Abstract 5164: Lacking clonal relationship in 20% of relapsing diffuse large B-cell lymphomas

Abstract

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Nearly half of the patients can be cured with standard therapeutic regimens. However, a substantial number of patients experience a recurrence. In general, lymphoma recurrences are considered to represent a relapse of the original neoplasm, but this concept has been recently challenged by demonstration of clonally unrelated relapses by immunoglobulin (heavy chain) gene (IGH) rearrangement analysis. Although being the most widely used method for clonality testing, IGH fragment length analysis has a very limited output of information not giving any insight about tumor heterogeneity and evolution in time. Also, the result is based only on a single gene in the whole genome, and therefore it can be error-prone. We applied a genome-wide clonality testing on 17 paired primary and relapsed DLBCL aiming to provide an unambiguous answer about the existence of clonally unrelated recurrences in this entity. Additionally, we profiled 10 cases of non-relapsing DLBCL searching for genetic markers at diagnosis which could predict lymphoma relapse. Methods: Genomic DNA extracted from formalin-fixed paraffin-embedded tissue with at least 70% tumor content was used for the analysis. Array-comparative genomic hybridization was utilized to detect chromosomal copy number aberrations and to determine clonal relationship status of each primary-relapse pair. This result was then verified by IGH gene fragment length analysis. Directed deep-sequencing was performed on a custom hot-spot panel consisting of most frequently mutated genes in DLBCL. Results: Among 17 cases of recurring DLBCL, 3 relapses (17%) were identified which were clonally unrelated to the primary disease by copy number aberration and IGH fragment length analysis. Different modes of tumor progression could be detected within clonally related set of relapses, providing evidence of a common early progenitor cell population in some patients. Moreover, some DLBCL exhibit substantial intra- and inter- tumoral heterogeneity, which is probably a source of variation in patient outcomes and clonal progression. Comparison of copy number aberration and point mutation profiles between relapsing and non-relapsing tumors yielded significant differences, which could be useful for understanding the genetic basis of DLBCL recurrence. Conclusions: We provide a clear evidence for the existence of clonally unrelated relapses in DLBCL. The existence of clonally unrelated relapses might be of clinical importance since relapses are usually treated more aggressively than primary neoplasms with a significant treatment-related morbidity, and this may be by-passed in the former instances. Moreover, the high definition clonal analyses provide new insights into the molecular profiles of tumors in vivo, and therefore might contribute to the development of more personalized approaches for cancer treatment. Citation Format: Darius Juskevicius, Alexander Rufle, Christian Ruiz, Stephan Dirnhofer, Alexandar Tzankov. Lacking clonal relationship in 20% of relapsing diffuse large B-cell lymphomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5164. doi:10.1158/1538-7445.AM2014-5164