<i style="mso-bidi-font-style:normal"><span style="font-size:11.0pt;font-family:"Times New Roman";mso-fareast-font-family: "Times New Roman";mso-bidi-font-family:Mangal;mso-ansi-language:EN-GB; mso-fareast-language:EN-US;mso-bidi-language:HI" lang="EN-GB">NRAS</span></i><span style="font-size:11.0pt;font-family:"Times New Roman";mso-fareast-font-family: "Times New Roman";mso-bidi-font-family:Mangal;mso-ansi-language:EN-GB; mso-fareast-language:EN-US;mso-bidi-language:HI" lang="EN-GB"> Mutations in <i style="mso-bidi-font-style:normal">de novo</i> acute leukemia: Prevalence and clinical significance</span>

Abstract

The activating mutations of the Ras gene or other abnormalities in Ras signaling pathway lead to uncontrolled growth factor-independent proliferation of hematopoietic progenitors. Oncogenic mutations in <i style="mso-bidi-font-style:normal">NRAS</i> gene have been observed with variable prevalence in hematopoietic malignancies. In the present study, <i style="mso-bidi-font-style:normal">NRAS</i> mutations were detected using bidirectional sequencing in 264 acute leukemia cases — 129 acute lymphocytic leukemia (ALL) and 135 acute myeloid leukemia (AML) and 245 age- and gender-matched controls. Missense mutation was observed only in the 12^thcodon of <i style="mso-bidi-font-style:normal">NRAS</i> gene in 4.7% of AML and 3.16% of ALL cases. The presence of <i style="mso-bidi-font-style:normal">NRAS</i> mutation did not significantly influence blast % and lactate dehydrogenase (LDH) levels in AML patients. When the data were analyzed with respect to clinical variables, the total leukocyte count was elevated for mutation positive group, compared to negative group. In AML patients with <i style="mso-bidi-font-style:normal">NRAS</i> mutations, 60% failed to achieve complete remission (CR), as compared to 34.8% in mutation negative group. These results indicated that <i style="mso-bidi-font-style:normal">NRAS</i> mutations might confer poor drug response. In AML, disease free survival (DFS) in <i style="mso-bidi-font-style:normal">NRAS</i> mutation positive group was lesser, compared to mutation negative group (9.5 months <i style="mso-bidi-font-style: normal">vs</i>. 11.68 months). In ALL patients, DFS of <i style="mso-bidi-font-style: normal">NRAS</i> mutation positive group was lesser than mutation negative group (9.2 months <i style="mso-bidi-font-style:normal">vs</i>. 27.5 months). The CR rate was also lower for mutation-positive patients group, compared to mutation-negative group. In conclusion, these results suggested that presence of <i style="mso-bidi-font-style:normal">NRAS</i> mutation at 12^th codon was associated with poor response and poorer DFS in both ALL and AML.