[Molecular and clinical characteristics and prognosis of myelodysplastic neoplasms with biallelic TET2 inactivation].

Abstract

Objective: To explore the clinical characteristics and prognostic significance of myelodysplastic neoplasms (MDS) with biallelic TET2 inactivation (bi-TET2) . Methods: Clinical data from 1 730 newly diagnosed de novo MDS patients treated at Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College between August 2016 and June 2025, with next-generation sequencing data, were retrospectively collected. The clinical characteristics and prognosis of patients with biallelic TET2 inactivation were analyzed. Results: Thirty-nine patients (2.3% ) harbored bi-TET2, including two with copy-neutral loss of heterozygosity on chromosome 4q24. Compared with patients with monoallelic TET2 mutations (n=147) and those without TET2 mutations (n=1 544), patients with bi-TET2 carried more gene mutations overall [4 (IQR: 3, 6) vs 4 (IQR: 2, 5) vs 2 (IQR: 1, 4), P<0.001] and had higher frequencies of mutations in ASXL1 (38.5% vs 29.9% vs 20.5%, P=0.001), SRSF2 (28.2% vs 12.9% vs 4.5%, P<0.001), SF3B1 (25.6% vs 18.4% vs 11.7%, P=0.004), EZH2 (18.0% vs 7.5% vs 4.5%, P=0.002), CUX1 (12.8% vs 3.4% vs 1.4%, P<0.001), KRAS (10.3% vs 4.3% vs 2.1%, P=0.006), CBL (10.3% vs 3.4% vs 2.6%, P=0.030), ZRSR2 (10.3% vs 6.1% vs 3.2%, P=0.017), and CEBPA (7.7% vs 1.4% vs 1.2%, P=0.019). Patients with bi-TET2 were older at diagnosis [65 (IQR: 58, 69) vs 61 (IQR: 50, 67) vs 55 (IQR: 44, 64) years, P<0.001] and had a higher proportion of normal karyotype (69.2% vs 46.3% vs 44.8%, P=0.024). Patients with bi-TET2 had a significantly shorter median overall survival (OS) time than patients with monoallelic TET2 mutations and those without TET2 mutations [18.5 (95% CI: 13.1-25.0) vs 40.6 (95% CI: 22.8-60.9) vs 54.7 (95% CI: 47.1-69.4) months, P=0.009]. Stratified analysis by IPSS-M prognostic risk categories showed that, in the high-risk group (moderate high-risk, high-risk, and very high-risk), patients with bi-TET2 had a significantly shorter median OS time[12.4 (95% CI: 8.4-NA) months] than patients with monoallelic TET2 mutations [19.7 (95% CI: 14.9-39.9) months] and those without TET2 mutations [32.0 (95% CI: 27.6-37.4) months, P<0.001]. In contrast, no significant difference in OS was observed in the low-risk group (very low-risk, low-risk, and moderate low-risk) . Conclusion: Patients with MDS harboring biallelic TET2 inactivation exhibit distinct clinical and molecular characteristics and in patients with relatively high IPSS-M risk, their prognosis is worse than that of patients with monoallelic TET2 mutations.