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In Reply

Human Genetics Group, Spanish National Cancer Centre, Madrid, Spain

Sandeep S. Dave, Louis M. Staudt

Lymphoid Malignancies Section, National Cancer Institute, Bethesda, MD

Elaine S. Jaffe

Laboratory of Pathology, National Cancer Institute, Bethesda, MD

Roger Milne

Genotyping Unit, Spanish National Cancer Centre, Madrid, Spain

Javier Alves

Department of Pathology, Hospital La Paz, Madrid, Spain

Jose Rodríguez

Department of Oncology, Hospital Son Dureta, Palma de Mallorca, Spain

In their correspondence Pitini et al stated, in regard to our recently published article,¹ that gene expression profiling does not identify differences among peripheral T-cell lymphomas unspecified (PTCLu) and angioimmunoblastic T-cell lymphomas (AITLs). The main purpose of our study was not to define the molecular differences between these two PTCL subgroups. In contrast, we applied gene expression analysis to investigate molecular signatures associated with prognosis. In fact, we identified a consistent proliferation signature related to survival of nodal PTCL. In our study, high proliferation was not associated with any of the analyzed PTCL subtypes, unspecified or AITL, but was associated with worse prognosis. It is true that the unsupervised analysis using a set of highly variable genes among the samples did not completely separate the two subgroups based on their gene expression profile. It is to be expected that perfectly separating two related entities like AITL and PTCLu would be difficult when using a large number of genes and a limited number of cases. Moreover, these entities are clinically and histologically heterogeneous, which make the identification of specific molecular features difficult. In a previous study, Ballester et al² were able to classify well-defined T-cell lymphoma entities and described a gene signature associated with AITL, although their unsupervised analysis did not show a complete separation between PTCLu and AITL. The signature defining AITL in this study was organized around immunoglobulin genes, which could reflect the presence of a high number of B cells, which is one of the characteristic features of these tumors. In another study, de Leval et al³ also described an AITL signature which was enriched in microenvironment-related genes. In this study, the authors were able to separate AITL as a homogeneous group from other PTCLu tumors by using a combination of different methods of analysis, principle component analysis with hierarchic clustering. Our results do not contradict these other results as we did not perform an analysis to identify differentially expressed genes between AITL and PTCLu. We agree that microarray studies have been helpful in better classifying other types of lymphomas,⁴ but perhaps we are still a long way off from using them as a diagnostic tool for highly heterogeneous tumors such as PTCL. The results obtained from massive gene expression experiments based on microarrays are highly dependent on the research questions proposed, the set of genes included in each microarray platform, the methods of analysis applied, and very importantly, the number of cases included in the study.

We fully agree with the comment that novel treatment approaches are needed in this group of lymphomas due to their associated poor prognosis. However, the role of doxorubicin in these entities is as yet unclear. We hypothesized that, given the existence in our study of tumors with a high proliferation signature, which is in turn associated with high expression of topoisomerase II, it is possible that this population could benefit from chemotherapy regimens that include inhibitors of topoisomerase II such as doxorubicin. Therefore, further investigation based in our hypothesis is warranted before accepting the lack of efficacy that a major drug such as doxorubicin has in the treatment of PTCL.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Cuadros M, Dave SS, Jaffe ES, et al: Identification of a proliferation signature related to survival in nodal peripheral t-cell lymphomas. J Clin Oncol 25:3321-3329, 2007[Abstract/Free Full Text]

2. Ballester B, Ramuz O, Gisselbrecht C, et al: Gene expression profiling identifies molecular subgroups among nodal peripheral T-cell lymphomas. Oncogene 25:1560-1570, 2006[CrossRef][Medline]

3. de Leval L, Rickman DS, Thielen C, et al: The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 109:4952-4963, 2007[Abstract/Free Full Text]

4. Rosenwald A, Wright G, Chan WC, et al: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:1937-1947, 2002[Abstract/Free Full Text]

Related Correspondence

• Gene Expression Profiling Does Not Identify Molecular Subgroup Among Nodal Peripheral T-Cell Lymphomas
  Vincenzo Pitini, Carmela Arrigo, and Giuseppe Altavilla
  JCO 2007 25: 4851 [Full Text]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cuadros, M. Articles by Rodríguez, J. Search for Related Content PubMed Articles by Cuadros, M. Articles by Rodríguez, J. Related Articles Related Correspondence