Margaret L. Gulley, Thomas C. Shea, Yuri Fedoriw

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Presentation transcript:

Genetic Tests To Evaluate Prognosis and Predict Therapeutic Response in Acute Myeloid Leukemia Margaret L. Gulley, Thomas C. Shea, Yuri Fedoriw The Journal of Molecular Diagnostics Volume 12, Issue 1, Pages 3-16 (January 2010) DOI: 10.2353/jmoldx.2010.090054 Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 1 Prognosis in AML strongly correlates with cytogenetic findings.18192021 Favorable prognosis is associated with t(15;17), t(8;21), or inv(16) whether alone or in combination with other chromosomal abnormalities, with the possible exception of inv(16) or t(8;21) with complex karyotype. An intermediate prognosis is associated with normal karyotype or select abnormalities: +6, +8, −7q, −9q, −12p, +21, +22, −Y. Adverse outcome is associated with abnormal 3q, 11q, 17p, 20q, 21q, or with −5, −5q, −7, −7q, −9q, t(6;9), t(9;22), or with complex karyotype. Abnormalities of the MLL gene on 11q23 impart a dismal prognosis.22,23 In children, poor survival is associated with monosomies or complex karyotype.5 (Adapted from Grimwade18 with permission). The Journal of Molecular Diagnostics 2010 12, 3-16DOI: (10.2353/jmoldx.2010.090054) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 2 The PML and RARA genes are shown, along with three forms of PML-RARA fusion transcripts. Breaks in PML are clustered into three regions: intron 3, the distal half of exon 6, or intron 6. RARA breakpoints are spread across intron 2. In the PML-RARA fusion transcript, either exon 3 or exon 6 of PML is juxtaposed with exon 3 of RARA to produce short (S), long (L), or variable (V) length coding sequence. The short form, also called the bcr3 isoform, may carry a worse prognosis. The Journal of Molecular Diagnostics 2010 12, 3-16DOI: (10.2353/jmoldx.2010.090054) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 3 Relative frequencies of common recurrent genetic abnormalities in acute myeloid leukemia. The Journal of Molecular Diagnostics 2010 12, 3-16DOI: (10.2353/jmoldx.2010.090054) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 4 FLT3 internal tandem duplication is identified in genomic DNA that has been amplified across exons 14 and 15 using PCR and then sized by capillary electrophoresis. Amplicons representing the wild-type allele are 325 bp in length (circled in black). In each of three AML cases, a larger amplicon is also seen (circled in red), consistent with FLT3 internal tandem duplication in the leukemic cells. The Journal of Molecular Diagnostics 2010 12, 3-16DOI: (10.2353/jmoldx.2010.090054) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 5 NPM1 mutation is identified in genomic DNA from four cases of AML by amplification of a segment of exon 12 followed by sizing of the amplicons using capillary electrophoresis. Amplicons representing the normal, wild-type allele are 267 ± 1 bp in length, while abnormal amplicons are usually 4 bp larger, consistent with insertional mutation in the leukemic cell DNA. The Journal of Molecular Diagnostics 2010 12, 3-16DOI: (10.2353/jmoldx.2010.090054) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions

Figure 6 Genetic and phenotypic abnormalities that are unique to the tumor provide a marker by which to measure tumor burden. Up to a billion leukemic cells remain in a patient who is in hematological (morphological) remission. Sensitive assays can detect and measure residual disease to permit early intervention when tumor burden is rising. The Journal of Molecular Diagnostics 2010 12, 3-16DOI: (10.2353/jmoldx.2010.090054) Copyright © 2010 American Society for Investigative Pathology and Association for Molecular Pathology Terms and Conditions