Analysis of clinical and genomic profiles of therapy-related myeloid neoplasm in Korea

Abstract

Background: Therapy-related myeloid neoplasm (T-MN) rarely occurs among cancer survivors, and was characterized by poor prognosis. T-MN has germline predisposition in a considerable proportion. Here, clinical characteristics and germline/somatic variant profiles in T-MN patients were investigated, and the findings were compared with those of previous studies.

Methods: A review of medical records, cytogenetic study, targeted sequencing by next-generation sequencing, and survival analysis were performed on 53 patients with T-MN at a single institution in Korea.

Results: The patients were relatively younger compared to T-MN patients in other studies. Our T-MN patients showed a high frequency of complex karyotypes, -5/del(5q), and -7/del(7q), which was similar to the Japanese study group but higher than the Australian study group. The most common primary disease was non-Hodgkin lymphoma, followed by breast cancer. The detailed distributions of primary diseases were different across study groups. Seven patients (13.2%) harbored deleterious presumed/potential germline variants in cancer predisposition genes (CPG) such as BRIP1, CEBPA, DDX41, FANCM, NBN, NF1, and RUNX1. In the somatic variant profile, TP53 was the most frequently mutated gene, which was consistent with the previous studies about T-MN. However, the somatic variant frequency in our study group was lower than in other studies. Adverse factors for overall survival were male sex, older age, history of previous radiotherapy, previous longer cytotoxic therapy, and -5/del(5q).

Conclusion: The findings of our study corroborate important information about T-MN patients. As well as a considerable predisposition to CPG, the clinical characteristics and somatic variant profile showed distinctive patterns. Germline variant testing should be recommended for T-MN patients. If the T-MN patients harbor pathogenic germline variants, the family members for stem cell donation should be screened for carrier status through germline variant testing to avoid donor-derived myeloid neoplasm. For the prediction of the prognosis in T-MN patients, sex, age, past treatment history, and cytogenetic findings can be considered.

Keywords: Germline predisposition; Next-generation sequencing; Somatic mutation; Therapy-related myeloid neoplasm.

Fig. 1

Study population and design. T-MN Therapy-related myeloid neoplasm; FISH Fluorescence in situ hybridization; NGS Next-generation sequencing; BM Bone marrow

Fig. 2

Variants filtering strategy. *The Strand-biased variants refer to the variants whose forward and reverse stranded alternative counts have a ratio of either 2:8 or 8:2. ^†The Panel of Normals approach was used to determine the selection criteria for variants for somatic variants, with a threshold of variant frequency (refer to https://gatk.broadinstitute.org/hc/en-us/articles/360035890631-Panel-of-Normals-PON-). VAF Variant allele frequency; MAF Minor allele frequency; gnsomAD The genome aggregation database; KOVA Korean variant archive; KRGDB Korean reference genome database; DM Disease-causing variant, HGMD The human gene variant database; gnomAD_genome/exome_ALL; gnomAD_genome/exome_EAS, The allele frequencies from all populations and East Asian population, respectively through genome/exome sequencing

Fig. 3

Landscape of somatic variants observed in 53 T-MN patients. This plot summarizes the landscape of somatic single nucleotide variants and small insertions–deletions variants observed in 53 T-MN patients in the SNUH study group using 93-gene filtering. The bottom of the plot illustrates the clinical characteristics of the patients and cytogenetic results. “Cytotoxic therapy” indicated previous therapy before the occurrence of T-MN. CT Chemotherapy; RT Radiotherapy; MDS Myelodysplastic syndrome; MDS/MPN Myelodysplastic/myeloproliferative neoplasm; AML Acute myeloid leukemia; r Rearranged; NA Not assessed; ELN2017, AML risk stratification by genetics suggested by 2017 European LeukemiaNet (ELN) recommendations from an international expert panel; IPSS-R, revised International Prognostic Scoring System (IPSS-R) for MDS assessment

Fig. 4

Changes in somatic variants in the progression of T-MN in four patients harboring longitudinal samples. This plot exclusively shows the changes in somatic variant profiles observed in the four T-MN patients with longitudinal samples. a tmn11. b tmn27. c tmn42. d tmn53. “Patient ID-A” samples were initial BM samples diagnosed with T-MDS. “Patient ID-B” samples were subsequent BM samples at the progression of T-MDS

Fig. 5

Comparison of somatic variants frequency among the SNUH, Singhal, and cBioPortal groups within 43 genes. This plot summarizes the frequency of somatic variants observed in the three study groups within 43 genes commonly analyzed in the three groups. Mutated genes observed in each study group are listed in descending order of the variant frequency. The high-ranked genes (TP53, RUNX1, DNMT3A, ASXL1, CBL, and TET2) observed in the SNUH group are indicated in colored with variant frequency

Fig. 6

Distribution of somatic TP53 variants in the SNUH, Singhal, and cBioPortal study groups. This lollipop plot describes the distribution of TP53 variants according to protein domain. Lollipop plots for the other 37 genes are shown in Additional file 4

Fig. 7

Kaplan–Meier survival curves of significant prognostic factors affecting overall survival in 53 T-MN patients

Fig. 8

Forest plot by Multiple Cox Proportional Hazards Model of 53 T-MN patients. −7/del(7q), complex karyotype, and somatic TP53 variant were omitted from explanatory variables due to their multicollinearity with −5/del(5q). CI Confidence intervals