Impact of mutational variant allele frequency on prognosis in myelodysplastic syndromes

Lingxu Jiang; Lu Wang; Chuying Shen; Shuanghong Zhu; Wei Lang; Yingwan Luo; Hua Zhang; Wenli Yang; Yueyuan Han; Liya Ma; Yanling Ren; Xinping Zhou; Chen Mei; Li Ye; Weilai Xu; Haiyang Yang; Chenxi Lu; Jie Jin; Hongyan Tong

Impact of mutational variant allele frequency on prognosis in myelodysplastic syndromes

Am J Cancer Res. 2020 Dec 1;10(12):4476-4487. eCollection 2020.

Authors

Lingxu Jiang^{1

2}, Lu Wang^{1

2}, Chuying Shen^{1

2}, Shuanghong Zhu^{1

2}, Wei Lang^{1

2}, Yingwan Luo^{1

2}, Hua Zhang^{1

2}, Wenli Yang^{1

2}, Yueyuan Han^{1

2}, Liya Ma^{1

2}, Yanling Ren^{1

2}, Xinping Zhou^{1

2}, Chen Mei^{1

2}, Li Ye^{1

2}, Weilai Xu^{1

2}, Haiyang Yang¹, Chenxi Lu¹, Jie Jin¹, Hongyan Tong^{1

2}

Affiliations

¹ Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310003, Zhejiang Province, P. R. China.
² Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310003, Zhejiang Province, P. R. China.

PMID: 33415012
PMCID: PMC7783761

Abstract

The clinical relevance of variant allele frequency (VAF) of recurrent mutations in myelodysplastic syndromes (MDS) has been increasingly reported. However, the prognostic value of mutational VAF across the genetic spectrum of MDS has not been extensively evaluated. In this study, we profiled the mutational spectrum of 382 newly diagnosed MDS patients using targeted next-generation sequencing. Exploratory analysis found that mutational VAF of some genes including TET2, TP53, and SF3B1 had significant associations with patient survival. Specifically, TET2 VAF ≥ 32% (HR 1.69, P = 0.025) and TP53 VAF ≥ 27% (HR 3.58, P < 0.001) were independently associated with shorter overall survival (OS). In contrast, SF3B1 VAF ≥ 15% had an independent association with better prognosis (HR 0.52, P = 0.048). In addition, high TET2 VAF was associated with an increased response to hypomethylating agents relative to low TET2 VAF (P = 0.009). Patients with high TP53 VAF more often possessed complex karyotypes than those with low VAF (P = 0.034). And patients with high SF3B1 VAF were more frequently classified as MDS with ring sideroblasts (MDS-RS) category than those with low VAF (P = 0.012). Meanwhile, we found that for some other genes like EZH2 and NRAS, once their mutations appeared, it meant poor survival regardless of mutational VAF. These findings suggest that mutational VAF of certain genes should be considered into the routine prognostic prediction and risk stratification of MDS patients.

Keywords: Myelodysplastic syndromes; mutation; next-generation sequencing; prognosis; variant allele frequency.