ArticleProceedings of the National Academy of Sciences of the United States of America2013
Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
47 citing papers in PubMed, 2 syntheses or guidelines pooled it, 86 citations in OpenAlex.
- Cancer in Costello syndrome: a systematic review and meta-analysis.British journal of cancer · 2023Pooled it
- Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: IV: Current and Future Utilization of Molecular-Genetic Tests for Testicular Germ Cell Tumors.The American journal of surgical pathology · 2020Guideline
- Costello Syndrome Associated With Somatic Mosaicism of Rare p.Gly13Asp HRAS Variant: Expanding the Phenotypic Spectrum.Molecular genetics & genomic medicine · 2026Article
- Stem cell competition.Current topics in developmental biology · 2026Review
- Spermatocytic tumor coexisting with a contralateral inguinoscrotal undifferentiated sarcoma: a case report.BMC urology · 2025Article
- Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Review
- SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.American journal of human genetics · 2024Article
- [Sperm Mosaic Variants and Their Influence on the Offspring].Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2024Review
- Neonatal hyperinsulinism-broadening the differential diagnosis.Paediatrics & child health · 2023Article
- Case Report: Sequential postzygoticFrontiers in genetics · 2023Article
- Article
- The impact of paternal age on new mutations and disease in the next generation.Fertility and sterility · 2022Review
- Discovery of an unusually high number of de novo mutations in sperm of older men using duplex sequencing.Genome research · 2022Article
- The RASopathies: from pathogenetics to therapeutics.Disease models & mechanisms · 2022Review
- Increased osteoclastogenesis contributes to bone loss in the Costello syndromeFrontiers in cell and developmental biology · 2022Article
- RASopathy Cohort of Patients Enrolled in a Brazilian Reference Center for Rare Diseases: A Novel Familial LZTR1 Variant and Recurrent Mutations.The application of clinical genetics · 2022Article
- Sperm mosaicism: implications for genomic diversity and disease.Trends in genetics : TIG · 2021Review
- Pathogenic postzygotic mosaicism in the tyrosine receptor kinase pathway: potential unidentified human disease hidden away in a few cells.The FEBS journal · 2021Review
- Hyperinsulinemic Hypoglycemia in a Patient with Costello Syndrome: An Etiology to Consider in Hypoglycemia.Molecular syndromology · 2020Article
- Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts.Annals of oncology : official journal of the European Society for Medical Oncology · 2020Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 7 institutions in 3 countries.
Funding
Abstract
The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GC>TT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.