Spatial Heterogeneity in Large Resected Diffuse Large B-Cell Lymphoma Bulks Analysed by Massively Parallel Sequencing of Multiple Synchronous Biopsies

Abstract

Diffuse large B-cell lymphoma (DLBCL) usually needs to be treated immediately after diagnosis from a single lymph node biopsy. However, several reports in other malignancies have shown substantial spatial heterogeneity within large tumours. Therefore, we collected multiple synchronous biopsies of twelve patients that had diagnostic or therapeutic resections of large lymphoma masses and performed next-generation sequencing of 213 genes known to be important for lymphoma biology. Due to the high tumour cell content in the biopsies, we were able to detect several mutations which were present with a stable allelic frequency across all the biopsies of each patient. However, ten out of twelve patients had spatially discordant mutations and similar results were found by the analysis of copy number variants. The median Jaccard similarity coefficient, a measure of the similarity of a sample set was 0.77 (range 0.47–1), and some of the involved genes such as CARD11, CD79B, TP53, and PTEN have a known prognostic or therapeutic relevance in DLBCL. This shows that single biopsies underestimate the complexity of the disease and might overlook possible mechanisms of resistance and therapeutic targets. In the future, the broader application of liquid biopsies will have to overcome these obstacles.

CT-based radiomics model with machine learning for predicting primary treatment failure in diffuse large B-cell Lymphoma

“…Beyond inter-individual variability, the coexistence of different clonal population within a single patient's disease is acknowledged in a various number of cancers. Recently, the same spatial diversity was highlighted in DLBCL with frequent mutational disparity between different tumor sites in a same patient, even at initial diagnosis prior to treatment initiation [28] . This phenomenon can explain mixed response in some DLBCL patients where one or more lesions are progressing on treatment while others are responding.…”

Molecular Monitoring of Lymphomas

“…Importantly, lymphomas demonstrate spatial heterogeneity both within primary tumors and across disease sites (17,18). Clonal selection and evolution over time and under therapeutic pressure can result in additional clinically relevant heterogeneity (19).…”