| Title: | Cancer risk in adults with pathogenic germline variants in RAS/MAPK genes using genomic ascertainment |
| Journal: | Genetics in Medicine |
| Published: | 25 Mar 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41904680/ |
| DOI: | https://doi.org/10.1016/j.gim.2026.102561 |
| URL: | https://pmc.ncbi.nlm.nih.gov/articles/PMC13078660/ |
Publication 18199
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Abstract
PURPOSE: Genomic ascertainment of electronic health record-linked exome data was used to quantify germline pathogenic/likely pathogenic (P/LP) variant prevalence, cancer prevalence, and survival in adults with non-NF1 RAS/mitogen-activated protein kinase genes (RASopathies).</p>
METHODS: Germline RASopathy variants were examined from adult participants in UK Biobank (UKBB; n=469,802), Geisinger MyCode (n=167,050) and Mount Sinai BioMe (n=30,470). Variants were classified as per American College of Medical Genetics/Association for Molecular Pathology criteria and reviewed by a RASopathy variant expert. Heterozygotes harbored a RASopathy P/LP variant; non-heterozygotes harbored wild type or benign/likely benign RASopathy variation. To distinguish germline variants from clonal hematopoiesis, benign tissues were Sanger sequenced. Phenotype data were extracted.</p>
RESULTS: Noonan syndrome-associated genes heterozygotes (excluding known Noonan syndrome with multiple lentigines variants) were most common with an estimated prevalence ranging between 1:1,772-1:3,330 in the cohorts. In SPRED1 (HGNC:20249) heterozygotes, cancer prevalence was only significantly increased in UKBB (OR:3.8 [95% CI: 2.48-8.64]; p=1.2x10-3). In MyCode and UKBB cohorts, no sufficient evidence of increased cancer risk was found in Noonan-, CBL- (HGNC:1541) and CFC syndrome heterozygotes.</p>
CONCLUSION: In some RASopathies, adult cancer risk may not be elevated. These findings merit replication. There may be an increased cancer risk for adult SPRED1 heterozygotes.</p>
18 Authors
- Jung Kim
- Gina Ney
- Megan N. Frone
- Jeremy S. Haley
- Mark L. Ramos
- Uyenlinh L. Mirshahi
- Esteban Astiazaran-Symonds
- Mariya Shandrina
- Gretchen Urban
- H. Shanker Rao
- Rick Stahl
- Alicia Golden
- Marielle E. Yohe
- Andrea M. Gross
- Yi Ding
- David J. Carey
- Bruce D. Gelb
- Douglas R. Stewart
1 Application
| Application ID | Title |
|---|---|
| 54389 | Frequency, phenotypic spectrum, and penetrance of pathogenic variation in cancer susceptibility genes in the general population |
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