Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14

Ruark, Elise; Seal, Sheila; McDonald, Helen; Zhang, Feng; Elliot, Anna; Lau, KingWai; Perdeaux, Elizabeth R; Rapley, Elizabeth; Eeles, Rosalind; Peto, Julian; Kóte-Jarai, Zsofia; Muir, Kenneth; Nsengimana, Jérémie; Shipley, Janet; Bishop, D. Timothy; Stratton, Michael R.; Easton, Douglas F.; Huddart, Robert; Rahman, Nazneen; Turnbull, Clare

doi:10.1038/ng.2635

Cited by 148 publications

(141 citation statements)

References 46 publications

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“…In comparison, activating KIT mutations appear in approximately 20% of seminomas (1), whereas multiple GWAS-identified loci associated with TGCT account altogether for approximately 25% to 32% of the genetic risk of developing TGCT (4,5). In this context, the ubiquitous occurrence of the RHAMM defect raises the possibility that RHAMM represents a convergence hub of the activity of multiple TGCT ÃÃÃ , P < 0.0001 (P ¼ 0.0000027); ÃÃ , P < 0.01 (P ¼ 0.0024).…”

Section: Rhamm Downregulation and Delocalization From The Spindle Appmentioning

confidence: 99%

“…Despite extensive research, the etiology of TGCT is not well understood. Loss of heterozygosity, allelic imbalance, and genome-wide association studies (GWAS) have identified several loci and genes conferring TGCT susceptibility; however, most of them are not functionally characterized (4)(5)(6)(7). On the basis of these and other data, models of TGCT development have been proposed (8) but the initiating event behind these cancers remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma

Frappart

Moll

et al. 2016

Cancer Research

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Hypofertility is a risk factor for the development of testicular germ cell tumors (TGCT), but the initiating event linking these pathologies is unknown. We hypothesized that excessive planar division of undifferentiated germ cells promotes their self-renewal and TGCT development. However, our results obtained from mouse models and seminoma patients demonstrated the opposite. Defective planar divisions of undifferentiated germ cells caused their premature exit from the seminiferous tubule niche, resulting in germ cell depletion, hypofertility, intratubular germ cell neoplasias, and seminoma development. Oriented divisions of germ cells, which determine their fate, were regulated by spindle-associated RHAMM-a function we found to be abolished in 96% of human seminomas. Mechanistically, RHAMM expression is regulated by the testis-specific polyadenylation protein CFIm25, which is downregulated in the human seminomas. These results suggested that spindle misorientation is oncogenic, not by promoting selfrenewing germ cell divisions within the niche, but by prematurely displacing proliferating cells from their normal epithelial milieu. Furthermore, they suggested RHAMM loss-of-function and spindle misorientation as an initiating event underlying both hypofertility and TGCT initiation. These findings identify spindle-associated RHAMM as an intrinsic regulator of male germ cell fate and as a gatekeeper preventing initiation of TGCTs. Cancer Res; 76(21); 6382-95. Ó2016 AACR.

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Section: Rhamm Downregulation and Delocalization From The Spindle Appmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma

Frappart

Moll

et al. 2016

Cancer Research

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“…Genome-wide association studies (GWAS) in humans identified susceptibility loci such as KIT ligand (KITL), Sprouty 4 (SPRY4), Bcl2 antagonist killer (BAK1), Doublesex-and Mab3-related transcription factor (DMRT1), Deleted in azoospermia RNA-binding protein (DAZL), PRDM transcriptional regulator (PRDM14), the telomerase reverse transcriptase TERT, and its cofactor AFT7IP (9)(10)(11)(12)(13)(14)(15). Individually and collectively, however, these susceptibility genes account for only a modest portion of inherited risk.…”

mentioning

confidence: 99%

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

Carouge

Blanc

Knoblaugh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Testicular tumors, the most common cancer in young men, arise from abnormalities in germ cells during fetal development. Unconventional inheritance for testicular germ cell tumor (TGCT) risk both in humans and mice implicates epigenetic mechanisms. Apolipoprotein B mRNA-editing enzyme complex 1 (APOBEC1) cytidine deaminase and Deadend-1, which are involved in C-to-U RNA editing and microRNA-dependent mRNA silencing, respectively, are potent epigenetic modifiers of TGCT susceptibility in the genetically predisposed 129/Sv inbred mouse strain. Here, we show that partial loss of either APOBEC1 complementation factor (A1CF), the RNA-binding cofactor of APOBEC1 in RNA editing, or Argonaute 2 (AGO2), a key factor in the biogenesis of certain noncoding RNAs, modulates risk for TGCTs and testicular abnormalities in both parent-of-origin and conventional genetic manners. In addition, non-Mendelian inheritance was found among progeny of A1cf and Ago2 mutant intercrosses but not in backcrosses and without fetal loss. Together these findings suggest nonrandom union of gametes rather than meiotic drive or preferential lethality. Finally, this survey also suggested that A1CF contributes to long-term reproductive performance. These results directly implicate the RNA-binding proteins A1CF and AGO2 in the epigenetic control of germ-cell fate, urogenital development, and gamete functions.he germline is the only cell lineage that transmits genetic and epigenetic information across generations. Early in mammalian development, primordial germ cells (PGCs) escape a somatic fate to become unipotent precursors of gametes, the highly specialized cells that give rise to the totipotent zygote upon fertilization (1). Various molecular mechanisms regulate pluripotency by modulating gene expression and protein activity throughout development (2). Failure of pluripotency control can lead to infertility, carcinoma in situ, gamete dysfunctions, and unusual modes of inheritance. Carcinoma in situ anomalously express markers of pluripotency and can give rise to testicular germ cell tumors (TGCTs) (3-7). Studying the genetics, epigenetics, and biology of germ cells (GCs) and TGCTs can provide unique insights about GC development, pluripotency control, tumorigenesis, and unconventional inheritance.TGCTs are the third most heritable cancer and are the most common cancers in young men 15-35 y old (8). Genome-wide association studies (GWAS) in humans identified susceptibility loci such as KIT ligand (KITL), Sprouty 4 (SPRY4), Bcl2 antagonist killer (BAK1), Doublesex-and Mab3-related transcription factor (DMRT1), Deleted in azoospermia RNA-binding protein (DAZL), PRDM transcriptional regulator (PRDM14), the telomerase reverse transcriptase TERT, and its cofactor AFT7IP (9-15). Individually and collectively, however, these susceptibility genes account for only a modest portion of inherited risk. Many genes and inherited factors remain to be discovered, their functions in normal development characterized, and the ways that dysfunction leads to TGCTs inve...

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“…Variants have been found near genes involved in male germ cell development (DAZL, HPGDS, SMARCAD1, SEPT4, TEX14, RAD51C, PPM1E, and TRIM37), chro mosomal segregation (MAD1L1, TEX14, and SKA2), the DNA damage response (SMARCAD1, RFWD3, and RAD51C), and epigenetic regulation (JMJD1C/KDM3A and KDM2A) [83,85,91] . Mouse models would help to evaluate the roles of these genes in the tumorigenesis of germ cells.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, PGClike cells induced from homozygous Tfap2c mutant ESCs show upregulation of cell cycle regulators (Cdk6) and pluripotency genes (Eras, Klf4), but downregulation of germline genes (Dmrt1, Nanos3) [84] . Furthermore, the susceptibility locus for human testicular germ cell cancer has been found near PRDM14 [85] . Collectively, these germline genes also function as gatekeepers of PGC dedifferentiation.…”

Section: Regulators Of Germ Cell Developmentmentioning

confidence: 99%

Reprogramming of germ cells into pluripotency

Sekita¹,

Nakamura²,

Kimura³

2016

WJSC

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Primordial germ cells (PGCs) are precursors of all gametes, and represent the founder cells of the germline. Although developmental potency is restricted to germ-lineage cells, PGCs can be reprogrammed into a pluripotent state. Specifically, PGCs give rise to germ cell tumors, such as testicular teratomas, in vivo , and to pluripotent stem cells known as embryonic germ cells in vitro . In this review, we highlight the current knowledge on signaling pathways, transcriptional controls, and post-transcriptional controls that govern germ cell differentiation and de-differentiation. These regulatory processes are common in the reprogramming of germ cells and somatic cells, and play a role in the pathogenesis of human germ cell tumors.

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Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14

Cited by 148 publications

References 46 publications

Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma

Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

Reprogramming of germ cells into pluripotency

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