An investigation of somatic mutations in IDH genes in peripheral blood in the all of us research program Free

Background: Somatic mutations in isocitrate dehydrogenase (IDH) genes are commonly seen in acute myeloid leukemia (AML) and other myeloid neoplasms, especially in older adults. IDH mutations are associated with higher risk of disease progression for myelodysplastic neoplasm (MDS, PMID: 38319256) and clonal hematopoiesis (CH, PMID: 37483562), as well as with concurrent seronegative rheumatoid arthritis (RA, PMID: 38457663). Here, we performed a phenotypic investigation of participants of All of Us Research Program who were detected to have oncogenic mutations in IDH1 or IDH2.

Design: We used the 40x-deep genome sequencing data in All of Us (v7, n = 245,394). IDH1 mutations included those at the p.R132 site, while IDH2 included those at the p.R140 site. The detection limit for variant allele fraction (VAF) was 10%. About 80% of the sequenced participants also had electronic health record (EHR) data available. Diagnostic codes for myeloid neoplasms, cytopenia, and autoimmune diseases, as well as complete blood count data, were included for phenotype investigation.

Results: In total there were 15 participants with IDH1 mutations and 58 with IDH2 mutations. Among them, 56% were male. The median blood collection age was 73 years (range: 32-95). The median VAF was 29% (range: 10%-52%). For those with EHR data after blood collection, the median follow-up after collection was 31 months (range: 1-49). About 30% of the participants with IDH mutations had even been diagnosed with myeloid neoplasms, including AML, MDS, myeloproliferative neoplasms, and chronic myelomonocytic leukemia. Only 10-20% of the participants with the mutations did not have any records for cytopenia diagnoses or abnormal blood counts. About 15% of the participants with the mutations had autoimmune diseases such as rheumatoid arthritis and autoimmune hepatitis. About 5% participants with IDH mutations died.

Conclusion: In a general hospital setting, IDH somatic mutation rate was low. Myeloid malignancy or cytopenia were present in majority of the individuals with detected IDH mutations (VAF > 10%). Since IDH mutations can be targeted by ivosidenib or enasidenib, adequate hematological evaluation of individuals with incidental finding of these mutations and enrollment to clinical trials should be considered in the future guidelines.