Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours

Litchfield, Kevin; Summersgill, Brenda; Yost, Shawn; Sultana, Răzvan; Labreche, Karim; Dudakia, Darshna; Renwick, Anthony; Seal, Sheila; Al‐Saadi, Reem; Broderick, Peter; Turner, Nicholas C.; Houlston, Richard S.; Huddart, Robert; Shipley, Janet; Turnbull, Clare

doi:10.1038/ncomms6973

Cited by 162 publications

(198 citation statements)

References 65 publications

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“…S2). In addition to gain of 12p in individual samples, SCNAs were consistent with available historical data (van Echten et al 1995;Faulkner et al 2000;Looijenga et al 2000;Skotheim and Lothe 2003;McIntyre et al 2007;Litchfield et al 2015), notably recurrent pan-TGCT gains of Chromosomes 7, 8, 22, and X, and losses of Chromosomes 4,5,10,11,13,18, and Y (Fig. 1); also evident are the relative gains of Chromosomes 19 and 22 in SEs relative to NSEs (van Echten et al 1995;Summersgill et al 1998).…”

Section: Series Descriptionsupporting

confidence: 60%

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

et al. 2016

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Testicular germ cell tumors (TGCTs) share germline ancestry but diverge phenotypically and clinically as seminoma (SE) and nonseminoma (NSE), the latter including the pluripotent embryonal carcinoma (EC) and its differentiated derivatives, teratoma (TE), yolk sac tumor (YST), and choriocarcinoma. Epigenomes from TGCTs may illuminate reprogramming in both normal development and testicular tumorigenesis. Herein we investigate pure-histological forms of 130 TGCTs for conserved and subtype-specific DNA methylation, including analysis of relatedness to pluripotent stem cell (ESC, iPSC), primordial germ cell (PGC), and differentiated somatic references. Most generally, TGCTs conserve PGC-lineage erasure of maternal and paternal genomic imprints and DPPA3 (also known as STELLA); however, like ESCs, TGCTs show focal recurrent imprinted domain hypermethylation. In this setting of shared physiologic erasure, NSEs harbor a malignancy-associated hypermethylation core, akin to that of a diverse cancer compendium. Beyond these concordances, we found subtype epigenetic homology with pluripotent versus differentiated states. ECs demonstrate a striking convergence of both CpG and CpH (non-CpG) methylation with pluripotent states; the pluripotential methyl-CpH signature crosses species boundaries and is distinct from neuronal methyl-CpH. EC differentiation to TE and YST entails reprogramming toward the somatic state, with loss of methyl-CpH but de novo methylation of pluripotency loci such as NANOG. Extreme methyl-depletion among SE reflects the PGC methylation nadir. Adjacent to TGCTs, benign testis methylation profiles are determined by spermatogenetic proficiency measured by Johnsen score. In sum, TGCTs share collective entrapment in a PGC-like state of genomic-imprint and DPPA3 erasure, recurrent hypermethylation of cancer-associated targets, and subtype-dependent pluripotent, germline, or somatic methylation.

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Section: Series Descriptionsupporting

confidence: 60%

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

et al. 2016

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“…Our results as well as other studies [3,9,24] indicate that activation of the MAPK and/or PI3K pathways by somatic point mutations is one of the main driving forces of GCT development regardless of histological subtype or site of origin. We showed that the function of activating MTOR mutations may be effectively suppressed by a specific inhibitor suggesting that these mutations can be exploited to treat at least a subset of CNS GCTs that shows resistance to conventional chemotherapy.…”

Section: Clinical Associationmentioning

confidence: 48%

“…1; Supplementary Tables S14, S15). Recently, a whole exome sequencing study on 42 tGCTs was published [9]. When the exome mutation profiles are compared with our current study, few genes are shared between the two cohorts except KIT and KRAS, which were found mutated at a comparable frequency.…”

Section: Mutational Profiles Of Cns and Testicular Gctsmentioning

confidence: 86%

Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy

Ichimura¹,

Fukushima²,

Totoki³

et al. 2016

Acta Neuropathol

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Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs.

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“…Other recognized risk factors for TGCT include a history of undescended testis (UDT) and other testicular abnormalities such as hypogonadism and microlithiasis 45,46 . Elevated TGCT risk is also associated with Down syndrome (trisomy 21) 47 and Klinefelter syndrome (47XXY karyotype) 48 and, intriguingly, somatic gains of both chromosomes 21 and X are frequently observed in TGCTs 49 . Furthermore, cooccurrence in families of ovarian germ cell tumour and TGCT has also been recurrently reported, suggesting shared oncogenic pathways 50 .…”

mentioning

confidence: 98%

The genomic landscape of testicular germ cell tumours: from susceptibility to treatment

et al. 2016

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The genomic landscape of testicular germ cell tumour (TGCT) can be summarized using four overarching hypotheses. Firstly, TGCT risk is dominated by inherited genetic factors, which determine nearly half of all disease risk and are highly polygenic in nature. Secondly KIT-KITLG signalling is currently the major pathway that is implicated in TGCT formation, both as a predisposition risk factor and a somatic driver event. Results from genome-wide association studies have also consistently suggested that other closely related pathways involved in male germ cell development and sex determination are associated with TGCT risk. Thirdly, the method of disease formation is unique, with tumours universally stemming from a noninvasive precursor lesion, probably of fetal origin, which lies dormant through childhood into adolescence and then eventually begins malignant growth in early adulthood. Formation of a 12p isochromosome, a hallmark of TGCT observed in nearly all tumours, is likely to be a key triggering event for malignant transformation. Finally, TGCT have been shown to have a distinctive somatic mutational profile, with a low rate of point mutations contrasted with frequent large-scale chromosomal gains. These four hypotheses by no means constitute a complete model that explains TGCT tumorigenesis, but advances in genomic technologies have enabled considerable progress in describing and understanding the disease. Further advancing our understanding of the genomic basis of TGCT offers a clear opportunity for clinical benefit in terms of preventing invasive cancer arising in young men, decreasing the burden of chemotherapy-related survivorship issues and reducing mortality in the minority of patients who have treatment-refractory disease.

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Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours

Cited by 162 publications

References 65 publications

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy

The genomic landscape of testicular germ cell tumours: from susceptibility to treatment

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