Development of an improved variant calling pipeline and the analysis of altered allelic transcription of recurrent mutations in Acute Myeloid Leukaemia

Nazeer Batcha, Aarif Mohamed (2018): Development of an improved variant calling pipeline and the analysis of altered allelic transcription of recurrent mutations in Acute Myeloid Leukaemia. Dissertation, LMU München: Medizinische Fakultät

Abstract

Recurrent mutated genes in acute myeloid leukaemia are suspected to contribute to leukaemogenesis by different mechanisms but the ratios in which the recurrently mutated alleles are transcribed from DNA to RNA in the respective genes are widely unknown. A systematic comparison of variant allele frequencies of recurrent mutated genes was carried out using a large AML cohort (N=499). Around 95% of variants were detected to be transcribed from DNA to RNA by the application of a minimum read depth cut-off of 10x (90% transcribed among recurrent mutations). The analysis on 11 recurrently mutated genes in AML determined preferential mutant allele transcript abundance for GATA2, RUNX1, TET2, SRSF2, IDH2 and NPM1 and preferential wild-type transcript abundance for PTPN11, CEBPA and WT1, respectively. Presence of allelic imbalances among the common variants of GATA2, RUNX1 and IDH2 were also demonstrated in patients without recurrent mutations in the respective genes. Further inquiry based on the differential expression of genes and transcript isoforms between patients with and without recurrent mutations in the respective genes showed no significant difference except for SRSF2, CEBPA and WT1. In summary, this study compared the variant allele frequencies of recurrently mutated genes and exhibits allele-specific transcript abundance of these genes in AML. The observed differences can be interpreted as a novel, currently underestimated mechanism how mutations contribute to leukaemogenesis and necessitate further analysis.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Acute Myeloid Leukaemia, AML, DNA, RNA, Sequencing, Variant Calling, VAF, Cancer, Genetics
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 17. Dezember 2018
• 1. Bericht­erstatter:in: Mansmann, Ulrich