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Cytogenetic correlations among most types of peripheral T-cell lymphoma (PTCL) have not been very informative to date. This study aimed to identify recurrent chromosomal abnormalities in angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large cell lymphoma (ALK-ALCL) and peripheral T-cell lymphoma, unspecified (PTCL-US), and to evaluate their prognostic value. We reviewed the cytogenetic findings of 90 previously-diagnosed cases of PTCL and correlated the cytogenetic findings with the specific histological subtype. The most common abnormalities for AITL were 5q (55%), 21 (41%) and 3q (36%) gains, concurrent trisomies of 5 and 21 (41%), and loss of 6q (23%). In ALK(-) ALCL, gains of 1q (50%) and 3p (30%), and losses of 16pter (50%), 6q13q21 (30%), 15 (30%), 16qter (30%) and 17p13 (30%) were frequent findings. In PTCL-US, frequent gains involved 7q22q31 (33%), 1q (24%), 3p (20%), 5p (20%), and 8q24qter (22%), and losses of 6q22q24 (26%) and 10p13pter (26%). We did not observe any association between specific chromosomal abnormalities and overall survival (OS). However, cases with complex karyotypes, most frequently observed in ALK(-) ALCL and PTCL-US, had a significantly shorter OS. Although, genetic differences were noted in these subtypes, further studies are needed to determine the key pathogenetic events in PTCL.
Compared to the B-cell lymphoma, peripheral T-cell lymphoma (PTCL) is a relatively rare disease in the western hemisphere (Lakkala-Paranko et al, 1987; The Fifth International Workshop on Chromosomes in Leukemia-Lymphoma., 1987; Armitage et al, 2004). PTCLs can be further categorized into angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell (ALCL), and peripheral T-cell lymphoma, unspecified (PTCL-US), as well as a number of rare subtypes (Jaffe et al, 2001). To date, cytogenetic studies have demonstrated complex clonal abnormalities in most cases of PTCL. Although the karyotypes are complex among uncategorized PTCL, frequent rearrangements involving chromosomes 1, 6q, 14q11, 7p, 7q, 9p, and 10p have been reported (Berger et al, 1988; Inwards et al, 1990; Kaneko et al, 1988; Lepretre et al, 2000; Schlegelberger et al, 1994a,b, 1996). Recurrent abnormalities noted among specific subtypes of PTCL include the t(2;5)(p23;q35) and other translocation variants in ALK-positive ALCL (Wellmann et al, 1995; Rosenwald et al, 1999), and trisomies of 3 and 5 in AITL (Schlegelberger et al, 1994b, 1996). Comparative genomic hybridization (CGH) studies analyzing two out of the three main subtypes of PTCL have also been recently reported (Zettl et al, 2004; Thorns et al, 2007). The intent of this study was to determine the overall incidence of the various types of cytogenetic abnormalities in nodal PTCL as a group, and also specifically within its three major histological subtypes. For this study, we focused our efforts on cases of AITL, ALCL which were previously determined to be ALK(-) by either immunostaining or cytogenetic studies, and PTCL-US. We also correlated the chromosome findings with the clinical outcome.
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Peripheral T-cell lymphoma (PTCL) is relatively uncommon, accounting for less than 10% of all non-Hodgkin lymphomas in western countries. Nevertheless, as a group, they are clinically aggressive and have a poor response to therapy compared to high-grade B-cell lymphoma (The Non-Hodgkin’s Lymphoma Classification Project., 1997). PTCLs with a nodal presentation can be divided into three major subtypes including AITL, ALCL, and PTCL-US (Jaffe et al, 2001). Reports of standard cytogenetic findings in PTCL with nodal presentation, though rare and typically consisting of small numbers of patients, have frequently revealed complex chromosomal abnormalities (Schlegelberger et al, 1994c; Lepretre et al, 2000). This was also demonstrated in the current study with the observation that 36/90 cases (40%) had ≥5 structurally aberrant chromosomes. In cases with adequate material, classical cytogenetic characterization was facilitated by M-FISH investigation, allowing us to better characterize 34% of the cases in our series.
The absence of recurrent translocations among the PTCL subtypes has made it difficult to identify their genetic basis. Sole structural abnormalities are of unique cytogenetic significance because they are thought to represent primary changes that are important in the pathogenesis of the disease. Three cases in this report (Table SI: cases 27, 30 and 46) had a balanced translocation as their sole abnormality. One of these structural rearrangements, t(7;14)(q36;q11.2), was present in a case of PTCL-US. T-cell neoplasms frequently exhibit rearrangements of band 14q11.2, TRA@ and TRD@, or less frequently at regions 7q34∼q36 and 7p15, the sites of the TRB@ and TRG@, respectively (Greiner et al, 1995; Jaffe et al, 2001; Armstrong & Look, 2005). Although rearrangements of the T-cell receptor genes are frequently reported in T-cell lymphoma, cytogenetic rearrangements of these regions are uncommon in PTCL-US (Sanger et al, 1986; Lepretre et al, 2000; Leich et al, 2007). Classical cytogenetic and early molecular studies failed to detect a significant number of TR rearrangements; however, more sensitive molecular methodologies such as PCR suggest that TR intragenic rearrangements, in particular TRG@ and TRB@, are present in a majority of cases (Theodorou et al, 1994, 1996). In the current study, a total of six cases (6/90, 6%) contained rearrangements involving 14q11.2, of which, five were observed in PTCL-US. The other sole translocations, t(9;11)(p24;q14) and t(3;22)(p21;q11), neither of which has been described as a recurrent abnormality in lymphoma, were present in ALK(-) ALCL. Translocations involving the PICALM (CALM) gene, a member of the ap-3-like family of clathrin assembly proteins, at 11q14 have been observed in other T-cell neoplasms (Bohlander et al, 2000). Interestingly, the t(3;22) translocation involves band 3p21, the site of the T-cell leukemia translocation-altered gene (TCTA), and band 22q11, the site of the non-muscle myosin heavy chain gene (MYH9), which was recently described as an ALK fusion partner in ALCL (Lamant et al, 2003).
Several recurrent breakpoints were noted in all three PTCL subgroups, including regions previously associated with B- and T-cell lymphoma, such as 1p36, 6q21, 7p15, 11q13, 14q11.2, 14q32, 17p13, 19q13, 22q11.2 and 22q13 (Berger et al, 1988; Inwards et al, 1990; Kaneko et al, 1988; Lepretre et al, 2000; Michaux et al, 1996; Schlegelberger et al, 1994a,b, 1996). Recurrent breakpoints were also observed at 16q22 and 16q24, regions not currently associated with lymphoma. A clustering of breakpoints unique to PTCL-US was found on chromosomes 8p and 12p. Specifically, five cases had breaks at 8p21 and four cases had breaks at 12p13 (Table SI: cases 47, 62, 68, 69, 74, 77, 78, 79 and 90). Various genes localized to band 12p13 have been associated with rearrangements in T-cell malignancies, including ETV6 in PTCL (Yagasaki et al, 2001) and CCND2 with over-expression in T-cell acute lymphoblastic leukemia (ALL) (Karrman et al, 2006). High level amplifications of 12p13 have also been detected by CGH in three PTCL-US cases (Zettl et al, 2004) and a recent study using a cDNA microarray reported a PTCL-US subgroup with a gene expression signature including over-expression of CCND2 (Ballester et al, 2006).
Numerical and structural abnormalities of chromosome 1 are common in a variety of malignant diseases (Olah et al, 1989). Although very limited information is available on the cytogenetic findings of ALK(-) ALCL, in concordance with the findings in our series, a CGH study by Zettl et al (2004) also found the frequent gain of 1q in ALK(-) ALCL. A more recent CGH study by Salaverria et al (in press) found gains of 1q to be the most common alteration in ALK(-) ALCL as well. Frequent gains of 1q have also been observed in adult T-cell leukemia/lymphoma; however, to a lesser extent (Tsukasaki et al, 2001; Oshiro et al, 2006). Gains of 3p were also frequently noted in our cases of ALK(-) ALCL cases (30%). Although gain of chromosome 3 is a recurrent finding in PTCL, it has not been shown to be specifically associated with ALK(-) ALCL (Lepretre et al, 2000).
We observed frequent gains of chromosomes 3, 5, and 21 in AITL. Previously, other classical cytogenetic studies have also reported the gain of chromosomes 3 and 5 in AITL (Schlegelberger et al, 1994b, 1996; Lepretre et al, 2000). Schlegelberger et al (1994c) reported a recurrent dup(5)(q23q31–32) in their series of AITL. In the present study, duplication of 5q31q33–35 was found to be the most frequent minimum duplicated region. Thus, the duplication of 5q31–32 appears to be a distinctive and critical alteration in AITL. A number of growth factor and growth factor receptor genes, such as IL3 (interleukin-3) and PDGFRB (platelet-derived growth factor receptor, beta polypeptide), have been localized to this region (http://AtlasGeneticsOncology.org). A gain of chromosome 21 was observed in 41% of our AITL cases. Although this gain has been reported as a recurrent change in PTCL, it has not been previously associated specifically with AITL (Lepretre et al, 2000). Interestingly, all AITL cases in this series exhibiting a gain of 21 also had a gain of chromosome 5. In contrast, a recent matrix-based CGH study of AITL failed to detect significant gains of chromosomes 3 or 5, but did note recurrent gains of chromosomes 22q, 19, and 11q13 (Thorns et al, 2007). The current study also showed a similar gain of 11q (14% vs. 13%), a slightly higher gain of 19 (27% vs. 15%), and a slightly lower gain for 22q (14% vs. 23%) as compared to the CGH study reported by Thorns et al (2007).
Gains of material on chromosome 7q were found in approximately one-third of our PTCL-US cases and, with the exception of chromosome Y loss, this was the most frequent aberration noted in this subgroup. Chromosome 7 gain is a common finding in several benign and malignant neoplasms, as well as in non-neoplastic lesions and apparently normal tissue (Heim et al, 1989; Bardi et al, 1992; Mitelman et al, 2007). While it has been suggested that this gain may represent a primary and pathogenetically-important abnormality in some solid tumors, it is often regarded as a common secondary change and may be associated with disease progression (Johansson et al, 1993). Although no statistical correlation between 7q gain and clinical outcome was apparent in our series, it was frequently found in complex karyotypes, providing suggestive evidence for a secondary abnormality. In agreement with the current study, gains of 7q have also been reported in PTCL-US with the use of CGH (Zettl et al, 2004). Comparison of the regions of 7q gain in both studies revealed an overlapping minimal region at 7q22q31. However, no specific association with lymphoma has been documented for this region.
Interstitial deletions of 6q are a common finding in non-Hodgkin lymphoma, including PTCL, but thus far no particular region has been associated with a specific histological subtype (Schouten et al, 1990; Yoon & Ko, 2003). The frequent loss of 6q21 in PTCL, as well as other diseases, such as childhood ALL, suggests the presence of a tumor suppressor gene which may contribute to the development of malignancy (Gérard et al, 1997). In this study, the region of genetic loss most common to all three PTCL subgroups clustered at 6q21. However, the region of loss in ALK(-) ALCL most often extended proximally to 6q16, whereas the minimal region for PTCL-US extended distally from 6q22 to 6q24. Our results, in conjunction with previously-reported data, indicate that the loss of 6q in PTCL varies in location from 6q16 to 6q24 and occurs in 20–30% of cases, regardless of the specific subtype (Lepretre et al, 2000; Zettl et al, 2004; Thorns et al, 2007). The lack of a specific locus or correlation with a particular subtype may indicate that the abnormalities of 6q represent a later event in the multistep process of lymphomagenesis.
Another recurrent genetic alteration in our series was loss of the terminal region of the short arm of chromosome 16. Loss of 16p13 was observed in 50% of ALK(-) ALCL but has not been associated with this subgroup in previous reports (Zettl et al, 2004; Salaverria et al, in press). In three of the five ALK(-) ALCL cases, the 16pter loss resulted from unbalanced translocations with various chromosomes. The CREBBP (CREB binding protein) gene is located in 16p13 and is involved in recurrent translocations in acute myeloid leukemia and therapy-related acute myeloid leukemia (Borrow et al, 1996; Sobulo et al, 1997). Other genes within this region that are associated with lymphoma include CIITA, involved in translocations with BCL6 in B-cell lymphoma, and TNFRSF17 (BCM) which has been reported in translocations in T-cell lymphoma of the small intestine (Laabi et al, 1992; Yoshida et al, 1999).
To summarize, ALK(-) ALCL and PTCL-US are both characterized cytogenetically by complex structural abnormalities along with numerical changes, whereas AILT is more frequently characterized by simple gains, such as trisomy 3, 5 and 21. The only cytogenetic change that could be shown to correlate with clinical outcome, regardless of subtype, was the presence of a complex karyotype. Even though the morphological distinction between PTCL-US and ALK(-) ALCL may be controversial and the genetic features similar in many respects, there are also distinct differences between these subgroups. The results of this study confirm that recurring genomic imbalances occur in PTCL with nodal presentation, and that these abnormalities may at times be helpful in the characterization of these disorders and may provide prognostic information.