Clonal hematopoiesis in patients with non-hematologic cancers: Prevalence and detectability in primary tumor tissue.

Abstract

e23318 Background: Clonal Hematopoiesis of Indeterminate Potential (CHIP) is defined by leukemia-associated mutations with a variant allele frequency of at least 2% in individuals without a hematological malignancy. While CHIP is typically identified through sequencing blood, this study investigates the prevalence of CHIP in tissue samples from solid tumor patients, as these mutations are common in such patients and impact outcomes. Methods: A descriptive study was conducted using data from the AACR project GENIE v17.0 to analyze the frequency of CHIP mutations in patients with solid malignancies. The analysis was limited to a single distinct sample per patient to avoid duplication, and samples from primary solid tumor sites were selected. Results: Among 153,133 solid tumor patients, 138,501 had a single sample analyzed, with 78,028 samples from primary tumor sites. Given the overlap between CHIP mutations and TP53 mutations in solid and liquid malignancies, analysis was conducted excluding samples with TP53 mutations. Even with this exclusion, CHIP mutations were present in 35% of samples, a higher percentage than previously reported. The most frequent mutations included SETDB1 (5.65%), SETD2 (5.13%), CREBBP (4.83%), mutations with vital role in AML with granulo-monocytic differentiation. Other notable mutations were ASXL1 (3.33%), TET2 (3.35%), GNAS (2.34%), along with SF3B1 (2.35%) and DNMT3A (2.31%) (table below). Less common but “higher risk” mutations included FLT3 (1.66%), JAK2 (1.70%), CBL (1.71%), PPM1D (2.43%) and IDH2 (1.10%). Mutations with less than 1% prevalence included GNB1 (0.70%) and SRSF2 (0.64%). Conclusions: This study reveals that CHIP mutations are common in primary tumors, and identifying high-risk mutations can help reduce therapy-related myeloid neoplasms by choosing less toxic treatments. Despite limitations such as distinguishing treatment timing and incomplete gene profiling, early detection and intervention through CHIP clinics are crucial. The solid tumor department refers patients to the CCF CHIP Pharmacovigilance Clinic for monitoring and prevention. Additionally, potential contamination of oncologic NGS tests by CHIP mutations highlights the need for specialized clinics to guide patients on these findings. Reference: The AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through An International Consortium, Cancer Discov. 2017 Aug;7(8):818-831 v 17.0-public. Mutation Samples without tp53 mutation Percentage SETD2 1844 5.13% CREBBP 1685 4.83% BCOR 1366 3.99% ASXL1 1190 3.33% TET2 1162 3.35% GNAS 959 2.34% SF3B1 863 2.35% DNMT3A 802 2.31% FLT3 693 1.66%