Evaluating the association between clonal hematopoiesis and germline pathogenic and likely pathogenic variants in cancer predisposition genes.

Abstract

1535 Background: Clonal hematopoiesis (CH) is most commonly associated with mutations in genes with a known or putative role in leukemia and with an increased risk for hematologic malignancies. Nearly 50% of primary breast cancers contain leukocytes with CH mutations and CH mutations can be found in breast cancer (BC) tumor infiltrating leukocytes years prior to the development of secondary leukemia. It is currently not known whether CH is more prevalent among BC patients with both germline pathogenic variants and likely pathogenic variants (collectively referred to as PV) in cancer predisposition genes. Here we evaluated the relationship of CH to PV in 546 BC patients (pts). Methods: 546 BC pts underwent targeted capture sequencing of tumor and peripheral blood (PB) samples using MSK-IMPACT. Sequencing results from PB were used for identifying PV affecting up to 89 cancer predisposition genes and somatic mutations in 15 genes commonly associated with CH using previously validated methods. All pts consented via an IRB-approved protocol. Results: The majority (82.3%) of pts had non-metastatic disease. 59.7% of the 546 pts received chemotherapy and 42.7% received radiation. Of the 546 pts, 90 patients had germline PV in a cancer predisposition gene for a total of 98 germline PV identified (8 patients had 2 germline PV). Mutations in DNMT3A followed by TET2 were the most common CH mutations identified. CHEK2 PV were statistically significantly associated with CH in a multivariate analysis after controlling for age, prior chemotherapy and radiation therapy (OR: 3.94, CI: 1.51-10.26, p-value ≤0.005). Age by decade was significantly associated with the presence of CH in that model (OR: 1.93, CI: 1.53-2.42, p value ≤0.001). Of the 8 patients with CHEK2 germline PV and CH, the most common mutated CH genes were DNMT3A (4 pts), followed by TET2 (2 pts), although our sample size is too small to test for significant enrichment for any specific CH gene, type of CH mutation, or trinucleotide context. Further, CH was not associated with germline PV in other cancer predisposition genes. Conclusions: Our findings provide evidence of an association between CHEK2 germline PV with CH in BC pts, which will be further tested in an expanded cohort. If this association is confirmed, it might have theoretical and practical implications, including cancer prevention strategies.