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Carcinoma in situ testis displays permissive chromatin modifications similar to immature foetal germ cells.

Almstrup K, Nielsen JE, Mlynarska O, Jansen MT, Jørgensen A, Skakkebæk NE, Rajpert-De Meyts E - Br. J. Cancer (2010)

Bottom Line: CIS cells show low levels of DNA methylation and repressive histone modifications H3K9me2 and H3K27me3, but high levels of H3K9 acetylation, H3K4 methylation and H2A.Z, which all are associated with an activated and accessible chromatin structure.CIS cells have a permissive and foetal-like chromatin structure, which is associated with a high transcriptional and proliferative activity, likely empowering neoplastic transformation.Developmental epigenetic cues in foetal germ cells are substantially different between humans and mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Growth and Reproduction, GR-5064, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. kristian@almstrup.net

ABSTRACT

Background: The majority of testicular germ cell cancers develop through a pre-invasive carcinoma in situ (CIS) stage. The CIS cell is a neoplastic counterpart of foetal germ cells. During their development, foetal germ cells undergo extensive and essential epigenetic modifications, but little is known about epigenetic patterns in CIS cells.

Methods: Immunohistochemistry was used to investigate epigenetic patterns in CIS, germ cell tumours, normal adult and foetal testicular tissue.

Results: CIS cells show low levels of DNA methylation and repressive histone modifications H3K9me2 and H3K27me3, but high levels of H3K9 acetylation, H3K4 methylation and H2A.Z, which all are associated with an activated and accessible chromatin structure. Collectively this renders a permissive chromatin structure and in accordance high levels of RNA polymerase II activity and proliferation (Ki-67 and mitotic index) is observed in CIS cells. Epigenetic patterns similar to that of CIS cells were observed in human gonocytes present within sex cords in foetal testes but correspond to migrating primordial germ cell in mice. Development of overt tumours involves epigenetic repression of the chromatin.

Conclusion: CIS cells have a permissive and foetal-like chromatin structure, which is associated with a high transcriptional and proliferative activity, likely empowering neoplastic transformation. Developmental epigenetic cues in foetal germ cells are substantially different between humans and mice.

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Epigenetic patterns in carcinoma in situ (CIS) testis visualised by immunohistochemistry. (A) A typical tubule with CIS cells marked by one of the classical markers, OCT4 (POU5F1) (de Jong et al, 2005; Rajpert-De Meyts et al, 2004). Note that CIS cells are bigger than unstained spermatogonia (visible in the tubule on the right) and have large irregular nuclei with coarse chromatin clumps. (B) Double staining for 5-methyl-cytosine (reddish brown) and the classical CIS marker placental-like alkaline phosphate (PLAP, dark blue). (C) H3K9me2. (D) Double staining for H3K27me3 (deep blue) and PLAP (reddish brown). (E) H3K4me1, (F) H3K4me2/3, (G) H3K9ac and (H) H2A.Z. Arrows denote CIS cells and arrowheads Sertoli cells. Bar represent 50 microns.
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fig1: Epigenetic patterns in carcinoma in situ (CIS) testis visualised by immunohistochemistry. (A) A typical tubule with CIS cells marked by one of the classical markers, OCT4 (POU5F1) (de Jong et al, 2005; Rajpert-De Meyts et al, 2004). Note that CIS cells are bigger than unstained spermatogonia (visible in the tubule on the right) and have large irregular nuclei with coarse chromatin clumps. (B) Double staining for 5-methyl-cytosine (reddish brown) and the classical CIS marker placental-like alkaline phosphate (PLAP, dark blue). (C) H3K9me2. (D) Double staining for H3K27me3 (deep blue) and PLAP (reddish brown). (E) H3K4me1, (F) H3K4me2/3, (G) H3K9ac and (H) H2A.Z. Arrows denote CIS cells and arrowheads Sertoli cells. Bar represent 50 microns.

Mentions: We first verified results from earlier work on the level of DNA methylation as measured by cytosine methylation (Smiraglia et al, 2002; Netto et al, 2008). The classical cytoplasmic CIS marker, placental-like alkaline phosphate, was used simultaneously with staining for 5-methyl-cytosine and indeed verified low levels of DNA methylation in CIS cells (Figure 1B). We also confirmed that non-seminomas have high levels of DNA methylation, whereas seminomas show variable but predominantly low DNA methylation levels (data not shown).


Carcinoma in situ testis displays permissive chromatin modifications similar to immature foetal germ cells.

Almstrup K, Nielsen JE, Mlynarska O, Jansen MT, Jørgensen A, Skakkebæk NE, Rajpert-De Meyts E - Br. J. Cancer (2010)

Epigenetic patterns in carcinoma in situ (CIS) testis visualised by immunohistochemistry. (A) A typical tubule with CIS cells marked by one of the classical markers, OCT4 (POU5F1) (de Jong et al, 2005; Rajpert-De Meyts et al, 2004). Note that CIS cells are bigger than unstained spermatogonia (visible in the tubule on the right) and have large irregular nuclei with coarse chromatin clumps. (B) Double staining for 5-methyl-cytosine (reddish brown) and the classical CIS marker placental-like alkaline phosphate (PLAP, dark blue). (C) H3K9me2. (D) Double staining for H3K27me3 (deep blue) and PLAP (reddish brown). (E) H3K4me1, (F) H3K4me2/3, (G) H3K9ac and (H) H2A.Z. Arrows denote CIS cells and arrowheads Sertoli cells. Bar represent 50 microns.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2967056&req=5

fig1: Epigenetic patterns in carcinoma in situ (CIS) testis visualised by immunohistochemistry. (A) A typical tubule with CIS cells marked by one of the classical markers, OCT4 (POU5F1) (de Jong et al, 2005; Rajpert-De Meyts et al, 2004). Note that CIS cells are bigger than unstained spermatogonia (visible in the tubule on the right) and have large irregular nuclei with coarse chromatin clumps. (B) Double staining for 5-methyl-cytosine (reddish brown) and the classical CIS marker placental-like alkaline phosphate (PLAP, dark blue). (C) H3K9me2. (D) Double staining for H3K27me3 (deep blue) and PLAP (reddish brown). (E) H3K4me1, (F) H3K4me2/3, (G) H3K9ac and (H) H2A.Z. Arrows denote CIS cells and arrowheads Sertoli cells. Bar represent 50 microns.
Mentions: We first verified results from earlier work on the level of DNA methylation as measured by cytosine methylation (Smiraglia et al, 2002; Netto et al, 2008). The classical cytoplasmic CIS marker, placental-like alkaline phosphate, was used simultaneously with staining for 5-methyl-cytosine and indeed verified low levels of DNA methylation in CIS cells (Figure 1B). We also confirmed that non-seminomas have high levels of DNA methylation, whereas seminomas show variable but predominantly low DNA methylation levels (data not shown).

Bottom Line: CIS cells show low levels of DNA methylation and repressive histone modifications H3K9me2 and H3K27me3, but high levels of H3K9 acetylation, H3K4 methylation and H2A.Z, which all are associated with an activated and accessible chromatin structure.CIS cells have a permissive and foetal-like chromatin structure, which is associated with a high transcriptional and proliferative activity, likely empowering neoplastic transformation.Developmental epigenetic cues in foetal germ cells are substantially different between humans and mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Growth and Reproduction, GR-5064, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. kristian@almstrup.net

ABSTRACT

Background: The majority of testicular germ cell cancers develop through a pre-invasive carcinoma in situ (CIS) stage. The CIS cell is a neoplastic counterpart of foetal germ cells. During their development, foetal germ cells undergo extensive and essential epigenetic modifications, but little is known about epigenetic patterns in CIS cells.

Methods: Immunohistochemistry was used to investigate epigenetic patterns in CIS, germ cell tumours, normal adult and foetal testicular tissue.

Results: CIS cells show low levels of DNA methylation and repressive histone modifications H3K9me2 and H3K27me3, but high levels of H3K9 acetylation, H3K4 methylation and H2A.Z, which all are associated with an activated and accessible chromatin structure. Collectively this renders a permissive chromatin structure and in accordance high levels of RNA polymerase II activity and proliferation (Ki-67 and mitotic index) is observed in CIS cells. Epigenetic patterns similar to that of CIS cells were observed in human gonocytes present within sex cords in foetal testes but correspond to migrating primordial germ cell in mice. Development of overt tumours involves epigenetic repression of the chromatin.

Conclusion: CIS cells have a permissive and foetal-like chromatin structure, which is associated with a high transcriptional and proliferative activity, likely empowering neoplastic transformation. Developmental epigenetic cues in foetal germ cells are substantially different between humans and mice.

Show MeSH
Related in: MedlinePlus