Identification of 22 susceptibility loci associated with testicular germ cell tumors

Pluta, John; Pyle, Louise C.; Nead, Kevin T.; Wilf, Rona; Li, Mingyao; Mitra, Nandita; Weathers, Benita; D’Andrea, Kurt; Almstrup, Kristian; Anson‐Cartwright, Lynn; Benı́tez, Javier; Brown, Christopher D.; Chanock, Stephen J.; Chu, Chen; Cortessis, Victoria K.; Ferlin, Alberto; Gamulin, Marija; Gietema, Jourik A.; Grasso, Chiara; Greene, Mark H.; Grotmol, Tom; Hamilton, Robert J.; Haugen, Trine B.; Hauser, Russ; Hildebrandt, Michelle A.T.; Johnson, Matthew E.; Karlsson, Robert; Kiemeney, Lambertus A.; Lessel, Davor; Lothe, Ragnhild A.; Loud, Jennifer T.; Loveday, Chey; Martín-Gimeno, Paloma; Meijer, Coby; Nsengimana, Jérémie; Quinn, David I.; Rafnar, Thorunn; Ramdas, Shweta; Richiardi, Lorenzo; Skotheim, Rolf Inge; Stefánsson, Kāri; Turnbull, Clare; Vaughn, David J.; Wiklund, Fredrik; Wu, Xifeng; Yang, Daphne; Zheng, Tongzhang; Wells, Andrew D.; Grant, Struan F A; Meyts, Ewa Rajpert‐De; Bishop, D. Timothy; McGlynn, Katherine A.; Kanetsky, Peter A.; Nathanson, Katherine L.

doi:10.1038/s41467-021-24334-y

Cited by 38 publications

(51 citation statements)

References 91 publications

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“…Genome-wide association studies (GWAS) have so far identified 78 susceptibility loci for TGCT ( 82 ). Although TGCT development is unique in several aspects, we know from GWAS that there are risk genes for TGCT that are involved in pathways commonly associated with other cancer types.…”

Section: Discussionmentioning

confidence: 99%

A Role of the TEX101 Interactome in the Common Aetiology Behind Male Subfertility and Testicular Germ Cell Tumor

et al. 2022

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Patients who develop testicular germ cell tumours (TGCT) are at higher risk to be subfertile than the general population. The conditions are believed to originate during foetal life, however, the mechanisms behind a common aetiology of TGCT and male subfertility remains unknown. Testis-expressed 101 (TEX101) is a glycoprotein that is related to male fertility, and downregulation of the TEX101 gene was shown in pre-diagnostic TGCT patients. In this review, we summarize the current knowledge of TEX101 and its interactome related to fertility and TGCT development. We searched literature and compilation of data from curated databases. There are studies from both human and animals showing that disruption of TEX101 result in abnormal semen parameters and sperm function. Members of the TEX101 interactome, like SPATA19, Ly6k, PICK1, and ODF genes are important for normal sperm function. We found only two studies of TEX101 related to TGCT, however, several genes in its interactome may be associated with TGCT development, such as PLAUR, PRSS21, CD109, and ALP1. Some of the interactome members are related to both fertility and cancer. Of special interest is the presence of the glycosylphosphatidylinositol anchored proteins TEX101 and PRSS21 in basophils that may be coupled to the immune response preventing further development of TGCT precursor cells. The findings of this review indicate that members of the TEX101 interactome could be a part of the link between TGCT and male subfertility.

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Section: Discussionmentioning

confidence: 99%

A Role of the TEX101 Interactome in the Common Aetiology Behind Male Subfertility and Testicular Germ Cell Tumor

et al. 2022

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“…Finally, mRNA translation has been implicated in TGCT susceptibility for the first time; with several genes mapping to variants of significance identified by this recent GWAS, which encode proteins interacting in mRNA translation, including RPL4 , GSTP1 and TRAP-gamma [8 ▪▪ ].…”

Section: Germline Risk Of Germ Cell Tumoursmentioning

confidence: 94%

“…The SNPs identified in these GWAS map to several loci containing genes encoding proteins that are implicated in several biological pathways in TGCT susceptibility: male germ cell development, sex determination and maturation, regulation of the mitotic cell, and mRNA translation [8 ▪▪ ]. Knowledge about the functional importance of these loci has been predominantly acquired through studies on mouse models.…”

Section: Germline Risk Of Germ Cell Tumoursmentioning

confidence: 99%

“…In mice, loss of this gene leads to testicular teratomas in over 90% of cases [29]. The rs10976519 variant on chromosome 9 was a variant of significance identified on GWAS, and maps to the DMRT1 gene [8 ▪▪ ]. In addition, two other genes identified by GWAS are known to regulate mitochondrial apoptosis ( BAK1 and BCL2L11 ), encoding proteins Bik and Bim respectively, and are implicated in early germ cell apoptosis in mouse models via elimination of supernumerary germ cells during spermatogenesis [30].…”

Section: Germline Risk Of Germ Cell Tumoursmentioning

confidence: 99%

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Genetics of testicular cancer: a review

Martin

Conduit

Loveland

et al. 2022

Current Opinion in Urology

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Purpose of reviewTesticular germ cell tumours (TGCTs) are the most common solid malignant cancer diagnosed in young males and the incidence is increasing. Understanding the genetic basis of this disease will help us to navigate the challenges of early detection, diagnosis, treatment, surveillance, and long-term outcomes for patients.Recent findingsTGCTs are highly heritable. Current understanding of germline risk includes the identification of one moderate-penetrance predisposition gene, checkpoint kinase 2 (CHEK2), and 78 low-to-moderate-risk single nucleotide polymorphisms identified in genome-wide-associated studies, which account for 44% of familial risk. Biomarker research in TGCTs has been challenging for multiple reasons: oncogenesis is complex, actionable mutations are uncommon, clonal evolution unpredictable and tumours can be histologically and molecularly heterogeneous. Three somatic mutations have thus far been identified by DNA exome sequencing, exclusively in seminomas: KIT, KRAS and NRAS. Several genetic markers appear to be associated with risk of TGCT and treatment resistance. TP53 mutations appear to be associated with platinum resistance. MicroRNA expression may be a useful biomarker of residual disease and relapse in future.SummaryThe biology of testicular germ cells tumours is complex, and further research is needed to fully explain the high heritability of these cancers, as well as the molecular signatures which may drive their biological behaviour.

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“…According to genomic datasets, over three-quarters of the inherited genetic risk may be transmitted through common variation [ 6 ]. The inherited TGCT risk is largely polygenic [ 7 ], and genome-wide association studies have revealed 78 susceptibility loci for TGCT [ 8 ]. Functional studies show that a large part of the risk genes is related to male germ cell development, sex determination, and genomic integrity [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Diverse Roles and Targets of miRNA in the Pathogenesis of Testicular Germ Cell Tumour

Das

Haugen

2022

Cancers

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Testicular germ cell tumour (TGCT) is the most common cancer type among young adults in many parts of the world. Although the pathogenesis of TGCT is not well understood, the involvement of heritable components is evident, and the risk is polygenic. Genome-wide association studies have so far found 78 susceptibility loci for TGCT, and many of the loci are in non-coding regions indicating the involvement of non-coding RNAs in TGCT pathogenesis. MicroRNAs (miRNAs), a class of non-coding RNAs, have emerged as important gene regulators at the post-transcriptional level. They are crucial in controlling many cellular processes, such as proliferation, differentiation, and apoptosis, and an aberrant miRNA expression may contribute to the pathogenesis of several cancers, including TGCT. In support of this notion, several studies reported differential expression of miRNAs in TGCTs. We previously demonstrated that miRNAs were the most common group of small non-coding RNAs in TGCTs, and several functional studies of miRNAs in TGCTs suggest that they may act as either oncogene or tumour suppressors. Moreover, individual miRNA targets and downstream pathways in the context of TGCT development have been explored. In this review, we will focus on the diverse roles and targets of miRNAs in TGCT pathogenesis.

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Identification of 22 susceptibility loci associated with testicular germ cell tumors

Cited by 38 publications

References 91 publications

A Role of the TEX101 Interactome in the Common Aetiology Behind Male Subfertility and Testicular Germ Cell Tumor

A Role of the TEX101 Interactome in the Common Aetiology Behind Male Subfertility and Testicular Germ Cell Tumor

Genetics of testicular cancer: a review

Diverse Roles and Targets of miRNA in the Pathogenesis of Testicular Germ Cell Tumour

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