Cancer risk in adults with pathogenic germline variants in RAS/MAPK genes using genomic ascertainment.

PURPOSE: Genomic ascertainment of electronic health record-linked exome data was used to quantify germline pathogenic/likely pathogenic variant prevalence, cancer prevalence, and survival in adults with non-NF1 RAS/mitogen-activated protein kinase genes (RASopathies).

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 pathogenic/likely pathogenic 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.

RESULTS

Noonan syndrome-associated genes heterozygotes (excluding known Noonan syndrome with multiple lentigines variants) were most common with an estimated prevalence ranging between 1:1772 to 1:3330 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 = 1.2 × 10-3). In MyCode and UKBB cohorts, no sufficient evidence of increased cancer risk was found in Noonan-, CBL- (HGNC:1541) and cardiofaciocutaneous syndrome heterozygotes.

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.