Abstract 1762P
Background
Somatic mutations of blood cells or bone marrow known as Clonal hematopoiesis of indeterminate potential (CHIP) can be confused for tumor-derived mutations and can lead to false positive observations. CHIP is common with increasing age and has been linked to an increased risk of hematological cancers and cardiovascular disease as well as therapy-related myeloid neoplasms. The SignateraTM assay filters CHIP mutations through tumor tissue and germline sequencing, thereby reducing false-positive results and focuses on tumor-specific mutations for each patient.
Methods
Whole exome sequencing results (average depth 250x) from patients’ buffy coat samples were analyzed (n=1968) to characterize CHIP mutations. Variant calling was performed using Freebayes variant caller with allele frequency threshold between 1% and 10%, followed by variant selection based on the top 54 genes implicated in myeloid disorders. The selected variants were further screened based on the reported variants in the literature and/or the Catalog of Somatic Mutations in Cancer (COSMIC).
Results
The analysis revealed CHIP mutations to be present in 16% (318/1968) of patients. The majority (80%; 256) of patients with CHIP had a single mutation, and 20% (63) of patients had 2-4 mutations detected. The genes most commonly affected in patients with CHIP in this cohort were DNMT3A -46%, TET2 - 16%, TP53 - 13%, NOTCH1 and EZH2 - 6% each, CDKN2A and ASXL1- 5% each. Incidence of CHIP increased exponentially from 8.5% in patients younger than 30 years to 22% in patients 60 years and above. Renal cell carcinoma (41%) and multiple myeloma patients (29%) had higher prevalence of CHIP compared to patients with breast (23%), colorectal (17%), bladder (17%) and lung cancer (14%). Presence of at least one CHIP mutation was associated with reduced PFS (HR=1.7, CI 95%: 1.06-2.89, p=0.03) and time to progression compared to those with no CHIP detected (median 10.65 vs 5.3 months, p<0.0001).
Conclusions
Identification and filtering of CHIP is essential for ctDNA-based minimal residual disease detection. CHIP is associated with reduced time to disease progression and poor patient outcome and thus should be characterized and considered for disease management in older patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Natera, Inc.
Disclosure
E. Kalashnikova, H. Wu, S. Mehta, R. Salari, H. Sethi: Financial Interests, Personal, Full or part-time Employment: Natera, Inc.; Financial Interests, Personal, Stocks/Shares: Natera, Inc. B. Zimmermann: Financial Interests, Personal, Full or part-time Employment: Natera, Inc.; Financial Interests, Personal, Stocks/Shares: Natera, Inc.; Financial Interests, Personal, Leadership Role: Natera, Inc.; Financial Interests, Personal, Ownership Interest: Natera, Inc. P.R. Billings: Financial Interests, Personal, Full or part-time Employment: Natera, Inc.; Financial Interests, Personal, Stocks/Shares: Natera, Inc.; Financial Interests, Personal, Leadership Role: Natera, Inc.; Non-Financial Interests, Personal, Advisory Board: Mission Bio. A. Aleshin: Financial Interests, Personal, Full or part-time Employment: Natera, Inc.; Financial Interests, Personal, Stocks/Shares: Natera, Inc.; Financial Interests, Personal, Leadership Role: Natera, Inc.; Non-Financial Interests, Personal, Advisory Board: Mission Bio; Non-Financial Interests, Personal, Advisory Board: Notable Labs. All other authors have declared no conflicts of interest.