AACR 2017 | Poster 3939/6 – two evolutionary models proposed for development of drug resistance between primary and relapsed Diffuse Large B-Cell Lymphoma

At the American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, on Tuesday 4^th April, a poster session titled “Tumor Evolution and Heterogeneity 2” took place.

One of the posters on display (3939 / 6) was titled “Evolution and drug resistance of primary and relapse tumors in Diffuse Large B-Cell Lymphoma” by Rainer Lehtonen from the University of Helsinki, Helsinki, Finland, and colleagues.

This group carried out integrated multi-omics (whole genome, transcriptome, and methylome) analyses complemented with mathematical modelling of pared primary and relapsed DLBCL tumors. They aimed to provide a comprehensive view of tumor evolution, drug resistance, and disease heterogeneity. In total, 23 fresh frozen and 28 paraffin embedded samples from 24 advanced disease patients with at least one relapse were included.

Key Highlights:

• When comparing patients with time to next event <1yr versus >2yrs, 241 significantly (P < 0.05) differentially expressed genes (DEGs)
• Divergent evolution prominent in GCB whereas subclonal mutations are rare in ABC subtype
• Few genomic differences detected between primary and relapse tumors (P = 0.047, Pearson's Chi-squared test on 7 patients with WGS data); suggests pre-treatment drug resistance is likely caused by global hypo- or hypermethylation at relapse stage
• In GCB subtype, primary and relapse branches largely diverge before diagnosis and subsequently develop independently
• Number of emerging primary or relapse specific clonal and subclonal mutations correlate with PSF and OS
• Contribution of the somatic hypermutation signature was higher in resistant tumors and correlated with time to disease progression
• Identified 72 relapse tumor related genes including many known B-Cell Lymphoma genes such as CD79B, IGLL5, PIM1, SGK1
• Patients with subclonal mutations in these genes had shorter PSF and OS (P = 0122 and 0.0071, respectively)

The group concluded the poster by hypothesizing two evolutionary models, which take into account disease subtype, PFS and OS, treatment response at diagnosis and relapse, and molecular features:

1. GCB: Buildup of mildly advantageous and deleterious mutations in hypermutable genes, associated with hypermutation signature, and not in individual driver mutations. This results in development of relapsed tumors through branching evolution. Divergence of primary and relapse branches thought to occur long before diagnosis and then develop independently
2. ABC: A small number of highly advantageous/deleterious mutations occur early in DLBCL development resulting in higher resistance to treatment at diagnosis. Less acquired mutations are needed for relapsed tumor to develop

Reference:

1. Lehtonen R. et al. Evolution and drug resistance of primary and relapse tumors in diffuse large B-cell lymphoma [Poster]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; 2017. Poster nr [3939 / 6].