Identification of prognostic and susceptibility markers in chronic myeloid leukemia using next generation sequencing

Abstract

BackgroundIncidence of Chronic Myeloid Leukemia (CML) is continuously increasing and expected to reach 100,000 patients every year by 2030. Though the discovery of Imatinib Mesylate (IM) has brought a paradigm shift in CML treatment, 20% patients show resistance to this tyrosine kinase inhibiter (TKI). Therefore, it is important to identify markers, which can predict the occurrence and prognosis of CML. Clinical Exome Sequencing, panel of more than 4800 genes, was performed in CML patients to identify prognostic and susceptibility markers in CML.MethodsEnrolled CML patients (n=18) were segregated as IM responders (n=10) and IM failures (n=8) as per European Leukemia Net (ELN), 2013 guidelines. Healthy controls (n=5) were also enrolled. DNA from blood of subjects was subjected to Next Generation Sequencing. Rare mutations present in one patient group and absent in another group were considered as prognostic markers, whereas mutations present in more than 50% patients were considered as susceptibility markers.ResultMutations in genes associated with cancer related functions were found in different patient groups. Four variants: rs116201358, rs4014596, rs52897880 and rs2274329 in C8A, UNC93B1, APOH and CA6 genes, respectively, were present in IM responders; whereas rs4945 in MFGE8 was present in IM failures. Mutations in HLA-DRB1 (rs17878951), HLA-DRB5 (rs137863146), RPHN2 (rs193179333), CYP2F1 (rs116958555), KCNJ12 (rs76684759) and FUT3 (rs151218854) were present as susceptibility markers.ConclusionThe potential genetic markers discovered in this study can help in predicting response to IM as frontline therapy. Susceptibility markers may also be used as panel for individuals prone to have CML.

Implementation of an NGS‐based sequencing and gene fusion panel for clinical screening of patients with suspected hematologic malignancies

“…[15][16][17][18][19][20][21][22] Assays which contain a customized set of genes (and/or hotspots) have been useful on a research basis to describe the extent of myeloid mutations, 13,15,20,21,[23][24][25][26][27] while clinical testing can benefit from studies which use and validate more widely available commercial assays. 1,2,4,[7][8][9][10][11][12]14,19,22,28,29 While the previously referenced studies examined mutations in a single gene, such as insertions, deletions, and point mutations, the study of gene fusions in hematological malignancies using NGS gene panels has been less common, and the use of gene panels that concurrently assess both single-gene variants and gene fusions even more rare. A recent study compared two commercially available RNA-based fusion panels and found that they are suitable for initial diagnosis, though their sensitivity was less than that of traditional targeted, PCR-based assays.…”

Pharmacogenomic landscape of Indian population using whole genomes

“…The variant rs116201358 in C8A gene is found to be strikingly higher in frequency among South Asian populations in comparison with other subpopulations (IndiGen: 0.13; gnomAD‐ALL: 0.007; and gnomAD‐SAS: 0.12) and is associated with the better treatment outcome of imatinib mesylate, a drug used to treat chronic myeloid leukemia. 33 Similarly, another potentially deleterious variant rs11568367 in the ABCB11 gene showing high prevalence in the Indian population (IndiGen: 0.11; and gnomAD‐ALL: 0.003) is associated with significantly impaired function of taurocholate transport. 34 The variant rs202242769 in the CYP21A2 gene is found to be extremely higher in the Indian population in comparison with all the other subpopulations, including other South Asian populations (IndiGen: 0.227; gnomAD‐ALL: 0.0053; and gnomAD‐SAS: 0.0221) and is associated with the change in hormone levels in the patients with congenital adrenal hyperplasia as well as in some healthy individuals.…”

Bioinformatics analysis of UNC93B1 gene and prognostic value in breast cancer

“…There was no signi cant difference in the expression of UNC93B1 between the <51-year-old group and the >51-year-old group (Figure 3A, P=0.7626, Table 2). The Scarff-Bloom-Richardson grading system (SBR Grade) is based on histological grade or negative based on tumor size (<2 cm, 2-5 cm, ≥5 cm), lymph node status (positive or negative) and vascular invasion status (positive) ) Breast cancer [9] Nottingham prognostic index. (NPI) Based on histopathological factors (tumor size, lymph node stage and tumor grade) [12].…”

“…UNC93B1 modi es TLR3 expression and localization, which may in uence cancer progression [8]. UNC93B1 may be a mutated gene for the cancer-related function of chronic myeloid leukemia (CML) [9]. However, the analysis of UNC93B1 in breast cancer is rare, and the relationship between UNC93B1 expression and the survival of breast cancer patients is still unknown in this study, various online analysis databases were used to evaluate the correlation between UNC93B1 expression and prognostic factors of breast cancer, and to explore the prognostic signi cance of UNC93B1 gene in breast cancer treatment.…”