Abstract 5901: Germline tissue sequencing in patients with solid tumors uncovers clonal hematopoiesis variants

Abstract

Abstract The peripheral blood (PB) is broadly used as a source of germline tissue for next generation sequencing in both clinical and research settings. Incidental or secondary findings are often uncovered at the time of germline sequencing. Current guidelines focus on secondary findings as they relate to inherited cancer predisposition. However, sequencing done on the PB has the potential of uncovering cancer-associated somatic variants. Somatic variants in genes associated with hematologic malignancies could indicate the presence of clonal hematopoiesis, clonal cytopenias or in rare instances an undiagnosed hematologic malignancy. In this abstract, we describe leukemia-associated somatic variants identified through whole exome sequencing (WES) in the PB of genomic research participants. A total of 24 patients with clonal hematopoiesis were identified from our institutional cohort of the ORIEN avatar study of 807 patients with solid tumors. Pathogenic and likely pathogenic variants were selected from protein coding sequences and splice sites of 64 genes involved in hematologic malignancies. Matched tumor and PB samples allowed for inclusion of variants found exclusively in the PB sample. Chart reviews were performed, and blood indices were collected for patients with clonal hematopoiesis variants. The median age of patients in this cohort was 73 years old (range 42-82) and 54% (n=13) were still living at the time of chart review. There were 27 variants distributed amongst 24 patients with 8% (n=2) of patients having 2 or more variants identified. The median reported variant allele frequencies (VAF) was 0.447. Most variants were missense (n=14) followed by stop gain (n=5), frameshift (n=3), splice site (n=3), stop lost (n=1), and inframe insertion (n=1). TP53 and DNMT3A (n=4) variants were identified most frequently followed by JAK2, KRAS, MYD88 (n=3), and PTEN (n=2). The rest of the genes accounted for one variant each, including TET2 and IDH2. Complete blood count (CBC) values were recorded for WBC, Hgb, MCV, RDW, platelets, and ANC, 79% (n=19) of patients had abnormal CBCs. No patients in this cohort were seen by a hematologist. Our results indicate that approximately 3% of patients identified in a research based solid tumor cohort had clonal hematopoiesis. Most of these patients had abnormalities in their hematologic parameters and would likely benefit from referral to hematology. Our data demonstrate the importance of considering somatic variation when the PB is used as germline tissue in research settings. Clonal hematopoiesis has significant clinical consequences ranging from risk of blood cancers to cardiovascular disease. We argue for the need to establish accepted frameworks for identification and evaluation of clonal hematopoiesis in participants of genomics research. Further analysis of associations between incidence of CHIP, cancer type, and prior treatment are underway Citation Format: Jennie Vagher, Aaron Atkinson, Mikaela Larson, David Nix, Andrew Post, Courtney Scaife, Jonathan Tward, Cindy Matsen, Jason P. Hunt, Marcus Monroe, Mia Hashibe, Deborah M. Stephens, Nicola J. Camp, Wallace L. Akerley, Trudy Oliver, Douglas Grossman, Sheri L. Holmen, Howard Colman, Randy Jensen, Kevin B. Jones, Afaf E. Osman. Germline tissue sequencing in patients with solid tumors uncovers clonal hematopoiesis variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5901.