patel PH, Yan Y, Riisnaes R, Attard G, Sebastian De Bono J: Evaluation of PTEN status in circulating tumor cells (CTCs) and matched tumor tissue from patients with castrate-resistant prostate cancer (CRPC): 2013 Genitourinary Cancers Symposium. J Clin Oncol 2013, Abstract 62.