The clinical and histological features of primary cutaneous anaplastic large-cell lymphoma (C-ALCL) have been well characterized, but little is known about its underlying pathogenetic and genetic alterations. Previous comparative genomic hybridization (CGH) studies focusing on C-ALCL that included a limited number of samples yielded nonhomogeneous results (B et al., 2000; Mao et al., 2003; Prochazkova et al., 2003; Fischer et al., 2004; Zettl et al., 2004). Recently,ralph lauren pas cher, three studies that were based on array CGH (aCGH) and included a small number of C-ALCL patients were published (Mao et al., 2003; Laharanne et al., 2010; van Kester et al., 2010),ralph lauren soldes.
We have investigated the genomic profile of 19 C-ALCL patients using a 60-mer 44K oligonucleotide-array-CGH platform and compared our results with those of previous aCGH studies,polo ralph lauren homme. C-ALCL patients were selected according to the World Health Organization Organization for Research and Treatment for Cancer (EORTC) classification for cutaneous lymphomas (Willemze et al., 2005),ralph lauren. This EORTC multicenter study was conducted in the departments of pathology and dermatology of six European centers in Spain and Switzerland. The local ethics committees approved the study, and written informed consent was obtained from all patients,polo ralph lauren pas cher, in accordance the Declaration of Helsinki Principles. Clinical characteristics are detailed in Supplementary Table S1 online. The study was performed with 20 10 snap-frozen C-ALCL samples to ensure the high quality of the DNA,ralph lauren pas cher. Hematoxylin staining of a frozen section of each sample was performed tumor cell infiltration of at least 70 DNA was isolated using a commercial kit as described in manufacturer’s instructions (Dneasy Blood and Tissue Kit; Qiagen,polo ralph lauren, Hilden,polo ralph lauren pas cher, Germany). Data analysis was conducted as previously described (Salgado et al., 2010). 68.4 Mao et al. (2003) and van Kester et al,ralph lauren pas cher. (2010) found gains more frequently than losses, whereas Laharanne et al,ralph lauren 2013. (2010) detected losses more frequently. The highest frequencies of chromosomal aberrations were 60 (Mao et al., 2003) and 45 (Laharanne et al., 2010; van Kester et al., 2010), in contrast to 36.8 in our present study. Regarding the smallest overlapping regions of imbalance, 15 corresponded to losses and 9 to gains. The results are summarized in Figure 1 and detailed in Supplementary Table S2 online. The specific chromosomal regions and candidate genes mapped in these regions are detailed in Table 1,polo ralph lauren. The most frequent abnormalities observed were deletions located on 16q, 13q, 17p13, and 20q13,polo ralph lauren pas cher. Genomic losses of 13q34 (ING1) and 16q22.11 (CTCF) detected by aCGH were confirmed by fluorescence in situ hybridization in three patients. No significant correlation between the observed clinical features and the presence of chromosomal aberrations could be demonstrated. (2010) and Laharanne et al. (2010), two regions were lost in our study,ralph lauren soldes, at 13q33.3 and 16p11.2,ralph lauren pas cher. These regions were not detected in the first aCGH study (Mao et al,polo ralph lauren pas cher., 2003), probably because they may not have been among the 57 oncogenic regions of the AmpliOnc platform,polo ralph lauren pas cher. Similar to the findings of van Kester et al. (2010), we observed losses at 3p26.3, 6q21, 8p22, 13q12.11, 13q13.1, 16p11.2-16q11.2, 17p13.1,polo ralph lauren, and 17p13.3 (Supplementary Table S3 online). The main concordance between our results and those of van Kester et al. (2010) was a deletion at 16q11.2. However, differences were observed for a higher frequency of 16q losses in our series, including seven genomic regions located between 16q11.2 and 16q24.3. The most remarkable difference was the higher frequency of 7q gains reported by van Kester et al. (2010). These discrepancies could be due to the small number of C-ALCL cases analyzed heretofore,pull ralph lauren. The most interesting regions of loss were those affecting CTCF (16q22.1), ANKRD11 (16q24.3), ING1 (13q33.3), and TP53 (17p13.1), all of which are involved in the TP53 signaling pathway. Interestingly, 17p13.1 deletion was observed in four patients. Two of them presented recurrences and lymph node involvement. In one of these patients, we could confirm the TP53 deletion by fluorescence in situ hybridization, and we also detected a TP53 mutation both in the diagnostic sample and in the recurrence lesion (data not shown). Moreover, 10 of 19 (53 patients displayed one or more defects affecting this pathway, which we consider important in the pathogenesis of C-ALCL.
In conclusion, taking into account the results of these aCGH studies, we conclude that chromosomal imbalances detected in C-ALCL are heterogeneous and that no characteristic pattern of chromosomal aberrations has yet been identified.
Although a high percentage of C-ALCL patients showed genetic abnormalities, most of them presented a small number of alterations (median 4, range 0 and these were highly heterogeneous between patients and without a clear recurrent pattern, unlike other cutaneous T-cell lymphomas. Differences in sample selection criteria and technical approaches among studies (Mao et al., 2003; Laharanne et al., 2010; van Kester et al., 2010; our present study) may explain in part these inconsistent results. In addition, the possibility that C-ALCL represents a heterogeneous group of disorders from the genetic point of view cannot be completely ruled out. Moreover, other altered genetic mechanisms as gene mutations, methylation, aberrant miRNA expression, or the presence of acquired uniparental disomy do not implicate gains or losses of DNA could be involved in the pathogenesis of C-ALCL. (2000) Allelic deletion at 9p21-22 in primary cutaneous CD30( large cell lymphoma. J Invest Dermatol 115:1104 | Article | PubMed | ISI | ChemPort |Fischer TC, Gellrich S, Muche JM et al. (2004) Genomic aberrations and survival in cutaneous T cell lymphomas. J Invest Dermatol 122:579 | Article | PubMed | ISI | ChemPort |Laharanne E, Oumouhou N, Bonnet F et al. (2010) Genome-wide analysis of cutaneous T-cell lymphomas identifies three clinically relevant classes. J Invest Dermatol 130:1707 | Article | PubMedMao X, Orchard G, Lillington DM et al. (2003) Genetic alterations in primary cutaneous CD30 anaplastic large cell lymphoma. Genes Chromosomes Cancer 37:176 | Article | PubMed | ISI | ChemPort |Prochazkova M, Chevret E, Beylot-Barry M et al. (2003) Chromosomal imbalances: a hallmark of tumour relapse in primary cutaneous CD30 T-cell lymphoma. J Pathol 201:421 | Article | PubMed | ChemPort |Salgado R, Servitje O, Gallardo F et al. (2010) Oligonucleotide array-CGH identifies genomic subgroups and prognostic markers for tumor stage mycosis fungoides. J Invest Dermatol 130:1126 | Article | PubMedvan Kester MS, Tensen CP, Vermeer MH et al. (2010) Cutaneous anaplastic large cell lymphoma and peripheral T-cell lymphoma NOS show distinct chromosomal alterations and differential expression of chemokine receptors and apoptosis regulators. J Invest Dermatol 130:563 | Article | PubMed | ChemPort |Willemze R, Jaffe ES, Burg G et al. (2005) WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768 | Article | PubMed | ISI | ChemPort |Zettl A, R T, Konrad M-A et al. (2004) Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large-T-cell lymphoma delineates novel recurrent chromosomal alterations. Am J Pathol 164:1837 | PubMed | ISI | ChemPort |
Top of pageAcknowledgmentsWe thank Xarxa Tem de Bancs de Tumors de Catalunya for its permanent support and Erika Torres, Ma Jesus Artiga, and Esther Villalba from the tissue bank of IMIM-Parc de Salut Mar, CNIO, and Hospital Universitari de Bellvitge, respectively, for their excellent technical work.
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