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

Area of Science:

• Genetics
• Oncology
• Bioinformatics

Background:

• RAS/mitogen-activated protein kinase (MAPK) pathway genes are crucial in cell signaling.
• RASopathies are a group of genetic disorders caused by variants in these genes.
• Understanding germline variant prevalence and associated health risks is vital for clinical management.

Purpose of the Study:

• To quantify germline pathogenic/likely pathogenic (P/LP) variant prevalence in adults with non-NF1 RASopathies.
• To determine cancer prevalence and survival rates in individuals with RASopathy variants.
• To analyze the association between specific RASopathy variants and cancer risk.

Main Methods:

• Genomic data from electronic health records of UK Biobank, Geisinger MyCode, and Mount Sinai BioMe were analyzed.
• Variants were classified using American College of Medical Genetics/Association for Molecular Pathology criteria.
• Sanger sequencing of benign tissues distinguished germline variants from clonal hematopoiesis.

Main Results:

• Noonan syndrome-associated gene heterozygotes were the most common RASopathy group.
• A significantly increased cancer prevalence was observed in SPRED1 heterozygotes within the UK Biobank cohort.
• No sufficient evidence of increased cancer risk was found for Noonan, CBL, and CFC syndrome heterozygotes in the studied cohorts.

Conclusions:

• Adult cancer risk may not be elevated in all RASopathies.
• SPRED1 heterozygotes may have an increased risk of cancer in adulthood.
• Further replication studies are warranted to confirm these findings.