TY - JOUR
T1 - Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline
AU - WGS500 Consortium
AU - Giannoulatou, Eleni
AU - Maher, Geoffrey J
AU - Ding, Zhihao
AU - Gillis, Ad J M
AU - Dorssers, Lambert C J
AU - Hoischen, Alexander
AU - Rajpert-De Meyts, Ewa
AU - McVean, Gilean
AU - Wilkie, Andrew O M
AU - Looijenga, Leendert H J
AU - Goriely, Anne
N1 - Publisher Copyright:
© 2017 Giannoulatou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Biomarkers, Tumor/genetics
KW - DNA Copy Number Variations/genetics
KW - DNA Methylation
KW - Genome, Human
KW - Germ-Line Mutation/genetics
KW - High-Throughput Nucleotide Sequencing/methods
KW - Humans
KW - Male
KW - Receptor, Fibroblast Growth Factor, Type 3
KW - Sexual Maturation
KW - Spermatocytes/metabolism
KW - Testicular Neoplasms/genetics
UR - http://www.scopus.com/inward/record.url?scp=85019599692&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0178169
DO - 10.1371/journal.pone.0178169
M3 - Article
C2 - 28542371
SN - 1932-6203
VL - 12
SP - e0178169
JO - PloS one
JF - PloS one
IS - 5
M1 - e0178169
ER -