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B. Schuhmacher et al.
lead to insertion of mutations into genomic regions show- ing active transcription and a favorable epigenetic environ- ment.15,29,30 This might also contribute to the more aggres- sive clinical behavior of these entities if a high rate of aber- rant SHM affects further target genes that were not pro- filed here.
According to our data, SOCS1, previously shown to be mutated in NLPHL,12,31 was mutated in both histopatho- logical NLPHL variants and THRLBCL. SOCS1 was not mutated in the typical NLPHL cases of this study, as observed previously.12 This is likely related to the low number of typical NLPHL cases investigated. On the other hand, one may speculate that SOCS1 may act as a potential driver gene indicating disease progression and may thus represent a progression driver. However, the histopathological growth patterns of the NLPHL cases investigated were not considered in the study by Mottok et al.31 Despite the fact that typical NLPHL represents the majority of NLPHL cases, in our experience most frozen NLPHL samples are acquired from histopathological NLPHL variants. One reason for this may be because the patients with histopathological NLPHL variants present with more advanced disease and are more likely to pres- ent in a specialized medical center where frozen tissue can be preserved. A potential role of SOCS1 as a driver towards disease progression is further supported by pre- vious reports, in which SOCS1 missense mutations were found to be related to a more aggressive clinical behavior in a cohort of DLBCL cases treated with CHOP-like regi- mens.32 The prognostic impact of SOCS1 mutations should therefore be investigated in a larger cohort of NLPHL. Moreover, as the ultra-deep targeted sequencing approach used here is not very reliable in the identifica- tion of structural variants, these were not considered here. Given that a high number of SOCS1 aberrations have been reported to be insertions/deletions31,32 we, therefore, likely underestimate the frequency of SOCS1 mutations.
Mutations in the acetyltransferase CREBBP were usually not a result of aberrant SHM. They frequently affected the KIX domain that mediates binding to transcription factors,33 the HAT domain that performs histone acetyl- transferase activity and the C-terminal Q-rich domain,
which is part of a transactivation domain,33 consistent with the functional consequences reported for DLBCL and follicular lymphoma.34 Notably, two mutations in the HAT domain of CREBBP detected in DLBCL (nonsense R1341X and R1360X)34 also occurred at the same residue in a patient with NLPHL variant pattern E (R1341X) and a patient with THRLBCL (R1360P), suggesting that the HAT domain is under inactivating pressure in these GCB-cell derived malignancies. Thus, in addition to aberrant SHM, further transforming events are likely required for the development of NLPHL and THRLBCL.
Since the gene panel applied in the present study was based on genes previously identified in composite lym- phomas of NLPHL and DLBCL, we were not in a position to identify novel genes that are recurrently mutated in THRLBCL but not or only rarely in NLPHL. This is a clear limitation of our study. Thus, genome-wide mutation studies are warranted to comprehensively determine the mutational landscape of THRLBCL. Nevertheless, the fact that the most frequently mutated genes in NLPHL are also recurrently mutated in THRLBCL makes a strong point regarding the close relationship of these malignancies, which had been proposed in earlier studies based on histopathological features, related gene expression pro- files, and similar genomic imbalances.4,8,9 Perhaps de novo THRLBCL could principally represent a transformation from NLPHL, and thus share key mutations that were acquired in the earlier NLPHL lymphomagenesis. Considering the clinical presentation of the patients, one could speculate that typical and histopathological NLPHL variants have a similar relationship to THRLBCL, as is observed in follicular lymphoma grade 1/2 to 3a and trans- formation into DLBCL.
Acknowledgments
The authors would like to thank Ralf Lieberz, Smaro Soworka, Nina Becker, Elena Hartung and the EMBL GeneCore sequenc- ing team and the EMBL IT unit for their excellent technical assis- tance.
Funding
This project was supported by the Deutsche Forschungsgemeinschaft (grant HA6145/1-2 and HA6145/3-1).
References
1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC; 2008.
2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. Revised 4th edition. Lyon: IARC; 2017.
3. Van Loo P, Tousseyn T, Vanhentenrijk V, et al. T-cell/histiocyte-rich large B-cell lymphoma shows transcriptional features suggestive of a tolerogenic host immune response. Haematologica. 2010;95(3):440–448.
5.
6.
7.
Achten R, Verhoef G, Vanuytsel L, De Wolf-Peeters C. Histiocyte-rich, T-cell-rich B-cell lymphoma: a distinct diffuse large B- cell lymphoma subtype showing character- istic morphologic and immunophenotypic features. Histopathology. 2002;40(1):31–45. Braeuninger A, Küppers R, Strickler JG, Wacker HH, Rajewsky K, Hansmann ML. Hodgkin and Reed-Sternberg cells in lym- phocyte predominant Hodgkin disease rep- resent clonal populations of germinal cen- ter-derived tumor B cells. Proc Natl Acad Sci U S A. 1997;94(17):9337–9342. Bräuninger A, Küppers R, Spieker T, et al. Molecular analysis of single B cells from T- cell-rich B-cell lymphoma shows the deri- vation of the tumor cells from mutating germinal center B cells and exemplifies means by which immunoglobulin genes are modified in germinal center B cells. Blood. 1999;93(8):2679–2687.
Brune V, Tiacci E, Pfeil I, et al. Origin and
pathogenesis of nodular lymphocyte-pre- dominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med. 2008;205(10):2251–2268.
9. Hartmann S, Döring C, Vucic E, et al. Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma. Br J Haematol. 2015;169(3):415–422.
10. Fan Z, Natkunam Y, Bair E, Tibshirani R, Warnke RA. Characterization of variant patterns of nodular lymphocyte predomi- nant Hodgkin lymphoma with immunohis- tologic and clinical correlation. Am J Surg Pathol. 2003;27(10):1346–1356.
11. Hartmann S, Eichenauer DA, Plütschow A, et al. The prognostic impact of variant his- tology in nodular lymphocyte-predomi- nant Hodgkin lymphoma: a report from the German Hodgkin Study Group (GHSG). Blood. 2013;122(26):4246–4252; quiz 4292.
4. Hartmann S, Döring C, Jakobus C, et al. Nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte
rich large B cell lymphoma--endpoints of a spectrum of one disease? PloS One. 2013;8(11):e78812. 8.
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