Spotting rs112445441 in Non-Hodgkin Lymphoma: Another Clue for the Context-Dependent Crosstalk between RAS-MAPK and PI3K Mediated Pathways
Spotting rs112445441 in Non-Hodgkin Lymphoma: Another Clue for the Context-Dependent Crosstalk between RAS-MAPK and PI3K Mediated Pathways
Bibi Nazia Murtaza1, Mazhar Saeed Chaudry2, Shamaila Inayat Nadeem1, Muhammad Shahid Nadeem3 and Abdul Rauf Shakoori4,*
ABSTRACT
Phosphatidylinositol-3-kinase (PI3K) mediated or Ras/PI3K/PTEN/Akt/mTOR is one of the major effector pathways in the pathogenesis of Non-Hodgkin Lymphoma (NHL). Binding of growth factors/ mitogen/cytokine or interleukin to EGFR leads to Ras induced RAF-MAPK cascade activation. PTEN protein is involved in the negative regulation of PI3K pathway. Mutations in upstream kinases, growth factor receptors or intrinsic members of cascades can lead to induce or promote cancers. Number of somatic mutations in several genes, majority of which are involved in chromatin modification and transcriptional regulation, have been reported in NHL. G468R and G468A mutations in BRAF gene have been reported in NHL, BRAF is a member of RAS mediated MAPK pathway. In current study, hot spots of Kras gene were analysed in a 40 years old male patient, presented with NHL located in ascending colon with worst prognosis of disease. Through mutagenic PCR, codon 12 was analysed by creating a single nucleotide mismatch at the 3′-end of primers to produce a BstNI recognition sequence at codon 12 while codon 13 was analysed by introducing HaeIII recognition sequence. By using RFLP and sequencing, point mutation substituting the glycine (GGC) to aspartic acid (GAC) was observed at codon 13. The p.G13D or cDNA.230G>A/ g.5590G>A is previously recognized as rs112445441 and being reported for the first time in NHL. By in silico analysis, it is anticipated to be a diseases causing or pathogenic alteration by Mutation taster and SIFT analysis. Spotting the rs112445441 in NHL is supporting the idea of cross talk between RAS-ERK-MAPK and PI13K and this could be one of the factors behind the development of resistance to the current therapy and relapse in NHL. K ras mutant isoforms, being the negative predictors for prognosis, are vital to analyse before the start of adjuvant therapy. Further studies needed to confirm the functional aspects of rs112445441 and other variants involved in NHL pathogenesis.
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April 2020
Vol. 52, Iss. 2, Pages 425-824
