Prostate adenocarcinomas aberrantly expressing p63 are molecularly distinct from usual-type prostatic adenocarcinomas

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Abstract

We have described a rare group of prostate adenocarcinomas that show aberrant expression of p63, a protein strongly expressed in prostatic basal cells and absent from usual-type acinar prostate cancers. The partial basal-like immunophenotype of these tumors is intriguing in light of the persistent debate surrounding the cell-of-origin for prostate cancer; however, their molecular phenotype is unknown. We collected 37 of these tumors on radical prostatectomy and biopsy and assessed subsets for a diverse panel of molecular markers. The majority of p63-expressing tumors were positive for the ΔNp63 isoform (6/7) by immunofluorescence and p63 mRNA (7/8) by chromogenic in situ hybridization. Despite p63 positivity, these tumors uniformly expressed luminal-type cytokeratin proteins such as CK18 (13/13), CK8 (8/8), and markers of androgen axis signaling commonly seen in luminal cells, including androgen receptor (10/11), NKX3.1 (8/8), and prostein (12/13). Conversely, basal cytokeratins such as CK14 and CK15 were negative in all cases (0/8) and CK5/6 was weakly and focally positive in 36% (4/11) of cases. Pluripotency markers including β-catenin, Oct4, and c-kit were negative in p63-expressing tumors (0/11). Despite nearly universal expression of androgen receptor and downstream androgen signaling targets, p63-expressing tumors lacked ERG rearrangements by fluorescence in situ hybridization (0/14) and ERG protein expression (0/37). No tumors expressed SPINK1 or showed PTEN protein loss (0/19). Surprisingly, 74% (14/19) of p63-expressing tumors expressed GSTP1 protein at least focally, and 33% (2/6) entirely lacked GSTP1 CpG island hypermethylation by bisulfite sequencing. In contrast to usual prostatic adenocarcinomas, prostate tumors with p63 expression show a mixed luminal/basal immunophenotype, uniformly lack ERG gene rearrangement, and frequently express GSTP1. These data strongly suggest that p63-expressing prostate tumors represent a molecularly distinct subclass and further study of this rare tumor type may yield important insights into the role of p63 in prostatic biology and the prostate cancer cell-of-origin.

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References

  1. 1

    Osunkoya AO, Hansel DE, Sun X et al. Aberrant diffuse expression of p63 in adenocarcinoma of the prostate on needle biopsy and radical prostatectomy: Report of 21 cases. Am J Surg Pathol 2008;32:461–467.

  2. 2

    Giannico GA, Ross HM, Lotan T et al. Aberrant expression of p63 in adenocarcinoma of the prostate: A radical prostatectomy study. Am J Surg Pathol 2013;37:1401–1406.

  3. 3

    Ali TZ, Epstein JI . Basal cell carcinoma of the prostate: A clinicopathologic study of 29 cases. Am J Surg Pathol 2007;31:697–705.

  4. 4

    Toubaji A, Albadine R, Meeker AK et al. 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.

  5. 5

    Lotan TL, Gurel B, Sutcliffe S et al. PTEN protein loss by immunostaining: Analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011;17:6563–6573.

  6. 6

    Suh EK, Yang A, Kettenbach A et al. P63 protects the female germ line during meiotic arrest. Nature 2006;444:624–628.

  7. 7

    Wang F, Flanagan J, Su N et al. RNAscope: A novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn 2012;14:22–29.

  8. 8

    Yegnasubramanian S, Lin X, Haffner MC et al. Combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes (COMPARE-MS) for the rapid, sensitive and quantitative detection of DNA methylation. Nucleic Acids Res 2006;34:e19.

  9. 9

    Parsons JK, Saria EA, Nakayama M et al. Comprehensive mutational analysis and mRNA isoform quantification of TP63 in normal and neoplastic human prostate cells. Prostate 2009;69:559–569.

  10. 10

    Uchida K, Ross H, Epstein J et al. DeltaNp63 isoforms of p63 in aberrant diffuse p63 positive prostate cancer. Mod Path 2012;25:247.

  11. 11

    Romano RA, Ortt K, Birkaya B et al. An active role of the DeltaN isoform of p63 in regulating basal keratin genes K5 and K14 and directing epidermal cell fate. PLoS One 2009;4:e5623.

  12. 12

    Harper ME, Glynne-Jones E, Goddard L et al. Expression of androgen receptor and growth factors in premalignant lesions of the prostate. J Pathol 1998;186:169–177.

  13. 13

    Haffner MC, Aryee MJ, Toubaji A et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet 2010;42:668–675.

  14. 14

    Rubin MA, Maher CA, Chinnaiyan AM . Common gene rearrangements in prostate cancer. J Clin Oncol 2011;29:3659–3668.

  15. 15

    Tomlins SA, Rhodes DR, Yu J et al. The role of SPINK1 in ETS rearrangement-negative prostate cancers. Cancer Cell 2008;13:519–528.

  16. 16

    Carver BS, Tran J, Gopalan A et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet 2009;41:619–624.

  17. 17

    King JC, Xu J, Wongvipat J et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat Genet 2009;41:524–526.

  18. 18

    Han B, Mehra R, Lonigro RJ et al. Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression. Mod Pathol 2009;22:1083–1093.

  19. 19

    Bismar TA, Yoshimoto M, Vollmer RT et al. PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer. BJU Int 2011;107:477–485.

  20. 20

    Lee WH, Morton RA, Epstein JI et al. Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc Natl Acad Sci USA 1994;91:11733–11737.

  21. 21

    Yegnasubramanian S, Kowalski J, Gonzalgo ML et al. Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res 2004;64:1975–1986.

  22. 22

    Pignon JC, Grisanzio C, Geng Y et al. P63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia. Proc Natl Acad Sci USA 2013;110:8105–8110.

  23. 23

    Pettersson A, Graff RE, Bauer SR et al. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: A cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev 2012;21:1497–1509.

  24. 24

    Mills AA, Zheng B, Wang XJ et al. P63 is a P53 homologue required for limb and epidermal morphogenesis. Nature 1999;398:708–713.

  25. 25

    Yang A, Schweitzer R, Sun D et al. P63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999;398:714–718.

  26. 26

    Signoretti S, Waltregny D, Dilks J et al. P63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 2000;157:1769–1775.

  27. 27

    Signoretti S, Pires MM, Lindauer M et al. P63 regulates commitment to the prostate cell lineage. Proc Natl Acad Sci USA 2005;102:11355–11360.

  28. 28

    Romano RA, Smalley K, Magraw C et al. DeltaNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation. Development 2012;139:772–782.

  29. 29

    Choi N, Zhang B, Zhang L et al. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell 2012;21:253–265.

  30. 30

    Wang ZA, Mitrofanova A, Bergren SK et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol 2013;15:274–283.

  31. 31

    Grisanzio C, Signoretti S . P63 in prostate biology and pathology. J Cell Biochem 2008;103:1354–1368.

  32. 32

    Yi R, Poy MN, Stoffel M et al. A skin microRNA promotes differentiation by repressing 'stemness'. Nature 2008;452:225–229.

  33. 33

    Lawson DA, Zong Y, Memarzadeh S et al. Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proc Natl Acad Sci USA 2010;107:2610–2615.

  34. 34

    Goldstein AS, Huang J, Guo C et al. Identification of a cell of origin for human prostate cancer. Science 2010;329:568–571.

  35. 35

    Stoyanova T, Cooper AR, Drake JM et al. Prostate cancer originating in basal cells progresses to adenocarcinoma propagated by luminal-like cells. Proc Natl Acad Sci USA 2013;110:20111–20116.

  36. 36

    Lu TL, Huang YF, You LR et al. Conditionally ablated pten in prostate basal cells promotes basal-to-luminal differentiation and causes invasive prostate cancer in mice. Am J Pathol 2013;182:975–991.

  37. 37

    Nakayama M, Bennett CJ, Hicks JL et al. Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: A detailed study using laser-capture microdissection. Am J Pathol 2003;163:923–933.

  38. 38

    Mosquera JM, Perner S, Genega EM et al. Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res 2008;14:3380–3385.

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Acknowledgements

Funding for this research was provided in part by a Prostate Cancer Foundation Young Investigator Award (TLL), a David H. Koch Research Award (TLL), and the NIH/NCI Prostate SPORE P50CA58236.

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Correspondence to Tamara L Lotan.

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The authors declare no conflict of interest.

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