Hematologic Neoplasms, TP53 Somatic Mutation, DNA Sequencing Exons 4-9
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Patients with chronic lymphocytic leukemia (CLL) have variable disease course influenced by a series of tumor biologic factors. The presence of chromosomal 17p- or TP53 gene mutation confers a very poor prognosis to a subset of CLL patients, both at time of initial diagnosis, as well as at disease progression, or in the setting of therapeutic resistance. TP53 gene mutation status in CLL has emerged as the single most predictive tumor genetic abnormality associated with adverse outcome and poor response to standard immunochemotherapy; however, patients can be managed with alternative therapeutic options. Although the prognostic relevance of acquired TP53 gene mutation is best studied for CLL, similar findings are also reported for other hematologic malignancies including low-grade B-cell lymphoma, diffuse large B-cell lymphoma, and some types of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Therefore, while this test has been developed to be primarily focused on high-risk CLL patients, p53 gene sequencing analysis can also be performed in additional neoplasms, as clinically indicated.
This test is not intended for the evaluation of patients suspected of having an inherited, or germ line TP53 mutation cancer syndrome (eg, Li Fraumeni syndrome); if this is intended as a clinical indication, see TP53Z / TP53 Gene, Full Gene Analysis.
This test is complementary to FISH analysis for the 17p- abnormality, but more appropriately identifies the presence of mutational alteration and gene inactivation in tumor cells. For hereditary (germ line) TP53 mutation syndrome testing, an additional whole blood specimen is required. See TP53Z / TP53 Gene, Full Gene Analysis.
Evaluating chronic lymphocytic leukemia patients at diagnosis or during disease course for the presence of TP53 gene mutations indicating high risk of disease progression and adverse outcome
The presence of TP53 gene mutations indicates a high risk of disease progression and an adverse outcome.
Results are reported in standard nomenclature according to the most recent Human Genome Variation Society (HGVS) recommendations and an interpretive comment regarding the nature of the mutation (eg, known deleterious, suspected deleterious, synonymous change) will be included to complete the clinical report.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test will not detect all possible acquired mutations in the TP53 gene, because it is restricted to analyzing exons 4-9. However, this region encompasses more than 90% of described pathologic mutations and covers the coding exons of the critical DNA binding regions.
The analytical sensitivity of the assay can be affected by the absolute B-cell number in the peripheral blood or tissue sample, as well as the often subclonal nature of this tumor genetic abnormality. The assay attempts to compensate in part for this by performing an initial screening flow cytometry to assess B-cell quantity and by performing the cell enrichment step (for the peripheral blood specimens only) to isolate relatively pure CD19+ B-cells for analysis. Nevertheless, the nature of the Sanger sequencing method is such that typical reproducible analytic sensitivity will be in the order of 25% mutant allele burden.
Because optimal cell enrichment is dependent on the absolute B-cell quantity, samples with a very low WBC or initial percentage of B cells (determined from flow cytometry or WBC automated cell count) will likely result in poor assay performance and inability to detect possible TP53 gene mutations in the tumor population.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
Mutations present or absent as compared to a reference sequence of the normal TP53 gene
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Zenz T, Krober A, Scherer K, et al: Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood 2008;112:3322-3329
2. Lehmann S, Oqawa S, Raynaud SD, et al: Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia. Cancer 2008;112:1296-1305
3. Rossi D, Cerri M, Deambrogi C, et al: The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Clin Cancer Res 2009;15(3):995-1004
4. Zent CS, Call TG, Hogan WJ, et al: Update on risk-stratified management for chronic lymphocytic leukemia. Leuk Lymphoma 2006;47(9):1738-1746
5. UMD p53 database. Available at http://p53.free.fr/index.html
6. Trbusek M, Smardova J, Malcikova J, et al: Missense mutations located in structural p53 DNA-binding motifs are associated with extremely poor survival in chronic lymphocytic leukemia. J Clin Oncol 2011;29:2703-2708
7. Halldorsdottir AM, Lundin A, Murray F, et al: Impact of TP53 mutation and 17p deletion in mantle cell lymphoma. Leukemia 2011;25:1904-1908
8. Young KH, Leroy K, Moller MB, et al: Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood 2008;112:3088-3098