Non-Driver Mutations and Gene Sequence Variants Identified By Targeted Deep Sequencing in Polycythemia Vera and Essential Thrombocythemia

Abstract

Background:Driver mutations in myeloproliferative neoplasms involve mutations in the JAK2, MPL, and CALR genes. However, incorporation of next generation sequencing (NGS) testing into routine clinical practice may identify for mutations or variants in additional hematologic malignancy-associated genes, the roles of which have not been extensively elucidated in patients with polycythemia vera (PV) or essential thrombocythemia (ET). The purpose of this study is to characterize the clinical characteristics of ET/PV patients harboring additional non-driver mutations or gene variants.Methods:Eligible cases included patients with PV/ET diagnosed and treated at MD Anderson Cancer Center from January 2012 to January 2017. NGS sequencing of 28 genes known to be mutated in hematologic malignancies was performed on samples from 240 ET/PV patients. Non-driver mutations detected by the NGS platform were classified based on the allele frequency recorded in our database in conjunction with currently available and periodically updated public reference databases of somatic mutations or variants of unclear significance.Results:A total of 110 ET and 130 PV cases had NGS performed on samples collected at the time of initial referral. Among them, 21 (19%) ET cases and 28 (21.5%) PV cases had ≥1 non-driver somatic mutation detected. The distribution of non-driver somatic mutations in ET and PV are shown in Figure 1A. On grouping non-driver genes into functional pathways, the most frequent mutational targets were in genes associated with epigenetic regulation (PV, 22; ET, 25), mainly DNA methylation (PV, 18; ET, 20) followed by epigenetic modifier (PV, 4; ET, 5). In subjects with PV, TET2 (n = 12) was the most frequently mutated gene, followed by DNMT3A (n = 7), IDH1/2 (n = 5), and ASXL1 (n = 4). A similar pattern was noted in ET, with TET2 mutations (n = 8) being most frequent followed by DNMT3A (n = 7), and ASXL1 (n = 5). Older patients were more likely to display non-driver mutations in both ET (p < 0.001) and PV (p = 0.02). The combined prevalence of non-driver somatic mutations was 27% and 32% in PV and ET, respectively. Over a short median follow up of 3.9 (range, 1.0-37.1) months among PV patients with non-driver somatic mutations, no leukemic transformations occurred. Similarly, no leukemic transformations were observed in ET patients with additional non-driver somatic mutations over a median follow up of 3.8 (range, 1.1-36) months. Overall survival (OS) was significantly longer in patients without additional mutations in epigenetic modifiers (Figure 1C). The prognostic relevance of non-driver somatic mutations on OS was not determined due the small sample size and limited follow up duration. Of 13 (12%) triple-negative ET patients without non-driver somatic mutations, nine had non-synonymous gene sequence variants; the most common being in DNA methylation genes namely TET2 &IDH1/2 genes (Figure 1B).Conclusion:The spectrum of non-driver somatic mutations in our ET and PV study cohorts was dominated by mutations in the TET2, DNMT3A, ASXL1 genes, and were correlated with age (Buscarlet Blood, 2017). A larger sample size and longer follow-up is needed to determine the impact of non-driver somatic mutations on transformation-free and overall survival. Germline TET2 variants or their combinations with other variants/non-driver mutations may constitute low penetrance predisposition factors for myeloid neoplasms and their functional relevance warrants further exploration. [Display omitted] DisclosuresBose:Incyte Corporation: Honoraria. Kantarjian:Amgen: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding. Verstovsek:Astrazeneca: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Blueprint Medicines Corp: Research Funding; Galena BioPharma: Research Funding; Genentech: Research Funding; Galena BioPharma: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Lilly Oncology: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Lilly Oncology: Research Funding; CTI BioPharma Corp: Research Funding; Pfizer: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding; CTI BioPharma Corp: Research Funding; Bristol Myers Squibb: Research Funding; Astrazeneca: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Incyte: Research Funding.