Malignant Germ Cell Tumors Display Common MicroRNA Profiles Resulting in Global Changes in Expression of Messenger RNA Targets

Palmer, Roger D.; Murray, Matthew J.; Saini, Harpreet K.; Dongen, Stijn van; Abreu‐Goodger, Cei; Muralidhar, Balaji; Pett, Mark R.; Thornton, Claire M.; Nicholson, James C.; Enright, Anton J.; Coleman, Nicholas

doi:10.1158/0008-5472.can-09-3301

Cited by 245 publications

(337 citation statements)

References 46 publications

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“…The oncogenic miR-371~373 and miR-302/367 clusters20 (see Figure 3B) are over-expressed in all MGCTs, regardless of age, site, or histologic subtype. 21 Importantly, elevated levels of these miRNAs can be detected in the serum at the time of MGCT diagnosis as well as at relapse, and decline in response to treatment. It is estimated that 70% of non-germinomatous GCTs and 20% of germinomas are secreting.…”

Section: Introductionmentioning

confidence: 99%

Paediatric extracranial germ-cell tumours

Shaikh

Murray

Amatruda

et al. 2016

The Lancet Oncology

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The management of paediatric extracranial germ cell tumours (GCTs) carries a unique set of challenges. GCTs are a heterogeneous group of neoplasms that present across a wide range of age, site, histology, and clinical behaviour. They are managed by a diverse variety of specialists. Correspondingly, their staging, risk-stratification, and treatment approaches have evolved disparately along multiple trajectories. Paediatric GCTs differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate evidence-based care. Suboptimal outcomes remain for several patient groups, and among survivors there are significant long-term toxicities.The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into better patient outcomes. Future trials will be characterised by improved riskstratification systems, biomarkers for response and toxicity, rational reduction of therapy for low-risk patients and novel approaches for highrisk patients, and improved international collaboration across paediatric and adult cooperative research groups. Correspondingly, their staging, risk-stratification, and treatment approaches have evolved disparately along multiple trajectories. Paediatric GCTs differ from the adolescent and adult disease in many ways, leading to complexities in applying age-appropriate evidence-based care.Suboptimal outcomes remain for several patient groups, and among survivors there are significant long-term toxicities. The challenge moving forward will be to translate new insights from molecular studies and collaborative clinical data into better patient outcomes. Future trials will be characterised by improved risk-stratification systems, biomarkers for response and toxicity, rational reduction of therapy for low-risk patients and novel approaches for high-risk patients, and improved international collaboration across paediatric and adult cooperative research groups.

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Section: Introductionmentioning

confidence: 99%

Paediatric extracranial germ-cell tumours

Shaikh

Murray

Amatruda

et al. 2016

The Lancet Oncology

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“…In addition, it is suggested that specific miR are involved in the maturation of mouse gonocytes to pre-spermatogonia (McIver et al, 2012a,b). Most recently, detection of miR in serum of GCC (adult and pediatric) patients has been reported from two independent groups (Belge et al, 2012, Murray and Coleman, 2012, Palmer et al, 2010. This opens novel possibilities for the diagnosis and follow-up of GCT patients.…”

Section: Mirnas In the Development Of Germ Cells And Gccmentioning

confidence: 95%

Development of malignant germ cells - the genvironmental hypothesis

Looijenga¹,

Agthoven²,

Biermann³

2013

Int. J. Dev. Biol.

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Human germ cell tumors are of interest because of their epidemiology, clinic and pathobiology. Histologically, they are subdivided into various elements, with similarities to embryogenesis. Recent insight triggered development of a higher order division into five types of human germ cell tumors. In the context of male germ cells, only three are relevant; Type I: teratomas and yolk sac tumors of neonates and infants; Type II: seminomas and nonseminomas of (predominantly) adolescents and adults; and Type III: spermatocytic seminomas of the elderly. Various animal models, both occurring spontaneous or induced, are reported, of which their relevance is still a matter of debate. Recent multidisciplinary studies have led to a significant increase in our understanding of the parameters involved in the earliest pathogenetic steps of human germ cells tumors, particularly the seminomas and nonseminomas (Type II). This paper will discuss a number of interesting insights into the normal and aberrant regulation of germ cell development, resulting in the so-called genvironmental hypothesis. This assumes a subtle interaction between environmental-and (epi)genetic parameters, resulting in clinical/phenotypical characteristics. These influence signaling pathways and thereby developmental processes, including gonadal development, germ cell proliferation, maturation and apoptosis. In the case of a disturbed physiology, either due to the germ cell itself, or the micro-environment, embryonic germ cells, during a specific window of sensitization, might be blocked in their maturation, resulting in carcinoma in situ or gonadoblastoma, the precursors of seminomas and nonseminomas. The level of testicularization of the gonad determines the histological composition of the precursor. These insights will allow a better definition of individuals at risk of developing a germ cell malignancy, and allow a better selection of scientific approaches to elucidate the corresponding pathogenesis.

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“…GCT display micro-RNA profiles similar to embryonic stem cells, and these embryonic miRNA types are already highly upregulated and detectable in pre-invasive GCNIS cells [97]. Interestingly, the characteristic miRNA profiles are similar in GCT that arise in children and adults, and are detectable in all histological subtypes and components, except teratoma [21,98,99]. This specific TGCT profile, which was detected by several groups independently from each other, includes a high level of miR-371-3 cluster, miR-302 and miR-367.…”

Section: Traces Of Gct In Blood: Classical Biochemical Markers and MImentioning

confidence: 99%

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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Malignant Germ Cell Tumors Display Common MicroRNA Profiles Resulting in Global Changes in Expression of Messenger RNA Targets

Cited by 245 publications

References 46 publications

Paediatric extracranial germ-cell tumours

Paediatric extracranial germ-cell tumours

Development of malignant germ cells - the genvironmental hypothesis

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

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