n this doctoral thesis we have studied some methodological aspects in the MYC gene characterization with clinical utility in the diagnosis, treatment and prognostic evaluation of aggressive B-cell lymphomas. Specifically, we have applied this knowledge to the study of a lymphoma subgroup: diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL) In the first study we found that some diffuse large B-cell lymphomas (DLBCLs), such as Burkitt’s lymphoma a(BL), harbored MYC gene rearrangements. MYC gene translocation was associated with higher MYC protein expression as assessed by immunohistochemistry (70% vs. 28% in the whole series and 61% vs. 28% in DLBCL cases). MYC protein expression was not related with increased MYC gene copy numbers, the other immunohistochemical markers evaluated (CD10, BCL6, BCL2 and MUM1), the proliferative index (Ki67) or the cell of origin according to Hans algorithm. Moreover, we found that some DLBCLs lacking MYC gene rearrangements show high levels of MYC protein expression, due to unknown mechanisms. In the second study, we assessed the impact of FISH probe selection in the evaluation of MYC gene rearrangement. The results obtained with one fusion IGH-MYC and two break-apart commercial probes in a series of 91 aggressive B-cell lymphomas were compared. All cases (n=13) with IGH-MYC translocation could be detected with all three probes. However, 7 of 13 cases (54%) with non-IGH-MYC (IGK-MYC, IGL-MYC or non-IG-MYC) were unambiguously detected by just one of the probes tested, whereas the other probes yielded non-conclusive or negative results (false negative). On the other hand, when the IGH-MYC fusion probe was used, 9 of 15 cases (60%) with hybridization patters suggestive of a non-IGH-MYC rearrangement were attributable to MYC copy gain rather than MYC translocation, as demonstrated by both break-apart probes (false positive). Our results indicate that detection of MYC gene rearrangement could be optimized by a two-probe approach involving the application of both IGH-MYC dual-fusion and MYC break-apart selected probes. Finally, in the third study, we evaluated the role of MYC, BCL2 and BCL6 gene status and their protein expression in a series of 42 CNS-DLBCL. We observed high MYC protein expression in 43% of cases, and this was associated with lower overall survival (OS). MYC protein expression was not related to MYC gene rearrangement, since translocation was not found in any instance. Cases with concurrent expression of MYC and BCL2 showed a lower OS, although the difference did not reach statistical significance. Translocation involving BCL2 gene was not detected in any case. The BCL6 gene was frequently translocated (44%), but it was unrelated to survival. In conclusion, we found that CNS-DLBCLs frequently show MYC protein overexpression and that its immunohistochemical detection may contribute to a more accurate risk stratification of CNS-DLBCL patients.
Date of Award | 1 Dec 2015 |
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Original language | Spanish |
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Awarding Institution | - Universitat Autònoma de Barcelona (UAB)
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Supervisor | Jose Luis Mate Sanz (Director) |
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Alteraciones del gen MYC en linfomas agresivos de células B: evaluación mediante fish, relación con la expresión protéica y valor pronóstico
Tapia Melendo, G. (Author). 1 Dec 2015
Student thesis: Doctoral thesis
Student thesis: Doctoral thesis