Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance

Jeyapalan, Jennie N.; Da, Noor; Sh, Lee; Cl, Tan; Va, Appleby; Jp, Kilday; Rd, Palmer; Schwalbe, EC; Clifford, Steven C.; Da, Walker; Murray, Micah M.; Coleman, Nicholas; Nicholson, Jeremy K.; Scotting, PJ

doi:10.1038/bjc.2011.218

Cited by 28 publications

(47 citation statements)

References 81 publications

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“…Like the consistent cytogenetic abnormalities described earlier, this contrasts the separation of infantile and YSTs from older children as proposed by others (Veltman et al 2003, Oosterhuis & Looijenga 2005. Whether the differential gene expression profiles observed between paediatric and adult GCTs, particularly in YSTs, can be explained by DNA methylation changes remains to be determined (Palmer et al 2008, Jeyapalan et al 2011.…”

Section: R55mentioning

confidence: 61%

“…However, the adult group included a large proportion of EC samples (which showed almost no hypermethylation), the rest of the non-seminomas showing methylation levels similar to the paediatric study, which included very few EC samples (Furukawa et al 2009). Analysis using the more comprehensive GoldenGate array confirmed the pronounced methylation phenotype of childhood YSTs: 10% of the genes analysed were hypermethylated in YSTs compared with seminomatous tumours, and in many cases, the methylation change was seen in almost all YST samples studied (Jeyapalan et al 2011). The methylation patterns reported here applied to children both above and below the age of 5 years.…”

Section: R55mentioning

confidence: 65%

“…The differing methylation profiles of the various GCT subtypes appear to be independent of location, gender (Furukawa et al 2009, Wermann et al 2010, Jeyapalan et al 2011 or genetic aberrations (Smiraglia et al 2002, Smith-Sorensen et al 2002, Lind et al 2007. With respect to age, differences between paediatric and adult GCTs have been suggested (Kato et al 2003, Furukawa et al 2009, Jeyapalan et al 2011; Table 2), but this does not stand up to close scrutiny. These apparent differences when comparing non-seminomatous tumours between ages appear to reflect the differing predominant GCT subtypes between adults and children.…”

Section: R55mentioning

confidence: 96%

“…Smiraglia et al (2002) suggested that CpG island methylation in non-seminomas could be associated with the increase in euchromatin DNA methylation occurring between days 16 and 17 in mouse male germ cells (Smiraglia et al 2002). Although the malignant non-seminomas exhibit increased hypermethylation (Netto et al 2008, Wermann et al 2010, they also exhibit hypomethylation of LINE1 repetitive elements (Jeyapalan et al 2011, Ushida et al 2012, which is reminiscent of other cancer cells and normal PGCs. The observation that different components of mixed tumours display distinct methylation profiles further supports the conclusion that aberrant methylation is a key factor in the development of GCT subtypes (Smith-Sorensen et al 2002, Honorio et al 2003, Netto et al 2008.…”

Section: Dna Methylation In Gctsmentioning

confidence: 99%

“…The first description of a methylator phenotype was in a subset of colon cancers said to have a CpG island methylator phenotype (CIMP; Toyota et al 1999). Subsequently, methylator phenotypes have been described in subpopulations of gliomas (Noushmehr et al 2010), breast cancers (Roll et al 2008, Bediaga et al 2010, Holm et al 2010, parathyroid tumours (Starker et al 2011), neuroblastomas (Alaminos et al 2004, Abe et al 2005, and GCTs (see below) (Lind et al 2007, Jeyapalan et al 2011. In colon cancer, early reports associated CIMPC tumours with a variety of clinical and genetic features; however, other studies failed to distinguish a distinct methylator phenotype (Toyota et al 1999, Yamashita et al 2003, Issa 2004).…”

Section: Dna Methylation In Cancermentioning

confidence: 99%

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DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions

Cusack¹,

Scotting²

2013

Reproduction

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Germ cell tumours (GCTs) are a diverse group of neoplasms that can be histologically subclassified as either seminomatous or non-seminomatous. These two subtypes have distinct levels of differentiation and clinical characteristics, the non-seminomatous tumours being associated with poorer prognosis. In this article, we review how different patterns of aberrant DNA methylation relate to these subtypes. Aberrant DNA methylation is a hallmark of all human cancers, but particular subsets of cancers show unusually high frequencies of promoter region hypermethylation. Such a 'methylator phenotype' has been described in non-seminomatous tumours. We discuss the possible cause of distinct methylation profiles in GCTs and the potential of DNA methylation to provide new targets for therapy. We also consider how recent developments in our understanding of this epigenetic modification and the development of genome-wide technologies are shedding new light on the role of DNA methylation in cancer aetiology.Reproduction (2013) 146 R49-R60

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Section: R55mentioning

confidence: 61%

Section: R55mentioning

confidence: 65%

Section: R55mentioning

confidence: 96%

Section: Dna Methylation In Gctsmentioning

confidence: 99%

Section: Dna Methylation In Cancermentioning

confidence: 99%

See 3 more Smart Citations

DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions

Cusack¹,

Scotting²

2013

Reproduction

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Replenishing co‐downregulated miR‐100‐5p and miR‐125b‐5p in malignant germ cell tumors causes growth inhibition through cell cycle disruption

Ferraresso,

Bailey,

Alonso‐Crisostomo

et al. 2024

Molecular Oncology

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MicroRNAs (miRNAs) are short, nonprotein‐coding RNAs, and their expression is dysregulated in malignant germ cell tumors (GCTs). Here, we investigated the causes and consequences of downregulated miR‐99a‐5p/miR‐100‐5p (functionally identical) and miR‐125b‐5p levels in malignant GCTs regardless of age, site, or subtype. Quantitative RT‐PCR was used to assess miR‐99a‐5p/miR‐100‐5p, miR‐125b‐5p, and associated gene expression in malignant GCT tissues/cell lines [seminoma (Sem), yolk sac tumor (YST), embryonal carcinoma (EC)]. Cells were treated with demethylating 5‐azacytidine and pyrosequencing was performed. Combination miR‐100‐5p/miR‐125b‐5p mimic replenishment was used to treat malignant GCT cells. Global messenger RNA (mRNA) targets of the replenished miRNAs were identified and Metascape used to study pathway effects. We found that expression levels of miR‐99a‐5p/miR‐100‐5p and miR‐125b‐5p, their respective pri‐miRNAs, and associated genes from chromosomes 11 and 21 (chr11/chr21) were downregulated and highly correlated in malignant GCT cells. Treatment with 5‐azacytidine caused upregulation of these miRNAs, with pyrosequencing revealing hypermethylation of their chr11/chr21 loci, likely contributing to miR‐100‐5p/miR‐125b‐5p downregulation. Combination miR‐100‐5p/miR‐125b‐5p mimic replenishment resulted in growth inhibition in Sem/YST cells, with miR‐100‐5p/miR‐125b‐5p mRNA targets enriched in downregulated genes, which were involved in cell cycle (confirmed by flow cytometry) and signaling pathways. Knockdown of the miR‐100‐5p/miR‐125b‐5p target tripartite motif containing 71 (TRIM71kd) recapitulated miR‐100‐5p/miR‐125b‐5p replenishment, with growth inhibition and cell cycle disruption of Sem/YST/EC cells. Further, replenishment led to reduced lin‐28 homolog A (LIN28A) levels and concomitant increases in let‐7 (MIRLET7B) tumor suppressor miRNAs, creating a sustained reversion of cell phenotype. In summary, combination miR‐100‐5p/miR‐125b‐5p mimic replenishment or TRIM71kd caused growth inhibition in malignant GCT cells via cell cycle disruption. Further studies are now warranted, including mimic treatment alongside conventional platinum‐based chemotherapy.

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Age‐related biological features of germ cell tumors

Collinson

Murray

Orsi

et al. 2013

Genes Chromosomes & Cancer

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Germ cell tumours (GCTs) are rare but clinically and pathologically diverse tumours that occur in an extensive range of age groups, from children to older adults and which include both seminomatous and nonseminomatous tumours. Current clinical management for both male and female teenagers and young adults (TYAs) with GCTs remains inconsistent, alternating between paediatric and adult multidisciplinary oncology teams, based on locally defined age cut-offs. We therefore reviewed available literature to determine the biological similarities and differences between GCTs in young children [0-12 years (y)], TYAs (13-24y), and older adults (>24y). GCTs arising in paediatric and adult populations in general showed marked molecular biological differences within identical histological subtypes, whereas there was a distinct paucity of available data for GCTs in the TYA population. These findings highlight that clinical management based simply on chronological age may be inappropriate for TYA and suggests that the optimal future management of GCTs should consider specific molecular biological factors in addition to clinical parameters in the context of patient specific age group specialty. 3 AimsThe aim of this review was to analyse molecular biological studies of germ cell tumours (GCTs) arising in the paediatric (≤12y) and older adult (>24y) age groups for key similarities and differences in an attempt to identify where the biology of GCTs from teenagers and young adult (TYA) patients lies within this framework. The review discusses current knowledge in this area and also highlights gaps that still need to be addressed. In the UK, the TYA age group includes male and females aged 13-24y; accordingly we have used this definition for the purposes of this review).The aims were achieved through a synthesis and analysis of available biological data for GCTs in children, TYAs and older adults. We anticipated that the goal would be to use a combination of both clinical and biological risk factors to improve clinical management decisions for TYA patients with GCTs (Murray et al., 2009).

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Methylator phenotype of malignant germ cell tumours in children identifies strong candidates for chemotherapy resistance

Cited by 28 publications

References 81 publications

DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions

DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions

Replenishing co‐downregulated miR‐100‐5p and miR‐125b‐5p in malignant germ cell tumors causes growth inhibition through cell cycle disruption

Age‐related biological features of germ cell tumors

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