Molecular Genetics of Peripheral T‐cell Lymphomas

Abstract

Peripheral T‐cell lymphomas (PTCLs) are rare neoplasms constituting a heterogeneous group of diseases. Recent studies based on high‐throughput technologies (including DNA microarray and deep sequencing) offered several evidences that discrete subgroups can be identified with peculiar molecular and clinical features. In this regard, gene expression profiling (GEP) analyses demonstrated that the commonest nodal PTCL subtypes (not otherwise specified, NOS; angioimmunoblastic, AITL; anaplastic large cell lymphoma, ALCL) can be efficiently diagnosed based on the expression of a few genes. Noteworthy, the molecular diagnosis of nodal PTCLs turned out to be more efficient than histopathology in providing an accurate prognostic stratification. In addition, GEP indicated commonly deregulated genes and pathways, including tyrosine kinase signalling, NFkB pathway, angiogenesis and chromatin remodelling, which may represent suitable therapeutics targets. Finally, sequencing studies recently identified new lesions associated with specific PTCL subtypes, such as IDH2, TET2 and RHOA mutations in follicular helper derived cases and t(6;9) in ALK‐ ALCL.

In this article, we review the available literature on genetics of PTCLs and, also based on our own experience, discuss prospective scenarios on this intriguing topic.

Key Concepts

  • The molecular genetics of peripheral T‐cell lymphomas is, with a few exceptions, poorly known.
  • Gene expression profiling studies provided evidences of molecular differences among subtypes and recognised commonly deregulated genes and pathways that may represent suitable therapeutic targets.
  • High‐throughput sequencing studies are ongoing and will further clarify the genetic basis of these complex diseases.

Keywords: peripheral T‐cell lymphoma; molecular genetics; targeted therapy; histogenesis; molecular classification; molecular diagnosis; gene expression profiling; high‐throughput sequencing

Figure 1. Potential therapeutic targets in PTCLs according to the molecular patterns.
Figure 2. PTCL/NOS subgrouping based on gene expression analysis. (a) Gene expression profiling identified the GATA3 and TBX21 subgroups. (b) Overall survival (OS) analysis of molecularly defined GATA3 and TBX21 subgroups showed significant difference in clinical outcome. Source: This figure was originally published in Blood. Iqbal J, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T‐cell lymphoma. Blood. 2014 May 8;123(19):2915‐23. © the American Society of Hematology.
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Further Reading

de Leval L, Rickman DS, Thielen C, et al. (2007) The gene expression profile of nodal peripheral T‐cell lymphomas demonstrates a molecular link between angioimmunoblastic T‐cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 109: 4952–4963.

Feldman AL, Dogan A, Smith DI, et al. (2011) Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK‐negative anaplastic large cell lymphomas by massively parallel genomic sequencing. Blood 117: 915–919.

Foss FM, Zinzani PL, Vose JM, et al. (2011) Peripheral T‐cell lymphoma. Blood 117: 6756–6767.

Iqbal J, Weisenburger DD, Greiner TC, et al. (2010) International Peripheral T‐cell Lymphoma Project. Molecular signatures to improve diagnosis in peripheral T‐cell lymphomas and prognostication in angioimmunoblastic T‐cell lymphoma. Blood 115: 1026–1036.

Iqbal J, Wright G, Wang C, et al. (2014) Lymphoma Leukemia Molecular Profiling Project and the International Peripheral T‐cell Lymphoma Project. Gene expression signatures delineate biological and prognostic subgroups in peripheral T‐cell lymphoma. Blood 123 (19): 2915–2923.

Laimer D, Dolznig H, Vesely PW, et al. (2012) The novel AP‐1 target gene PDGFRB represents an effective target for imatinib treatment in NPM‐ALK positive anaplastic large cell lymphomas. Nature 18 (11): 1699–1704.

Palomero T, Couronné L, Khiabanian H, et al. (2014) Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nature Genetics 46 (2): 166–170.

Piccaluga PP, Agostinelli C, Califano A, et al. (2007) Gene expression analysis of peripheral T‐cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. Journal of Clinical Investigation 117: 823–834.

Piccaluga PP, Agostinelli C, Califano A, et al. (2007) Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T‐follicular helper cells and VEGF deregulation. Cancer Research 67: 10703–10710.

Piccaluga PP, Fuligni F, De Leo A, et al. (2013) Molecular profiling improves classification and prognostication of nodal peripheral T‐cell lymphomas. Results of a phase 3 diagnostic accuracy study. Journal of Clinical Oncology. [Epub ahead of print].

Piccaluga PP, Rossi M, Agostinelli C, et al. (2014) Platelet‐derived growth factor alpha mediates the proliferation of peripheral T‐cell lymphoma cells via an autocrine regulatory pathway. Leukemia. DOI: 10.1038/leu.2014.50 [Epub ahead of print].

Pileri S, Weisenburger DD, Sng I, et al. (2008) Peripheral T‐cell lymphoma, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J and Vardiman JW (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn, pp. 306–308. IARC Press: Lyon.

Pileri SA and Piccaluga PP (2012) New molecular insights into peripheral T cell lymphomas. Journal of Clinical Investigation 122 (10): 3448–3455.

Piva R, Pellegrino E, Agnelli L, et al. (2010) Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large cell lymphoma within peripheral T‐cell neoplasm. Journal of Clinical Oncology 28: 1583–1590.

Sakata‐Yanagimoto M, Enami T, Yoshida K, et al. (2014) Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nature Genetics 46 (2): 171–175.

Swerdlow SH, Campo E, Harris NL, et al. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. Lyon: IARC Press.

Vose J, Armitage J and Weisenburger D (2008) International T‐cell lymphoma Project. International peripheral T‐cell and natural killer/T‐cell lymphoma study: pathology findings and clinical outcomes. Journal of Clinical Oncology 26: 4124–4130.

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Piccaluga, Pier Paolo, Navari, Mohsen, Etebari, Maryam, and Pileri, Stefano A(Dec 2015) Molecular Genetics of Peripheral T‐cell Lymphomas. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025238]