Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline.
Adult male germline stem cells (spermatogonia) proliferate by mitosis and, after puberty, generate spermatocytes that undertake meiosis to produce haploid spermatozoa. Germ cells are under evolutionary constraint to curtail mutations and maintain genome integrity. Despite constant turnover, spermato...
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0178169&type=printable |
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| author | Eleni Giannoulatou Geoffrey J Maher Zhihao Ding Ad J M Gillis Lambert C J Dorssers Alexander Hoischen Ewa Rajpert-De Meyts WGS500 Consortium Gilean McVean Andrew O M Wilkie Leendert H J Looijenga Anne Goriely |
| author_facet | Eleni Giannoulatou Geoffrey J Maher Zhihao Ding Ad J M Gillis Lambert C J Dorssers Alexander Hoischen Ewa Rajpert-De Meyts WGS500 Consortium Gilean McVean Andrew O M Wilkie Leendert H J Looijenga Anne Goriely |
| author_sort | Eleni Giannoulatou |
| collection | DOAJ |
| description | Adult male germline stem cells (spermatogonia) proliferate by mitosis and, after puberty, generate spermatocytes that undertake meiosis to produce haploid spermatozoa. Germ cells are under evolutionary constraint to curtail mutations and maintain genome integrity. Despite constant turnover, spermatogonia very rarely form tumors, so-called spermatocytic tumors (SpT). In line with the previous identification of FGFR3 and HRAS selfish mutations in a subset of cases, candidate gene screening of 29 SpTs identified an oncogenic NRAS mutation in two cases. To gain insights in the etiology of SpT and into properties of the male germline, we performed whole-genome sequencing of five tumors (4/5 with matched normal tissue). The acquired single nucleotide variant load was extremely low (~0.2 per Mb), with an average of 6 (2-9) non-synonymous variants per tumor, none of which is likely to be oncogenic. The observed mutational signature of SpTs is strikingly similar to that of germline de novo mutations, mostly involving C>T transitions with a significant enrichment in the ACG trinucleotide context. The tumors exhibited extensive aneuploidy (50-99 autosomes/tumor) involving whole-chromosomes, with recurrent gains of chr9 and chr20 and loss of chr7, suggesting that aneuploidy itself represents the initiating oncogenic event. We propose that SpT etiology recapitulates the unique properties of male germ cells; because of evolutionary constraints to maintain low point mutation rate, rare tumorigenic driver events are caused by a combination of gene imbalance mediated via whole-chromosome aneuploidy. Finally, we propose a general framework of male germ cell tumor pathology that accounts for their mutational landscape, timing and cellular origin. |
| format | Article |
| id | doaj-art-5ee5601fc0c34d3a8a8086765dae2fc3 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-5ee5601fc0c34d3a8a8086765dae2fc32025-08-20T03:26:16ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01125e017816910.1371/journal.pone.0178169Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline.Eleni GiannoulatouGeoffrey J MaherZhihao DingAd J M GillisLambert C J DorssersAlexander HoischenEwa Rajpert-De MeytsWGS500 ConsortiumGilean McVeanAndrew O M WilkieLeendert H J LooijengaAnne GorielyAdult male germline stem cells (spermatogonia) proliferate by mitosis and, after puberty, generate spermatocytes that undertake meiosis to produce haploid spermatozoa. Germ cells are under evolutionary constraint to curtail mutations and maintain genome integrity. Despite constant turnover, spermatogonia very rarely form tumors, so-called spermatocytic tumors (SpT). In line with the previous identification of FGFR3 and HRAS selfish mutations in a subset of cases, candidate gene screening of 29 SpTs identified an oncogenic NRAS mutation in two cases. To gain insights in the etiology of SpT and into properties of the male germline, we performed whole-genome sequencing of five tumors (4/5 with matched normal tissue). The acquired single nucleotide variant load was extremely low (~0.2 per Mb), with an average of 6 (2-9) non-synonymous variants per tumor, none of which is likely to be oncogenic. The observed mutational signature of SpTs is strikingly similar to that of germline de novo mutations, mostly involving C>T transitions with a significant enrichment in the ACG trinucleotide context. The tumors exhibited extensive aneuploidy (50-99 autosomes/tumor) involving whole-chromosomes, with recurrent gains of chr9 and chr20 and loss of chr7, suggesting that aneuploidy itself represents the initiating oncogenic event. We propose that SpT etiology recapitulates the unique properties of male germ cells; because of evolutionary constraints to maintain low point mutation rate, rare tumorigenic driver events are caused by a combination of gene imbalance mediated via whole-chromosome aneuploidy. Finally, we propose a general framework of male germ cell tumor pathology that accounts for their mutational landscape, timing and cellular origin.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0178169&type=printable |
| spellingShingle | Eleni Giannoulatou Geoffrey J Maher Zhihao Ding Ad J M Gillis Lambert C J Dorssers Alexander Hoischen Ewa Rajpert-De Meyts WGS500 Consortium Gilean McVean Andrew O M Wilkie Leendert H J Looijenga Anne Goriely Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline. PLoS ONE |
| title | Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline. |
| title_full | Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline. |
| title_fullStr | Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline. |
| title_full_unstemmed | Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline. |
| title_short | Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline. |
| title_sort | whole genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0178169&type=printable |
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