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. 2010 Oct 12;103(8):1269-76.
doi: 10.1038/sj.bjc.6605880. Epub 2010 Sep 7.

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

K Almstrup  1 , J E Nielsen, O Mlynarska, M T Jansen, A Jørgensen, N E Skakkebæk, E Rajpert-De Meyts
Affiliations

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

K Almstrup et al. Br J Cancer. .

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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Figures

Figure 1
Figure 1
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.
Figure 2
Figure 2
Histone modifications in human foetal gonads. Fetal testis tissues at GW 21–24 marked by immunohistochemical staining for (A) OCT4 (POU5F1) to visualise gonocytes, (B) 5-methylcytosine (5-meC), (C) H3K9me2, (D) H3K27me3, (E) H3K4me1, (F) H3K4me2/3, (G) H3K9ac and (H) H2A.Z. Arrows indicate foetal germ cells. Bar represents 50 microns.
Figure 3
Figure 3
RNA polymerase II activity in CIS cells. Immunohistochemical detection of RNA polymerase II (A) and its Ser2-phosphorylated variant as measured by the H5 antibody (B). Arrows denotes CIS cells and arrowheads Sertoli cells. Bar represent 50 microns.
See this image and copyright information in PMC

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