Robinson, Dennis P.

Abstract Background: The impact of a prior history of non-hematologic malignancy (NHM) on clinical outcomes among individuals with newly diagnosed chronic lymphocytic leukemia (CLL) or monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, is not well known. Methods: In this prospective study, we identified individuals with CLL/MBL who were seen in the Division of Hematology at the Mayo Clinic, Rochester. Participants provided consent within nine months of diagnosis, had no prior history of hematological malignancy, and completed a self-reported risk-factor questionnaire, including a prior history of NHM. Time to first treatment (TTFT) was defined as the time between the date of diagnosis and the earliest date of the first CLL treatment, death, or the last known treatment-free follow-up date. Overall survival (OS) was defined as the time from diagnosis to death or the last follow-up. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between a prior history of a NHM with OS and TTFT. We adjusted for sex and the CLL International Prognostic Index (CLL-IPI), a score comprised of five key CLL prognostic factors, including age and Rai stage. Results: Among the 1,090 CLL/MBL individuals, 833 (76%) had CLL. The median age at diagnosis was 64 years (range 24-89), with 65% being men, and 230 (21%) reported a prior history of NHM. The most common tumor was non-melanoma skin cancer (NMSC, 8.9%, 96 individuals), followed by prostate, testicular, and penile tumors (7.3%, 51 individuals), and melanoma (1.9%, 20 individuals). CLL/MBL patients with a prior history of a NHM were more likely to be over 65 years old (29%) than under 65 years old (14%, p < 0.0001). After a median follow-up of 2.9 years (range 0-21), 470 CLL/MBL patients progressed, requiring CLL treatment. CLL/MBL individuals with a prior history of NHM had a longer TTFT compared to those without (HR=0.69; 95% CI: 0.53-0.90; p=0.006). Individuals with a prior history of NHM who had either intermediate or high-very high CLL-IPI score had significantly longer TTFT (HR= 0.55; 95% CI: 0.33-0.92; p=0.02, and HR=0.65; 95% CI: 0.43-0.97; p=0.03, respectively) compared to those without NHM. After a median follow-up of 8.6 years (range 0-21), 359 individuals died. CLL/MBL patients with a prior history of NHM also experienced reduced OS compared to those without (HR=1.46; 95% CI: 1.08-1.97, p=0.013), particularly among those with low (HR=1.70; 95% CI: 0.96-3.00, p=0.07) or intermediate-risk (HR=2.08; 95% CI: 1.24-3.51, p=0.006), according to CLL-IPI. After excluding NMSC, results remained constant. Conclusions: At the time of diagnosis, one out of five CLL/MBL individuals had a prior history of a NHM. These individuals had a longer time to first CLL directed treatment and reduced OS, even after accounting for other important CLL prognostic factors, which deserves additional studies. Citation Format: Bryan A. Vallejo, Cristine Allmer, Kari G. Rabe, Dennis P. Robinson, Yucai Wang, Paul J. Hampel, Esteban D. Braggio, Neil E. Kay, James R. Cerhan, Sameer A. Parikh, Susan L. Slager. The impact of prior history of non-hematologic malignancies on time to first treatment and overall survival among individuals with CLL or MBL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7450.

Abstract Chronic Lymphocytic Leukemia (CLL) exhibits a substantial familial risk that extends beyond CLL to other B-cell lymphomas (including follicular lymphoma and diffuse large B-cell lymphoma). Monoclonal B-cell Lymphocytosis (MBL), a precursor to CLL, is also associated with a significant risk for hematologic malignancies overall and for lymphoid malignancies, specifically. Moreover, previous research has shown an association between the CLL polygenic risk score (CLL-PRS) and common lymphoma subtypes. This study aims to further evaluate CLL-PRS associations with hematological cancer overall and by lineage while also considering MBL status a strong risk factor for lymphoid malignancies. Utilizing the Mayo Clinic Biobank, we selected individuals aged 40 years or older, residing in proximal counties, who had no prior hematologic malignancies, and with available biospecimens. MBL screening was done using 8-color flow cytometry, and MBL with CLL (CD5+/CD20dim) or atypical CLL (CD5+/CD20+) immunophenotype were included. CLL-PRS was calculated from 41 known susceptibility variants, with weights being the log of the odds ratios from the largest CLL genome-wide association study. Incident hematologic malignancies were ascertained through ICD codes and confirmed via medical record review. Hazard ratios (HR) and 95% confidence intervals (CIs) for associations with hematologic malignancies were estimated through Cox regression. Of 7,332 participants, 1,150 (16%) screened positive for MBL; median age was 67 years (range 40-101), and 37% male. Median follow-up was 2.9 years (range 0-13), and 56 hematologic cancers were identified. After adjusting for age and sex, the CLL-PRS was associated with increased risk of developing hematologic (HR=1.49, 95%CI=1.12-1.98, P=0.006) which was all attributable to lymphoid cancers (HR=1.79, 95%CI=1.26-2.56, P=0.001). When adjusting for baseline MBL status in the models, the CLL-PRS associations remained significant but were attenuated for hematological (HR=1.33, 95%CI=0.99-1.79, P=0.058) and lymphoid (HR=1.56, 95%CI=1.07-2.26, P=0.020) malignancies, while MBL status was also significantly associated with risk of hematologic (HR=2.76, 95%CI=1.55-4.91, P=0.001) and lymphoid (HR=3.61, 95%CI=1.78-3.32, P<0.001) malignancies. In this prospective cohort study of individuals screened for MBL, CLL-PRS was associated with an elevated risk of hematologic malignancies overall and within the lymphoid lineage, underscoring a shared genetic etiology across many B-cell lymphomas. However, the associations between CLL-PRS and hematologic malignancies were attenuated when accounting for MBL status or when analyzing among MBL-positive individuals, highlighting the role of MBL status in these associations. Further research with expanded cohorts is needed to unravel these complex genetic and clinical interactions. Citation Format: Raphael Mwangi, Dennis P. Robinson, Sara J. Achenbach, Geffen Kleinstern, Aaron D. Norman, Kari G. Rabe, Janet E. Olson, Neil E. Kay, Rosalie Griffin, Nicholas J. Boddicker, Esteban Braggio, Sameer A. Parikh, Curtis A. Hanson, Celine M. Vachon, James R. Cerhan, Tait D. Shanafelt, Susan L. Slager. Genetic associations with hematologic malignancies: An evaluation of CLL polygenic risk score and MBL status in the Mayo Clinic Biobank Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6152.

Background: Monoclonal B-cell lymphocytosis (MBL) is a precursor condition to chronic lymphocytic leukemia (CLL) characterized by the presence of circulating monoclonal B-cell populations in the peripheral blood of otherwise healthy individuals. MBL increases risk of several adverse clinical outcomes, including development of hematological malignancies. Mosaic chromosomal alterations (mCAs) are a form of clonal hematopoiesis which affect large segments of DNA and include gains, losses, and copy number neutral loss of heterozygosity events. mCAs can be detected from SNP-array genotyping. Prior work has suggested mCAs as a potent risk factor for hematological malignancies. However, the nature of the relationship between mCAs and MBL is unknown. We sought to determine 1) the association between mCAs and MBL and 2) their combined effect on risk of hematological malignancies, in a large, prospectively collected, and well-annotated cohort of individuals with known MBL, mCA, and clinical outcomes. Methods: We examined the prevalence of mCA in a cohort of individuals from the Mayo Clinic Biobank who were screened for MBL using a sensitive eight-color flow cytometry assay. We classified MBL by the size of the clone relative to total B-cells, with high count (HC) defined as those individuals who had a percent clonal B-cell count ≥85% out of total B-cell count and low-count (LC) otherwise. Autosomal mCAs were detected from whole blood DNA collected at the time of MBL screening using a SNP-array-based assay. The MoChA pipeline was used to identify mCA events. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). To examine incident hematological cancers, we identified and validated all hematological cancers through medical record abstraction using the International Statistical Classification of Diseases codes. Cox regression was used to calculate hazard ratios (HR) and 95% CIs, stratified by MBL status or autosomal mCA status. All models were adjusted for age and sex. Results: We evaluated the prevalence of autosomal mCA in 3,764 individuals (792 individuals with MBL of whom 64 had HC-MBL and 2,972 without MBL). The prevalence of autosomal mCA was 7.7% ( n=288) with a median mCA cell fraction of 0.09 (range 0.01-1). Among those with and without MBL overall, the prevalence of mCA was 15.5% ( n=123) and 5.6% ( n=165), respectively (Figure 1). Compared to those without an autosomal mCA, individuals with an autosomal mCA were 2.4-fold more likely to have MBL (95% CI 1.9-3.2; P =2.0x10 -11; Figure 1). CLL-associated mCA (i.e., those commonly altered in CLL including trisomy 12 and deletion of 6q, 11q, 13q, and 17p) were present in 42 individuals, of whom 38 (90.5%) had MBL overall and 30 (71.4%) individuals had HC-MBL. Compared to those without a CLL-associated mCA, individuals with a CLL-associated mCA were 539.39-fold more likely to have HC-MBL (95% CI 190.3-1975.9; P <2.0x10 -16) and 6.7-fold more likely to have LC-MBL (95% CI 2.0-26.5; P =0.0031; Figure 1). Next, we evaluated the relationship between MBL and mCA with risk of developing a hematologic malignancy in 3,009 individuals with follow-up data (median 10 years). Forty-one individuals developed an incident hematological malignancy (68.3% lymphoid). When we evaluated the effect of autosomal mCA stratified by MBL status we observed elevated but non-significant risk of hematological malignancies (Figure 2). When we evaluated the effect of MBL stratified by autosomal mCA status we observed elevated and significant increased risk of developing a hematological malignancy (Figure 2). Conclusions: We found that the presence of an autosomal mCA is highly associated with having MBL. In particular, >90% of CLL-associated mCA carriers had MBL with ~7- and ~540-fold increased association for LC- and HC-MBL, respectively. These results suggest that almost all individuals in large biobanks with CLL-associated mCAs have undiagnosed MBL. However, not all individuals with MBL have an mCA. When evaluating risk of hematological malignancies, we found autosomal mCAs had >2-fold elevated but non-significant effects when stratified by MBL status while MBL remained a significant risk factor regardless of autosomal mCA status. Collectively these results support that MBL remains an important risk factor and suggests that mCAs hold potential to identify a subgroup of individuals at greater risk of developing a hematological malignancy.

Introduction Lymphoid malignancy (LM) is a heterogenous neoplasm with respect to biology, aggressiveness, and treatment with over 100 subtypes, including Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Genome-wide association studies have identified common variants associated with risk of specific LM subtypes, but less is known about the contribution of rare inherited pathogenic variants (PV) in the genetic architecture of LM risk. Rare PV have been shown to contribute to the genetic architecture of solid tumor cancer risk, many of which have been found in genes that are important to the DNA-damage repair (DDR) pathway (e.g., BRCA1, BRCA1, ATM). Here, we investigated the prevalence of PV in cancer predisposition genes regularly included on multi-gene panel testing based on NCCN guidelines and correlated with risk of LM overall and by common subtypes. Methods In this association study, cases were newly diagnosed lymphomas (excluding chronic lymphocytic leukemia) from Mayo Clinic who were enrolled between 2002 and 2015 in the Lymphoma SPORE Molecular Epidemiology Resource (MER) and MM from Mayo Clinic enrolled primarily between 1998 and 2022 in a clinical registry. Controls were from the Mayo Clinic Biobank who were enrolled between 2009 and 2016, from which we excluded individuals with a history of hematologic malignancy. All participants provided a blood sample for whole exome sequencing, performed by Regeneron on an Illumina NovaSeq panel (mean coverage of 48X). Variants were called using GATK v4 and variant annotation was performed using BioR. All loss-of-function variants (i.e., nonsense, frameshift, and consensus splice sites) and pathogenic missense in 19 cancer predisposition genes with a minor allele frequency < 0.5% were included in the analyses. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for the association between mutation status by gene (burden test) and risk of LM overall, and by subtype that had more than 5 mutation carriers. All analyses were adjusted for age (at diagnosis for cases and at enrollment for controls) and sex. Results A total of 6990 cases and 42432 controls were included. Median age was 63 years for both cases and controls (case range 18-94 years, control range 18-99 years). Males accounted for 58.5% (n=4090) of the cases and 41.7% (n=17762) of the controls. MM accounted for 31% (n=2138) of the cases, followed by diffuse large B-cell lymphoma (DLBCL, n=1146) and follicular lymphoma (FL, n=1132) each accounting for 16% of cases. CHEK2 (1.0%), ATM (0.4%), BRCA2 (0.4%), and BRCA1 (0.3%) had the most PV carriers in controls; these frequencies are in the range of published control populations. A total of 1816 (3.7%) individuals had a PV across the 19 genes, with 4.7% of cases and 3.5% of controls carrying any PV (OR=1.34, 95% CI: 1.18-1.51). ATM (OR=1.86, 95% CI: 1.36-2.49), CHEK2 (OR=1.74, 95% CI: 1.42-2.13) and TP53 (OR=9.07, 95% CI: 4.51-18.87) were all significantly associated with increased risk of LM overall (Figure 1). When investigating subtypes (Table 1), CHEK2 (OR=1.93, 95% CI: 1.23-2.89) and TP53(OR=10.97, 95% CI: 3.06-31.43) were significantly associated with DLBCL. ATM (OR=2.22, 95% CI: 1.13-3.90) was significantly associated with FL. ATM (OR=1.97, 95% CI: 1.16-3.12), CHEK2 (OR=1.75, 95% CI: 1.24-2.41) and TP53 (OR=7.67, 95% CI: 2.43-20.72) were significantly associated with MM and ATM (OR=8.62, 95% CI: 4.47-15.12), NBN (OR=6.94, 95% CI: 2.41-15.76) and TP53 (OR=38.30, 95% CI: 10.27-116.69) were significantly associated with mantle cell lymphoma (MCL). When subset to LM cases overall, there was no evidence of enrichment for young onset (age <60 years), male sex, or family history of hematologic malignancy between PV carriers and non-PV carriers. However, FL cases with an ATM PV tended to be less than 60 years (OR=3.21, P=0.09) compared to non- ATM PV carriers. Similarly, MM cases with a TP53 PV tended to be less than 60 years of age (OR=7.39, P=0.07) compared non-carriers. Discussion In this large case-control study, PV in established cancer predisposition genes were associated with increased risk of LM overall, demonstrating that rare inherited variants may play an important etiologic role. This study also suggests that PV in cancer predisposition genes may be subtype specific. These results will help inform LM risk for individuals who undergo genetic testing of cancer predisposition genes.

Abstract Lymphoma is the sixth most commonly diagnosed cancer in the US. Genome-wide association studies have identified common variants associated with risk of specific lymphoma subtypes, but less is known about the contribution of rare inherited variants in the genetic architecture of lymphoma risk. CHEK2 is important to DNA repair and 2 small studies have found evidence of an association between CHEK2 variants and risk of lymphoma. Here, we investigated loss of function (LoF) variants in CHEK2 with risk of lymphoma (overall and subtypes). The study population included newly diagnosed lymphoma cases from Mayo who were enrolled in the Lymphoma SPORE Molecular Epidemiology Resource (MER). Controls were from the Mayo Clinic Biobank, from which we excluded a prior hematologic malignancy. Whole exome sequencing was performed by Regeneron on an Illumina NovaSeq panel (mean coverage of 48X). Variants were called using GATK v4 and variant annotation was performed using BioR. All LoF variants (nonsense, frameshift and consensus splice sites) in CHEK2 with a minor allele frequency < 0.5% were included in the analyses. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for the association between CHEK2mutation status and risk of lymphoma overall, and by lymphoma subtypes that had more than 5 mutation carriers, which included diffuse large B-cell (DLBCL), follicular (FL), and T-cell lymphoma (TCL). All analyses were adjusted for age (at diagnosis for cases and at enrollment for controls) and sex. A total of 4,852 lymphoma cases and 49,724 controls were included in this analysis. Median age for both cases and controls was 62 years (range 18-99 years). Males accounted for 57.5% (n=2,789) of the cases and 40.6% (n=20,186) of the controls. The DLBCL (23.6% of cases) and FL (23.3% of cases) subtypes were the most common; 7.6% of cases had TCL. A total of 407 (0.7%) individuals had a LoF variant. The frequency of LoF variants was 1.2% in lymphoma cases and 0.7% in controls. LoF variants were associated with increased risk of lymphoma overall (OR=1.77; 95%CI: 1.32-2.33), DLBCL (OR=2.07; 95%CI: 1.20-3.13), and TCL (OR=2.78; 95%CI: 1.178-5.50), but not FL (OR=1.31; 95%CI: 0.65-2.34). CHEK2 c.1100delC was the most frequently mutated variant in this population, accounting for 76% of all LoF variants. Individuals with a c.1100delC variant had an increased risk of lymphoma overall (OR=1.90; 95%CI: 1.37-2.58), DLBCL (OR=2.06; 95%CI: 1.09-3.54), and TCL (OR=3.17; 95%CI:1.24-6.58), but not FL (OR=1.05; 95%CI: 0.41-2.15). When restricted to cases, there was no significant difference in age at diagnosis (P=0.62) or sex (P=0.53) between LoF variant carriers and non-carriers. In this large lymphoma case-control study, CHEK2 LoF variants were associated with increased risk of lymphoma, demonstrating that rare inherited variants may play an important role in the etiology of lymphoma. Additional work is needed to investigate missense variants in CHEK2 and risk of lymphoma. Citation Format: Nicholas J. Boddicker, Raphael Mwangi, Dennis P. Robinson, Allison C. Rosenthal, Thomas M. Habermann, Andrew L. Feldman, Lisa M. Rimsza, Rebecca L. King, Melissa C. Larson, Brianna J. Gysbers, Stephen M. Ansell, Jithma P. Abeykoon, Grzegorz S. Nowakowski, Thomas E. Witzig, Anne J. Novak, Susan L. Slager, James R. Cerhan. Germline CHEK2 variants and risk of lymphoma. [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 5233.

Abstract Low count (LC) MBL is characterized by a circulating population of clonal B-cells and is a precursor state to CLL. Most individuals with LC MBL do not progress to CLL and never come to clinical attention. An active area of research is to identify factors that distinguish those individuals with MBL who progress from those who do not. Currently, 41 single nucleotide polymorphisms (SNPs) are known to be associated with CLL risk, and a portion of these SNPs have also been found to be associated with MBL risk. We hypothesize that these CLL-susceptibility SNPs associated with both MBL and CLL risk are SNPs associated with developing a B-cell clone; whereas the remaining SNPs found not to be associated with MBL risk are associated with progression of the B-cell clone (i.e., progression from MBL to CLL). To test this hypothesis, we evaluated the association of these 41 SNPs with risk of progression to CLL using a case-control study of 1,911 CLL cases and 1,579 individuals with MBL from Mayo Clinic. Individuals with MBL were identified through screening using 8-color flow cytometry assay. Individuals with LC MBL (defined by having a clonal B-cell population with the percent clonal B-cells out of total B-cell count <85%) who had an immunophenotype consistent with CLL were included as controls. CLL cases were obtained through the Mayo Clinic hematology practice. DNA was genotyped from whole blood. We analyzed the 41 CLL susceptibility SNPs with risk of progression to CLL using logistic regression and estimated odds ratio (OR) and 95% confidence interval (CI), adjusting for sex and age. We evaluated the CLL polygenic risk score (CLL-PRS), comprised of a weighted average of the 41 SNPs, with risk of CLL. Out of the 41 established CLL susceptibility SNPs, 15 were associated with CLL progression from MBL to CLL (all P<0.05). Nine of these 15 significant SNPs were not previously found to be associated with risk of MBL. The most significant SNPs were rs9880772 (OR=1.23, CI: 1.11-1.36, P=6.1 × 10−5), rs888096 (OR=1.25, CI: 1.12-1.38, P=3.0 × 10−5), and rs305065 (OR=1.28, CI: 1.14-1.43, P=1.5 × 10−5). One SNP (rs77551289) had a suggestive association (OR=1.21, P=0.069). The remaining 25 SNPs had no evidence of association with progression (ORs ranging between 0.9-1.1 and all P>0.1). The CLL-PRS was also associated with CLL risk (continuous OR = 1.25, CI: 1.15 - 1.35, P = 6.7 × 10−8). In our study accounting for the presence of B-cell clonal population, we identified 15 out of 41 CLL-susceptibility SNPs to be significantly associated with progression from LC MBL to CLL. The remaining 25 non-significant CLL-SNPs were not associated with progression and may instead be associated with development or initiation of the B-cell clone. These findings suggest that the established CLL susceptibility SNPs may play differing role (i.e., development or progression of the clone) in the etiology of CLL. Citation Format: Raphael Mwangi, Geffen Kleinstern, Sara J. Achenbach, Dennis Robinson, Aaron D. Norman, Kari G. Rabe, Janet E. Olson, Neil E. Kay, Rosalie G. Waller, Nicholas J. Boddicker, James R. Cerhan, Esteban Braggio, Sameer A. Parikh, Curtis A. Hanson, Celine M. Vachon, Tait Shanafelt, Susan L. Slager. Genetic variants associated with progression from monoclonal B-cell lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL). [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 5222.

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.

AbstractNon‐Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case‐control studies to examine the association between moderate‐to‐vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B‐cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T‐cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study‐specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case‐control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.

Abstract Background: DLBCL is the most common non-Hodgkin lymphoma subtype in western countries and is clinically heterogeneous. Gene expression profiling has identified two major biologically distinctive DLBCL subtypes defined by their cell-of-origin (COO): germinal center B-cell (GCB) - characterized by BCL2 rearrangement and C-REL amplification, and activated B-cell (ABC) - characterized by constitutive activation of the NF-kB pathway. We evaluated putative DLBCL risk factors for etiologic heterogeneity as defined by COO. Methods: We used a clinic-based study of newly diagnosed NHL cases and frequency matched controls, enrolled from 2002-2014, with a total of 687 DLBCL cases and 2253 controls for this analysis. Using formalin-fixed, paraffin-embedded tumor tissue, we determined COO by either digital expression profiling (NanoString; classified as GCB, ABC, undetermined) or clinically using the Hans algorithm (immunohistochemical markers; classified as GCB, non-GCB, undetermined). Integrating these two sources of COO data, there were 271 GCB, 170 non-GCB, and 246 undetermined/missing (mainly due to lack of tissue) cases. Risk factor data were collected from self-administered questionnaires and included family history of hematologic malignancy; history of atopy, allergy, asthma, eczema, or autoimmune disease; blood transfusion; vaccination history; regular low-dose aspirin use; body mass index (BMI) 2 years prior diagnosis/enrollment; smoking history; alcohol consumption (never/current/former); leisure-time physical activity; and recreational sun exposure. Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for COO subtypes, adjusted for age, sex and residence. Results: The median age of cases was 64 years with 55% male; the median age of controls was 64 years and 53% male. The association with BMI (30+ vs. 18.5-24.9 kg/m2) was stronger for non-GCB (OR=2.21; 1.40-3.49) than for GCB (OR=1.70; 1.21-2.40) DLBCL (P-heterogeneity 0.02), while a family history of hematologic malignancy was associated with non-GCB (OR=2.27; 1.47-3.50) but not GCB (OR=1.30; 0.86-1.96) DLBCL, although the P-heterogeneity was not significant (P=0.13). For GCB, there was an inverse association with former (vs. never) alcohol use for GCB (OR=0.57; 0.39-0.83) but not for non-GCB (OR=0.98; 0.61-1.57) DLBCL (P-heterogeneity 0.007), and an inverse association with regular use of low-dose aspirin for GCB (OR=0.64; 0.47-0.87) but not for non-GCB (OR=0.88; 0.61-1.25) DLBCL (P-heterogeneity 0.05). No other risk factors evaluated showed important heterogeneity by COO. Conclusions: These initial results suggest most DLBCL risk factors do not show etiologic heterogeneity by DLBCL COO, although associations with BMI and family history with non-GCB DLBCL and alcohol and low-dose aspirin use with GCB DLBCL warrant follow-up. Citation Format: Geffen Kleinstern, Dennis P. Robinson, Lisa M. Rimsza, Melissa C. Larson, Rebecca L. King, Grzegorz S. Nowakowski, Carrie A. Thompson, Stephen M. Ansell, Matthew J. Maurer, Andrew L. Feldman, Susan L. Slager, Anne J. Novak, Thomas M. Habermann, James R. Cerhan. Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 741.