Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors
Open accessAbstract
Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that paternal age-effect mutations activate a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition.
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Most FGF receptor mutation cases originate from mutations in adult spermatogonia; despite strong positive selection, these mutations never make up large fractions of sperm.
“This is because the vast majority of cases arise from mutations occurring in adult spermatogonia, which although subject to strong positive selection never populate large proportions of the sperm.15,16”
From Craniosynostosis (2011) · cites this paper as [16]
The paper describes FGFR2 and FGFR3 mutations expanding in spermatogonia and reports low mutation frequencies in sampled sperm (no page number provided in our copy). It does not establish that the vast majority of FGF receptor mutation cases arise in adult spermatogonia or that such mutations never occupy large fractions of sperm. It also says that only a weak selective advantage per cell is needed to explain the observed sperm levels, rather than establishing strong selection. (LLM, conf=0.83)
Experimental — accuracy not yet measuredNearly all Apert syndrome mutations arise de novo and originate exclusively from the father.
“Nearly all Apert syndrome mutations arise de novo, and have been shown to originate exclusively from the father.”
From Craniosynostosis (2011) · cites this paper as [16]
These mutations provide a paradigm for paternal age effect mutations that are enriched in sperm owing to a selective advantage to mutant spermatogonial cells in the testis.
“These mutations provide a paradigm for paternal age effect mutations that are enriched in sperm owing to a paradoxical selective advantage to mutant spermatogonial cells in the testis.15,16”
From Craniosynostosis (2011) · cites this paper as [16]
For FGF receptor mutations, when both parents' blood tests are negative, recurrence risk is very low (well under 1%).
“In the case of FGF receptor mutations, provided that the blood of both parents is negative for the mutation, the recurrence risk is very low (well under 1%).”
From Craniosynostosis (2011) · cites this paper as [16]
The mutation-level results (section labeled Abstract; page unavailable) compare FGFR3 mutations in sperm and blood from healthy donors. Our copy does not give a recurrence-risk estimate for families in which both parents’ blood tests are negative; searches for recurrence risk and parental blood testing found no such passage. (LLM, conf=0.76)
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Testicular Cancer and Cryptorchidism
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“One study found that ERK1/2 – an intermediate of the GDNF pathway that leads to activation of FOS and other target genes, was increasingly phosphorylated in more than half of 26 seminomas potentially altering expression of downstream targets of the RAS/ERK1/2 pathway including FOS and ATF (Goriely et al., 2009).”
BackgroundGallo, L. H., Nelson, K. N., Meyer, A. N., & Donoghue, D. J. (2015) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2015.03.003 · Cited by 153 · see citing works
“Nonsyndromic Craniosynostosis [9]”
BackgroundInfluentialSomatic mosaicism: on the road to cancer
Fernández, L. C., Torres, M., & Real, F. X. (2015) · Nature reviews. Cancer · doi:10.1038/nrc.2015.1 · Cited by 134 · see citing works
Factors and pathways involved in capacitation: how are they regulated?
Jin, S., & Yang, W. (2016) · Oncotarget · doi:10.18632/oncotarget.12274 · Cited by 133 · see citing works
Fibroblast growth factor receptors, developmental corruption and malignant disease.
Kelleher, F., O'Sullivan, H., Smyth, E., McDermott, R., & Viterbo, A. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt254 · Cited by 134 · see citing works
“Importantly, FGFR3 mutations are also linked with spermatocytic seminomas, which occur more frequently in older men (31).”
BackgroundDe Novo Mutations Reflect Development and Aging of the Human Germline
Goldmann, J. M., Veltman, J. A., & Gilissen, C. (2019) · Trends in Genetics · doi:10.1016/j.tig.2019.08.005 · Cited by 125 · see citing works
Targeting Mutant Fibroblast Growth Factor Receptors in Cancer
Greulich, H., & Pollock, P. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.01.012 · Cited by 130 · see citing works
“underlies both the sporadic incidence of spermatocytic seminoma and the germline transmission of thanatophoric dysplasia type II [24].”
BackgroundRisk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations
Gratten, J., Wray, N. R., Peyrot, W. J., McGrath, J. J., Visscher, P. M., & Goddard, M. E. (2016) · Nature Genetics · doi:10.1038/ng.3577 · Cited by 118 · see citing works
Paul, C., & Robaire, B. (2013) · Nature Reviews Urology · doi:10.1038/nrurol.2013.18 · Cited by 109 · see citing works
FGFR3 Stimulates Stearoyl CoA Desaturase 1 Activity to Promote Bladder Tumor Growth
Du, X., Wang, Q.-R., Chan, E., Merchant, M. A., Liu, J., French, D. M., Ashkenazi, A., & Qing, J. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1329 · Cited by 108 · see citing works
Future applications of FGF/FGFR inhibitors in cancer
Ghedini, G. C., Ronca, R., Presta, M., & Giacomini, A. (2018) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2018.1491795 · Cited by 106 · see citing works
“are reported in 70% of non-muscle-invasive and in 20% of invasive bladder tumors [39–41], as well as in cervical [42], multiple myeloma [43,44], spermatocytic seminomas [45,46],”
BackgroundTesticular germ cell tumours: predisposition genes and the male germ cell niche
Gilbert, D. C., Rapley, E. A., & SHIPLEY, J. M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3021 · Cited by 103 · see citing works
“Recent work has identified mutations in fibroblast growth factor receptor 3 ( FGFR3 ) and HRAS genes as frequent and mutually exclusive events in these tumour”
BackgroundScreening for biomarkers of spermatogonia within the human testis: a whole genome approach
von Kopylow, K., Kirchhoff, C., Ježek, D., Schulze, W., Feig, C., Primig, M., Steinkraus, V., & Spiess, A. (2010) · Human Reproduction · doi:10.1093/humrep/deq053 · Cited by 101 · see citing works
“Indeed, activating mutations in FGFR3 have been suggested to promote clonal expansion of spermatogonia in congenital disorders and testicular tumors (Juul et al., 2007; Goriely et al., 2009).”
BackgroundGoriely, A., McGrath, J. J., Hultman, C. M., Wilkie, A. O. M., & Malaspina, D. (2013) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2013.12101352 · Cited by 110 · see citing works
Self-citationThe Structural Biology of the FGF19 Subfamily
Beenken, A., & Mohammadi, M. (2012) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4614-0887-1_1 · Cited by 93 · see citing works
Merker, A., Neumeyer, L., Hertel, N. T., Grigelioniené, G., Mäkitie, O., Mohnike, K. L., & Hagenäs, L. (2018) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.38853 · Cited by 90 · see citing works
Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes
Maher, G. J., Ralph, H. K., Ding, Z., Koelling, N., Mlcochova, H., Giannoulatou, E., Dhami, P., Paul, D. S., Stricker, S. H., Beck, S., et al. (2018) · Genome Research · doi:10.1101/gr.239186.118 · Cited by 85 · see citing works
Self-citationGiacomini, A., Chiodelli, P., Matarazzo, S., Rusnati, M., Presta, M., & Ronca, R. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.03.024 · Cited by 87 · see citing works
“FGFR3 mutations have also been identified n many other cancer types, including cervical cancers [50], muliple myeloma (MM) [51,52], prostate cancers [53], spermatocytic eminomas [54] and oral squamous carcinomas [55].”
Receptor tyrosine kinase mutations in developmental syndromes and cancer: two sides of the same coin
McDonell, L. M., Kernohan, K. D., Boycott, K. M., & Sawyer, S. L. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv254 · Cited by 86 · see citing works
“For instance, Lys650Glu (TDII), a recognized driver mutation in FGFR3 that results in constitutively elevated kinase activity, has been identified in spermatocytic seminoma (49), bladder carcinoma (50), and multiple myeloma (51).”
BackgroundGiannoulatou, E., McVean, G., Taylor, I. B., McGowan, S. J., Maher, G. J., Iqbal, Z., Pfeifer, S. P., Turner, I., Burkitt‐Wright, E., Shorto, J., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311381110 · Cited by 86 · see citing works
“Overall, our findings suggest that the HRAS mutation levels in sperm are determined by an interplay between the intrinsic genomic mutation rate of a residue and the selective advantage conferred by the resulting mutant protein on the spermatogonial cell (8, 10, 11).”
BackgroundInfluentialSelf-citationLim, J., Goriely, A., Turner, G. D., Ewen, K. A., Jacobsen, G. K., Græm, N., Wilkie, A. O. M., & Meyts, E. R. (2011) · The Journal of Pathology · doi:10.1002/path.2919 · Cited by 86 · see citing works
Self-citationIdentification of candidate gonadal sex differentiation genes in the chicken embryo using RNA-seq
Ayers, K. L., Lambeth, L. S., Davidson, N., Sinclair, A. H., Oshlack, A., & Smith, C. A. (2015) · BMC Genomics · doi:10.1186/s12864-015-1886-5 · Cited by 83 · see citing works
“FGFR3 has been shown to interact with FGF1 and FGF9 [76] and is thought to be important in the post-natal testis [77].”
BackgroundHuman spermatogonial stem cells: a possible origin for spermatocytic seminoma
Waheeb, R. S., & Hofmann, M.-C. C. (2011) · International Journal of Andrology · doi:10.1111/j.1365-2605.2011.01199.x · Cited by 81 · see citing works
“Interestingly, positive staining for phosphorylated ERK1/2 was shown in 56% of spermatocytic seminomas studied by Goriely and colleagues (Goriely et al., 2009).”
BackgroundInfluentialSignaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review
Zheng, J., Zhang, W., Li, L., He, Y., Wei, Y., Dang, Y., Nie, S., & Guo, Z. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.860985 · Cited by 79 · see citing works
“(Goriely et al., 2009).”
Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs
Meyts, E. R., Nielsen, J. E., Skakkebæk, N. E., & Almstrup, K. (2015) · Folia Histochemica et Cytobiologica · doi:10.5603/fhc.a2015.0020 · Cited by 77 · see citing works
“Other immunohistochemical markers include SYCP1, NSE (neuron-specific enolase), CHK2, VASA, UTF1, FGFR3 or HRAS, and DMRT1 [26, 27, 30, 46, 71].”
BackgroundInfluentialSelf-citationSpermatogonial Stem Cell Functions in Physiological and Pathological Conditions
Yang, Q., & Oatley, J. M. (2014) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-416022-4.00009-3 · Cited by 74 · see citing works
“Furthermore, the Ras oncogene family (H-Ras, K-Ras, and N-Ras) is often mutated in human TGCTs including spermatocytic seminomas (Goriely et al., 2009; Moul, Theune, &Chang, 1992).”
BackgroundThe impact of paternal age on new mutations and disease in the next generation
Wood, K., & Goriely, A. (2022) · Fertility and Sterility · doi:10.1016/j.fertnstert.2022.10.017 · Cited by 73 · see citing works
“…speci fi c point mutations that confer functional properties to the encoded protein spontaneously occur in SSCs within a seminiferous tubule of the adult testis, providing a competitive advantage and leading to clonal expansion of the mutant SSCs as the man ages (59, 60, 62, 64, 66 – 69, 71, 72).”
BackgroundSelf-citationChoi, S., Yoon, S., Calabrese, P. P., & Arnheim, N. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002420 · Cited by 73 · see citing works
“A study of the most common type of human testis cancers (seminomas) and rare spermatocytic seminomas both failed to find tumors carrying the MEN2B mutation [45,46].”
BackgroundPhenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C
Gripp, K. W., Hopkins, E., Sol‐Church, K., Stabley, D. L., Axelrad, M. E., Doyle, D., Dobyns, W. B., Hudson, C., Johnson, J. P., Tenconi, R., et al. (2011) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33884 · Cited by 72 · see citing works
“The predominance of the paternal germline origin in de novo HRAS mutations is consistent with previous reports [Sol-Church et al., 2006; Zampino et al., 2007; Goriely et al., 2009].”
ResultCellular evidence for selfish spermatogonial selection in aged human testes
Maher, G. J., Goriely, A., & Wilkie, A. O. M. (2013) · Andrology · doi:10.1111/j.2047-2927.2013.00175.x · Cited by 70 · see citing works
“, 2001)], and to further investigate the putative association with SpS, we stained adjacent sections of the three testes containing immunopositive tubules for other spermatogonial markers expressed in SpS (Goriely et al., 2009; Lim et al., 2011).”
BackgroundMethodInfluentialSelf-citationvon Kopylow, K., Staege, H., Schulze, W., Will, H., & Kirchhoff, C. (2012) · Histochemistry and Cell Biology · doi:10.1007/s00418-012-0991-7 · Cited by 67 · see citing works
Genetic Causes of Craniosynostosis: An Update
Goos, J. A. C., & Mathijssen, I. M. J. (2018) · Molecular Syndromology · doi:10.1159/000492266 · Cited by 67 · see citing works
“FGFR2 and FGFR3 are subject to the paternal age effect; that is the introduction of mutations in FGFR2 and FGFR3 [Goriely and Wilkie, 2010], and in other genes involved in growth-factor receptor-RAS signaling such as RET , PTPN11 , and HRAS [Goriely et al., 2009; Goriely and Wilkie, 2010; Schubbert et al., 2007] are c…”
BackgroundDe novo mutations, genetic mosaicism and human disease
Mohiuddin, M., Kooy, R. F., & Pearson, C. E. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.983668 · Cited by 66 · see citing works
“Due to the expansion of mutated spermatogonia that happens in the testes of healthy men during aging (Meng et al., 2000; Goriely et al., 2009; Giannoulatou et al., 2017), the quantity of mutated sperm raises continuously at higher rates than genome-wide paternal age effect.”
BackgroundZhang, Y., Wang, S., Wang, X., Liao, S., Wu, Y., & Han, C. (2012) · Cell Research · doi:10.1038/cr.2012.17 · Cited by 65 · see citing works
Murase, H., Inokuchi, M., Takagi, Y., Kato, K., Kojima, K., & Sugihara, K. (2014) · Molecular and Clinical Oncology · doi:10.3892/mco.2014.293 · Cited by 64 · see citing works
“FGFR3 mutations have been identified in several types of cancer, including cervical cancer (47), multiple myeloma, prostate cancer (48) and spermatocytic seminomas (49).”
Maher, G. J., McGowan, S. J., Giannoulatou, E., Verrill, C., Goriely, A., & Wilkie, A. O. M. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521325113 · Cited by 59 · see citing works
“K650E) that were previously validated experimentally in sperm and/or testes (12, 26, 29), we widened the spectrum of mutations found in testes for four of the five recognized PAE genes (FGFR2, FGFR3, HRAS, and PTPN11; we found no mutations in RET).”
BackgroundInfluentialSelf-citationSmall molecule inhibition of fibroblast growth factor receptors in cancer
Liang, G., Chen, G., Wei, X., Zhao, Y., & Li, X. (2013) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2013.05.002 · Cited by 63 · see citing works
“Testicular tumor (NR) [39]”
BackgroundInfluentialOntogenesis of Testis Development and Function in Humans
Stukenborg, J., Colón, E., & Söder, O. (2010) · Sexual Development · doi:10.1159/000317090 · Cited by 61 · see citing works
Krejčı́, P., Procházková, J., Smutny, J., Chlebová, K., Lin, P. W., Aklian, A., Bryja, V., Kozubı́k, A., & Wilcox, W. R. (2010) · Bone · doi:10.1016/j.bone.2010.03.021 · Cited by 61 · see citing works
“Apart from skeletal dysplasias, the same activating FGFR3 mutations are associated with at least seven other conditions affecting skin (epidermal nevi, seborrheic keratosis, acanthosis nigricans) and cancer development (multiple myeloma, prostate, bladder cancer, seminoma) [1,3,4], which are all caused by excessive ce…”
BackgroundFibroblast Growth Factor Receptor 2 Signaling in Breast Cancer
Lei, H., & Deng, C. (2017) · International Journal of Biological Sciences · doi:10.7150/ijbs.20792 · Cited by 61 · see citing works
“[118-120] Endometrial cancer D101Y, G227E, S252W, P253R, F276V, K310R, S373C, Y376C, C383R, A390T, M393R, V396D, L398M, I548D/V, N550H/K, K660E/M/N, C383R [68, 109, 112, 121] Gallbladder cancer N550K, S252W [118] Gastric cancer S267P, Q212K, G463E [120, 122, 123] Head and neck squamous cell cancer N550D [124] Lung can…”
New evidence for positive selection helps explain the paternal age effect observed in achondroplasia
Shinde, D. N., Elmer, D. P., Calabrese, P. P., Jérôme Boulanger, A., Arnheim, N., & Tiemann‐Boege, I. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt260 · Cited by 60 · see citing works
“The selective advantage is likely the result of changes in the growth factor receptorRAS and related signaling pathways caused by the mutant protein (19,21,25).”
BackgroundArbeithuber, B., Makova, K., & Tiemann-Boege, I. (2016) · DNA Research · doi:10.1093/dnares/dsw038 · Cited by 62 · see citing works
Genome Instability and DNA Repair in Somatic and Reproductive Aging
Panier, S., Wang, S., & Schumacher, B. (2023) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051122-093128 · Cited by 60 · see citing works
Targeting fibroblast-growth-factor-receptor-dependent signaling for cancer therapy
Heinzle, C. F., Sutterlüty, H., Grusch, M., Grasl‐Kraupp, B., Berger, W., & Marian, B. (2011) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.566217 · Cited by 55 · see citing works
“FGFR1 Extracellular Lung Breast [83,179,180] [83] Transmembrane Cytoplasmic Lung Brain [83] [184,185] FGFR2 Extracellular Skin Endometrial Ovary Lung [186] [187] [188] [83,187] Transmembrane Lung Endometrial [183] [187,189] Cytoplasmic Skin Endometrial Lung [186] [189] [83,187] FGFR3 Extracellular Lung Bladder Prostat…”
BackgroundFGFR3 is a target of the homeobox transcription factor SHOX in limb development
Decker, E., Durand, C., Bender, S., Rödelsperger, C., Glaser, A., Hecht, J., Schneider, K., & Rappold, G. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr030 · Cited by 56 · see citing works
Testicular cancer: biology and biomarkers
Looijenga, L. H. J., Stoop, H., & Biermann, K. (2014) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-013-1522-1 · Cited by 54 · see citing works
“Of special notion is the recent insight into specific mutations, including FGFR3 and HRAS in spermatocytic seminoma, which has been related to so-called paternal age effect [18].”
BackgroundGenome instability of ageing stem cells—Induction and defence mechanisms
Burkhalter, M. D., Rudolph, K. L., & Sperka, T. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.01.004 · Cited by 52 · see citing works
Development of malignant germ cells - the genvironmental hypothesis
Looijenga, L. H. J., van Agthoven, T., & Biermann, K. (2013) · The International Journal of Developmental Biology · doi:10.1387/ijdb.130026ll · Cited by 53 · see citing works
“In this context the specific pattern of mutations found in human spermatocytic seminomas are of inter- est in the canine counterparts (Goriely et al., 2009), as well as recent additional diagnostic markers in humans (Lim et al., 2011).”
BackgroundHealthy ageing and spermatogenesis
Pohl, E., Gromoll, J., Wistuba, J., & Laurentino, S. (2021) · Reproduction · doi:10.1530/rep-20-0633 · Cited by 51 · see citing works
Krejčı́, P. (2013) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2013.11.001 · Cited by 49 · see citing works
Jin, M., Yu, Y., Qi, H.-B., Xie, Y.-L., Su, N., Wang, X.-F., Tan, Q.-Y., Luo, F.-T., Zhu, Y., Wang, Q., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds390 · Cited by 47 · see citing works
Missing heritability: paternal age effect mutations and selfish spermatogonia
Goriely, A., & Wilkie, A. O. M. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2809-c1 · Cited by 43 · see citing works
“Well-documented examples are in the fibroblast growth factor receptor 2 ( FGFR2 ), FGFR3 , RET , protein tyrosine phosphatase, non-receptor type 11 ( PTPN11 ) and HRAS genes, heterozygous substitutions of which cause congenital skeletal disorders, sometimes with additional predisposition to cance”
BackgroundSelf-citationGiannoulatou, E., Maher, G. J., Ding, Z., Gillis, A., Dorssers, L. C. J., Hoischen, A., Meyts, E. R., McVean, G., Wilkie, A. O. M., Looijenga, L. H. J., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0178169 · Cited by 47 · see citing works
Self-citationCanine testicular tumors: two types of seminomas can be differentiated by immunohistochemistry
Hohšteter, M., Artuković, B., Severin, K., Kurilj, A. G., Beck, A., Šoštarić‐Zuckermann, I., & Grabarević, Ž. (2014) · BMC Veterinary Research · doi:10.1186/s12917-014-0169-8 · Cited by 46 · see citing works
“In contrast to CSEM, SSEM are c-KIT negative and have benign behavior, which is in accordance with their origin from differentiated germ cells, mostly spermatocytes [15,20-25].”
BackgroundResultStructural Mimicry of A-Loop Tyrosine Phosphorylation by a Pathogenic FGF Receptor 3 Mutation
Huang, Z., Chen, H., Blais, S. P., Neubert, T. A., Li, X., & Mohammadi, M. (2013) · Structure · doi:10.1016/j.str.2013.07.017 · Cited by 46 · see citing works
“Gain-of-function mutations in the tyrosine kinase domains of FGFRs underlie a wide array of human developmental disorders and malignancies (Beenken and Mohammadi, 2009; Goriely et al., 2009; Webster and Donoghue, 1997b; Wilkie, 2005).”
BackgroundReceptor Tyrosine Kinases: Structure, Functions and Role in Human Disease
Yarden, Y., & Wheeler, D. L. (2014) · Springer eBooks · doi:10.1007/978-1-4939-2053-2 · Cited by 44 · see citing works
Hu, R., Ulbright, T. M., & Young, R. H. (2017) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000001001 · Cited by 44 · see citing works
Rauen, K. A., Tidyman, W. E., Estep, A. L., Sampath, S., Peltier, H. M., Bale, S. J., & Lacassie, Y. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33342 · Cited by 44 · see citing works
“In fact, some activating Ras pathway mutations may confer an advantage to the sperm [Glaser et al., 2003; Glaser and Jabs, 2004; Goriely et al., 2009].”
BackgroundGermline Stem Cell Competition, Mutation Hot Spots, Genetic Disorders, and Older Fathers
Arnheim, N., & Calabrese, P. P. (2016) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-083115-022656 · Cited by 44 · see citing works
Goriely, A., Lord, H., Lim, J., Johnson, D., Lester, T., Firth, H. V., & Wilkie, A. O. M. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33513 · Cited by 41 · see citing works
“2010 Wiley-Liss, Inc. 2067 are progressively enriched over time by a process of clonal expansion, resulting in elevated levels of mutation in sperm [Goriely et al., 2009].”
BackgroundInfluentialSelf-citationGermline gain-of-function mutations of ALK disrupt central nervous system development
de Pontual, L., Kettaneh, D., Gordon, C. T., Oufadem, M., Boddaert, N., Lees, M. M., Balu, L., Lachassinne, E., Petros, A., Mollet, J., et al. (2011) · Human Mutation · doi:10.1002/humu.21442 · Cited by 41 · see citing works
“Most interestingly, two ‘‘missing germline mutations’’ at codon 61 (Q61R and Q61K) of HRAS have been identified in 5/30 spermatocytic seminomas (a rare testicular germ cell tumor of late-age onset) [Goriely et al., 2009].”
BackgroundKatoh, M. (2010) · Expert Review of Anticancer Therapy · doi:10.1586/era.10.128 · Cited by 40 · see citing works
Activating Somatic FGFR2 Mutations in Breast Cancer
Reintjes, N., Li, Y., Becker, A. A., Rohmann, E., Schmutzler, R. K., & Wollnik, B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060264 · Cited by 39 · see citing works
“This process has also been linked to the origin of testicular tumors and it has been suggested that the mechanisms involved in selfish selection are similar to those described for tumorigenesis [14,45].”
ResultLim, J., Maher, G. J., Turner, G. D. H., Dudka, W., Taylor, S., Meyts, E. R., Goriely, A., & Wilkie, A. O. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042382 · Cited by 38 · see citing works
“First, we optimised a panel of relevant antibodies to use in an immunohistochemical screen, based on the published antigenic characteristics of type A spermatogonia [16,37] and spermatocytic seminoma [15,16], and the insight that elevated activity through pathways involving receptor tyrosine kinase-RAS signalling is p…”
BackgroundMethodInfluentialSelf-citationFamilial testicular germ cell tumours
Kratz, C. P., Mai, P. L., & Greene, M. H. (2010) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2010.01.005 · Cited by 38 · see citing works
Krejci, P., Murakami, S., Procházková, J., Trantírek, L., Chlebová, K., Ouyang, Z.-F., Aklian, A., Smutny, J., Bryja, V., Kozubík, A., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.083626 · Cited by 38 · see citing works
Bush, J. M., Gardiner, D., Palmer, J. S., Meyts, E. R., & Veeramachaneni, D. N. R. (2011) · International Journal of Andrology · doi:10.1111/j.1365-2605.2011.01166.x · Cited by 36 · see citing works
“, 2004; Rajpert-De Meyts, 2006), or markers for more mature germ cells and human spermatocytic seminoma, such as MAGEA4, NY-ESO1 or FGFR3 (Aubry et al., 2001; Satie et al., 2002; Rajpert-De Meyts et al., 2003; Goriely et al., 2009).”
BackgroundInfluentialSelf-citationAge-Dependent De Novo Mutations During Spermatogenesis and Their Consequences
Cioppi, F., Casamonti, E., & Krausz, C. G. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-21664-1_2 · Cited by 35 · see citing works
Mitotic Arrest in Teratoma Susceptible Fetal Male Germ Cells
Western, P. S., Ralli, R., Wakeling, S. I., Lo, C. Y.-W., van den Bergen, J. A., Miles, D. C., & Sinclair, A. H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020736 · Cited by 32 · see citing works
“. The data presented here indicates that FGFR3 may play a role in regulating fetal male germ cell differentiation. However, activating mutations in FGFR3 have been linked to the formation of spermatocytic seminomas”
BackgroundBaldness, acne and testicular germ cell tumours
Trabert, B. L., Sigurdson, A. J., Sweeney, A. M., Amato, R. J., Strom, S. S., & McGlynn, K. A. (2010) · International Journal of Andrology · doi:10.1111/j.1365-2605.2010.01125.x · Cited by 31 · see citing works
Parental Age, Family Size, and Offspring's Risk of Childhood and Adult Acute Leukemia
Larfors, G., Hallböök, H., & Simonsson, B. (2012) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-12-0178 · Cited by 30 · see citing works
“ingly suggest that such mutations are in fact rare, but mutant sperms can in certain cases be positively selected and their mutations thereby amplified (25).”
BackgroundTargeting Receptor Tyrosine Kinases in Cancer
Köstler, W. J., & Zielinski, C. C. (2014) · Springer eBooks · doi:10.1007/978-1-4939-2053-2_10 · Cited by 26 · see citing works
Sperm mosaicism: implications for genomic diversity and disease
Breuss, M. W., Yang, X., & Gleeson, J. G. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.05.007 · Cited by 28 · see citing works
Burkitt‐Wright, E., Bradley, L., Shorto, J., McConnell, V. P. M., Gannon, C., Firth, H. V., Park, S., D’Amore, A., Munyard, P., Turnpenny, P. D., et al. (2012) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.35296 · Cited by 28 · see citing works
“A selective advantage for spermatogonia bearing activatingmutations in genes including HRAS and FGFR2 has been demonstrated [Goriely et al., 2009], but the dramatically elevated proportion of germline mutations predicting HRAS p.Gly12Val that are dinucleotide deletion/insertions, as opposed to…”
BackgroundPaternal age, de novo mutations, and offspring health? New directions for an ageing problem
Aitken, R. J. (2024) · Human Reproduction · doi:10.1093/humrep/deae230 · Cited by 26 · see citing works
“…are also central to the initiation and propagation of cancers, thereby explaining why patients possessing germ line mutations in this pathway, also exhibit an increased susceptibility to cancer in both their testes and the tissues of their progeny (Goriely et al. , 2009; Liu et al. , 2023).”
BackgroundEpigenetic modifications and self-renewal regulation of mouse germline stem cells
Lee, J., & Shinohara, T. (2011) · Cell Research · doi:10.1038/cr.2011.111 · Cited by 26 · see citing works
- Authors
- Goriely, A., Hansen, R. M. S., Taylor, I. B., Olesen, I. A., Jacobsen, G. K., McGowan, S. J., Pfeifer, S. P., McVean, G. A. T., Meyts, E. R.-D., & Wilkie, A. O. M.
- Affiliations
- John Radcliffe Hospital (GB)
- Copenhagen University Hospital (DK)
- University of Oxford (GB)
- Corresponding author
- Wilkie, Andrew O M
- Venue
- Nature Genetics
- Published
- 2009-10-25
- Volume
- 41
- Issue
- 11
- Pages
- 1247-1252
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2817493
- OpenAlex
- W1977828694
- Cited by
- 205
- References
- 60
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 16 · 2023: 4 · 2022: 9 · 2021: 7 · 2020: 10 · 2019: 9 · 2018: 8 · 2017: 14 · 2016: 14 · 2015: 16 · 2014: 10 · 2013: 21 · 2012: 19
- FWCI
- 19.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Wellcome Trust (078666)
- Topics
- Health Sciences › Medicine › Surgery › Testicular diseases and treatments
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- FGFR3, HRAS, spermatocytic seminoma, thanatophoric dysplasia, paternal age effect, germline mutations, clonal expansion, male germ cells, oncogenic mutations, congenital malformation syndrome, testicular tumors
- MeSH terms
- Adult, Aged, Aged, 80 and over, Base Sequence, Humans, Male, Middle Aged, Mutation, Genes, ras, Spermatozoa, Testicular Diseases, Testicular Neoplasms, Age Distribution, Genetic Predisposition to Disease, Receptor, Fibroblast Growth Factor, Type 3
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