Citations

Abstract Diffuse large B-cell lymphoma (DLBCL) is clinically and biologically heterogenous. Based on gene expression profiling of the tumor, DLBCL is classified into two major molecular subtypes linked to cell-of-origin (COO): germinal center (GCB) and activated B-Cell (ABC). The GCB subtype is characterized by a high prevalence of somatic mutations, particularly in apoptosis genes (e.g., BCL2) which is characteristic of follicular lymphoma (FL, another GCB lymphoma). The development of the validated NanoString gene expression test as well as immunohistochemistry markers that work in formalin-fixed, paraffin-embedded tissue allows for the classification of DLBCL by COO in epidemiological studies. We hypothesized that integration of COO with germline genetics could provide insight into the underlying biology driving this heterogeneity, as well as insight into putative function of germline risk variants. Prior genome wide association studies (GWAS) have identified 7 SNPs in 6 susceptibility loci for DLBCL, including: 2p23.3 (rs79480871 NCOA1), 3q13.33 (rs9831894 CD86), 3p24.1 (rs6773363 EOMES), 6p21.33 (rs2523607 HLA-B), 6p25.3 (rs116446171 EXOC2), and 8q24.21 (rs13255292 and rs4733601 PVT1 and MYC). Two of these loci were also identified in FL GWAS (different lead SNPs): 6p21.33 (rs3130437) and 8q24.21 (rs13254990 PVT1). Additional published FL susceptibility loci include: 3q28 (rs6444305 LPP), 6p21.32 (rs9268839), 11q23.3 (rs4938573 CXCR5), 11q24.3 (rs4937362 ETS1), and 18q21.33 (rs17749561 BCL2). Here we evaluated whether the published DLBCL/FL loci differ by COO molecular subtypes. We evaluated each of the 14 DLBCL/FL SNPs by case-case (GCB vs. nonGCB DLBCL) and polytomous case-control (GCB, nonGCB, and FL vs. controls) analyses. DLBCL cases were classified into GCB vs. nonGCB based on best available data from NanoString, RNAseq, followed by the Hans algorithm. A total of 778 DLBCL cases (470 GCB and 308 nonGCB), 1,050 FL cases, and 1,383 controls were analyzed. Odds ratios (OR) based on ordinal encoding of each SNP and 95% CI were calculated for each of the comparison groups. The ORs for four GWAS SNPs were significantly elevated in GCB vs. nonGCB DLBCL as well as in FL; two were FL GWAS SNPs from the HLA region (6p21.32 and 6p21.33) and the other two (BCL2 and ETS1) are important in the germinal center program. In contrast, one SNP (EXOC2) was significantly elevated in nonGCB-DLBCL and was not associated with GCB-DLBCL or FL; this SNP is also near IRF4 (MUM1), a gene important in the ABC program. For the remaining SNPs, there were suggestive associations for GCB-DLBCL and FL versus nonGCB DLBCL (CD86, CXCR5); nonGCB-DLBCL vs. GCB-DLBCL and FL (NCOA1, PVT1); and associations that showed no pattern with COO (EOMES, LPP, HLA-B and MYC). These findings provide insight into the shared pathogenesis of FL and GCB-DLBCL to inform etiologic mechanisms and risk assessment. Citation Format: Rosalie Griffin Waller, Dennis P. Robinson, Anne J. Novak, Lisa M. Rimsza, Kerstin Wenzl, Rebecca L. King, Andrew L. Feldman, Matthew J. Maurer, Grzegorz S. Nowakowski, Brian K. Link, Thomas M. Habermann, Susan L. Slager, James R. Cerhan. Etiologic heterogeneity of genetic risk for DLBCL cell-of origin molecular subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1181.

Abstract The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p<0.0001) and overall survival (7.8 years vs. 11.8 years, p<0.0001) were significantly inferior in the short DTI group than the long DTI cohort and remained significant for progression-free survival and overall survival in multivariable analysis. We show that the DTI is an important prognostic factor in patients newly diagnosed with MCL and is strongly associated with adverse clinical factors and poor outcomes. DTI should be reported in all the patients newly diagnosed with MCL who are enrolling in clinical trials and steps must be taken to ensure selection bias is avoided.