OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of spermatocytic seminoma reflecting distinct subpopulations of spermatogonia

Lim, Jasmine; Goriely, Anne; Turner, Gareth D. H.; Ewen, Katherine A.; Jacobsen, Grete Krag; Græm, Niels; Wilkie, Andrew O.M.; Meyts, Ewa Rajpert‐De

doi:10.1002/path.2919

Cited by 76 publications

(67 citation statements)

References 28 publications

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“…Therefore, our data support the common hypothesis of a different cell origin concerning spermatocytic seminoma and classic seminoma. 1,35 Although intratubular germ cell neoplasia unclassified is considered to be derived from developmentally arrested gonocytes, 2,[36][37][38] there is some controversy about the progenitor 39 Previous studies suspected primary spermatocytes 40 or spermatogonia 35,41 as progenitor cells. In our study, we found a strong expression of cancer testis antigens in spermatogonia and in spermatocytic seminoma, which is consistent with an origin of spermatocytic seminoma from spermatogonia, too.…”

Section: Discussionmentioning

confidence: 99%

Cancer testis antigen expression in testicular germ cell tumorigenesis

et al. 2014

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Cancer testis antigens are encoded by germ line-associated genes that are present in normal germ cells of testis and ovary but not in differentiated tissues. Their expression in various human cancer types has been interpreted as 're-expression' or as intratumoral progenitor cell signature. Cancer testis antigen expression patterns have not yet been studied in germ cell tumorigenesis with specific emphasis on intratubular germ cell neoplasia unclassified as a precursor lesion for testicular germ cell tumors. Immunohistochemistry was used to study MAGEA3, MAGEA4, MAGEC1, GAGE1 and CTAG1B expression in 325 primary testicular germ cell tumors, including 94 mixed germ cell tumors. Seminomatous and non-seminomatous components were separately arranged and evaluated on tissue microarrays. Spermatogonia in the normal testis were positive, whereas intratubular germ cell neoplasia unclassified was negative for all five CT antigens. Cancer testis antigen expression was only found in 3% (CTAG1B), 10% (GAGE1, MAGEA4), 33% (MAGEA3) and 40% (MAGEC1) of classic seminoma but not in nonseminomatous testicular germ cell tumors. In contrast, all spermatocytic seminomas were positive for cancer testis antigens. These data are consistent with a different cell origin in spermatocytic seminoma compared with classic seminoma and support a progression model with loss of cancer testis antigens in early tumorigenesis of testicular germ cell tumors and later re-expression in a subset of seminomas.

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Section: Discussionmentioning

confidence: 99%

Cancer testis antigen expression in testicular germ cell tumorigenesis

et al. 2014

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“…As far as spermatocytic tumour of older men is concerned, its gene expression profile -both at the transcript and protein level -resembles closely profiles of spermatogonia and early primary spermatocytes of the adult testis [26,27,70]. Accordingly, spermatocytic tumours do not express embryonic pluripotency genes and PGC/gonocyte specific markers, and markers of haploid spermatids (e.g.…”

Section: Immunohistochemical Markers Useful For Gct Diagnosis In Tissmentioning

confidence: 97%

“…Other immunohistochemical markers include SYCP1, NSE (neuron-specific enolase), CHK2, VASA, UTF1, FGFR3 or HRAS, and DMRT1 [26,27,30,46,71]. Recently, OCT2 was detected in a small subset of spermatocytic tumours and in A-dark spermatogonia [70], and in both cell types, OCT2 was found mutually exclusive with DMRT1 [75]. For diagnostic purposes in the clinics we suggest MAGE-A4 ( Figure 3) and DMRT1, which are the most robust immunohistochemical markers, as shown in Table 1.…”

Section: Immunohistochemical Markers Useful For Gct Diagnosis In Tissmentioning

confidence: 99%

“…p19-INK4) are also negative [26]. Among the best markers for spermatocytic tumour are the so-called cancer-testis antigens: SSX1-4, MAGE-A4, MAGE3, NY-ESO-1/CTAG1A, GAGE4, SAGE1 [27,[70][71][72][73][74] (Figure 3). Other immunohistochemical markers include SYCP1, NSE (neuron-specific enolase), CHK2, VASA, UTF1, FGFR3 or HRAS, and DMRT1 [26,27,30,46,71].…”

Section: Immunohistochemical Markers Useful For Gct Diagnosis In Tissmentioning

confidence: 99%

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Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs

Meyts

Nielsen

Skakkebæk

et al. 2015

Folia Histochem Cytobiol.

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This concise review summarises tissue and serum markers useful for differential diagnosis of germ cell tumours (GCT), with focus on the most common testicular GCT (TGCT). GCT are characterised by phenotypic heterogeneity due to largely retained embryonic pluripotency and aberrant somatic differentiation. TGCT that occur in young men are divided into two main types, seminoma and nonseminoma, both derived from a pre-invasive germ cell neoplasia in situ (GCNIS), which originates from transformed foetal gonocytes. In severely dysgenetic gonads, a GCNIS-resembling lesion is called gonadoblastoma. GCT occur rarely in young children (infantile GCT) in whom the pathogenesis is different (no GCNIS/gonadoblastoma stage) but the histopathological features are similar to the adult GCT. The rare spermatocytic tumour of older men is derived from post-pubertal spermatogonia that clonally expand due to gain-of function mutations in survival-promoting genes (e.g. FGFR3, HRAS), thus this tumour has a different expression profile than GCNIS-derived TGCT. Clinically most informative immunohistochemical markers for GCT, except teratoma, are genes expressed in primordial germ cells/gonocytes and embryonic pluripotency-related factors, such as placental-like alkaline phosphatase (PLAP), OCT4 (POU5F1), NANOG, AP-2γ (TFAP2C) and LIN28, which are not expressed in normal adult germ cells. Some of these markers can also be used for immunocytochemistry to detect GCNIS or incipient tumours in semen samples. Gene expression in GCT is regulated in part by DNA and histone modifications, and the epigenetic profile of these tumours is characterised by genome-wide demethylation, except nonseminomas. In addition, a recently discovered mechanism of post-genomic gene expression regulation involves small non-coding RNAs, predominantly micro-RNA (miR). Testicular GCT display micro-RNA profiles similar to embryonic stem cells. Targeted miRNA-based blood tests for miR-371-3 and miR-367 clusters are currently under development and hold a great promise for the future. In some patients miR-based tests may be even more sensitive than the classical serum tumour markers, b-chorio-gonadotrophin (b-hCG), a-fetoprotein (AFP) and lactate dehydrogenase (LDH), which are currently used in the clinic. In summary, research advances have provided clinicians with a panel of molecular markers, which allow specific diagnosis of various subtypes of GCT and are very useful for early detection at the precursor stage and for monitoring of patients during the follow-up.

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“…For a detailed analysis of impaired spermatogenesis, three markers were chosen (Table 1), octamer-binding protein 2 (OCT2 (POU2F2)) for early spermatogonia (Lim et al 2011), sarcoma antigen 1 (SAGE1) for dividing and differentiating spermatogonia (Lim et al 2011), and mitosis-meiosis transition (Looijenga 2011), and SMAD3 for pachytene spermatocytes (Hentrich et al 2011).…”

Section: Antibodiesmentioning

confidence: 99%

Role of compensatory meiosis mechanisms in human spermatogenesis

Borgers¹,

Wolter²,

Hentrich³

et al. 2014

Reproduction

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Disturbances of checkpoints in distinct stages of spermatogenesis (mitosis, meiosis, and spermiogenesis) contribute to impaired spermatogenesis; however, the efficiency of meiotic entry has not been investigated in more detail. In this study, we analyzed azoospermic patients with defined spermatogenic defects by the use of octamer-binding protein 2 for type A spermatogonia, sarcoma antigen 1 for mitosis-meiosis transition and SMAD3 for pachytene spermatocytes. Especially patients with maturation arrest (MA) at the level of primary spermatocytes showed significantly reduced numbers of spermatogonia compared with patients with histologically intact spermatogenesis or patients with hypospermatogenesis (Hyp). For a detailed individual classification of the patients, we distinguished between 'high efficiency of meiotic entry' (high numbers of pachytene spermatocytes) and 'low efficiency of meiotic entry' (low numbers of pachytene spermatocytes). Only patients with histologically normal spermatogenesis (Nsp) and patients with Hyp showed normal numbers of spermatogonia and a high efficiency of meiotic entry. Of note, only patients with histologically Nsp or patients with Hyp could compensate low numbers of spermatogonia with a high efficiency of meiotic entry. In contrast, patients with MA always showed a low efficiency of meiotic entry. This is the first report on patients with impaired spermatogenesis, showing that half of the patients with Hyp but all patients with MA cannot compensate reduced numbers in spermatogonia with a highly efficient meiosis. Thus, we suggest that compensatory meiosis mechanisms in human spermatogenesis exist.

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OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of spermatocytic seminoma reflecting distinct subpopulations of spermatogonia

Cited by 76 publications

References 28 publications

Cancer testis antigen expression in testicular germ cell tumorigenesis

Cancer testis antigen expression in testicular germ cell tumorigenesis

Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs

Role of compensatory meiosis mechanisms in human spermatogenesis

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