Citations

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.

e24089 Background: Little is known about risk and protective factors for dementia in cancer survivors. With increasing longevity due to improved cancer therapy, it’s prudent to study factors contributing to cognitive impairment in this patient population. Methods: We performed multivariable cox regression analyses to assess established risk factors for all-cause dementia (age, education, APOE4-status, social and physical activity engagement) in breast and prostate cancer survivors. Patients 50+ years old with pathology-confirmed cancer diagnosis at Mayo Clinic were identified from a longitudinal, population-based cohort – Mayo Clinic Study of Aging. Analyses were controlled for age, APOE4-status, education, and cancer treatment. Results: We included a total of 209 patients with breast cancer (mean age 75.4 years, 24% APOE4-positive, median follow-up 6.8 years) and 352 with prostate cancer (mean age 77 years, 26% APOE4-positive, median follow-up 6.4 years). 31 patients with breast cancer (15%) and 66 patients with prostate cancer (20%) were diagnosed with dementia at last follow-up. Older age was associated with increased risk for dementia (5-year increase – breast: hazard ratio (HR) 1.9 [95%CI 1.3-2.7, p = 0.001]; prostate: HR 2.4 [95%CI 1.8-3.2, p < 0.0001]). APOE4-positivity was associated with increased dementia risk in breast (HR 3.6 [95%CI 1.6-7.8, p < 0.002]), but not prostate cancer (HR 1.2 [95%CI 0.7-2.0, p = 0.5]). More education was associated with lower dementia risk in prostate cancer (education year: HR 0.91 [95%CI 0.84-0.98, p < 0.02]; education years > 12: HR 0.26 [95%CI 0.1-0.6, p < 0.001]). Physical activity engagement in mid-life was associated with lower dementia risk (prostate: HR 0.56 [95%CI 0.4-0.8, p < 0.005]; breast: HR 0.48 [95%CI 0.3-0.9, p < 0.02]). Conclusions: In this longitudinal, population-based study we found that some risk and protective factors for dementia in cancer survivors vary by cancer type. While advanced age is an expected dementia risk factor, there were mixed results for APOE4-positivity (increased risk only in breast cancer) and education (only protective in prostate cancer). Our results support further study into factors influencing dementia risk by cancer type in hopes of identifying preventative strategies.

7577 Background: Prior research has consistently shown that patients with chronic lymphocytic leukemia (CLL) have an ~2-fold increased risk of developing melanoma compared to controls. MBL is a common condition affecting 8-10 million adults over the age of 40 years in the United States and is a precursor to CLL. Little is known about the association between MBL and melanoma. Herein, we evaluated the risk of incident melanoma in a large cohort of individuals screened for MBL. Methods: Participants from the Mayo Clinic Biobank who had no prior history of hematologic malignancy, were 40 years or older, were residents of counties surrounding Mayo Clinic, and who provided blood samples between 7/2009 and 4/2022 were included in the study. Peripheral blood mononuclear cells were screened for MBL using highly sensitive eight-color flow cytometry. Individuals with MBL were classified as CLL-like MBL (CD5+, CD20dim) or atypical MBL (CD5+, CD20+) based on immunophenotypes, and also classified as low-count MBL (LCMBL) or high-count MBL (HCMBL) based on whether the percent clonal B-cell count was < 85% or ≥85%, respectively. Diagnosis of melanoma was ascertained using ICD codes and review of the electronic health records. All individuals were followed from date of sample upon which MBL screening was performed to the earliest of incident melanoma, loss to follow-up, withdrawal from the study, or September 30, 2022. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for age, sex, and history of melanoma in previous 5 years. Results: A total of 7,334 participants were screened for MBL, of which 1,151 (16%) individuals had MBL. Among those with MBL, 1,107 (96.2%) had CLL-like MBL and 1098 (95.4%) had LC MBL. The median age at entry into the MBL screening cohort was 67 years (range 40-101) and 37% were male; individuals with MBL were older (median age 72 vs 65 years) and male (49% vs 35%). After a median follow-up of 2.9 years (range 0-13.2), 121 of the 7,334 (1.6%) participants developed incident melanoma after the date of MBL screening. The 10-year cumulative incidence of melanoma among individuals with MBL was 7.8% (95% CI 4.5-13.5%) compared to 3.4% (2.7-4.4%) in those who screened negative for MBL. After adjusting for age, sex, and history of prior melanoma, we found a 1.81-fold increased risk of incident melanoma (95% CI 1.19-2.76) among individuals with MBL. The increased risk of melanoma persisted when the analysis was restricted to individuals with LCMBL (HR = 1.84; 95% CI 1.21-2.82). Conclusions: In the largest MBL screening cohort to date, we found that LCMBL, a common condition, was associated with an 84% elevated risk of melanoma, similar to the ~2-fold increased risk observed in patients with CLL. These data, together with our prior findings of a heightened risk of serious infections and lymphoid malignancies, suggest that individuals with LCMBL are at increased risk for adverse health outcomes.

7543 Background: Total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) may improve upon standard 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT)-based assessment of advanced DLBCL during treatment. We report the association of TMTV and SUVmax changes at interim PET-CT (PET2) on survival outcomes in patients with primary refractory DLBCL (prDLBCL) and early relapsing DLBCL (erDLBCL). Methods: Adult patients with prDLBCL (less than a complete response (CR) or progression by the end of treatment (EOT)) or erDLBCL (CR at EOT with relapse within 12 months) between 2005 and 2019 at Mayo Clinic Rochester were included. The % change (Δ) from baseline to PET2 (after 2 cycles of 1L therapy) of TMTV and SUVmax were measured. A PET segmentation threshold of 1.5 liver mean SUV + two standard deviations with a minimum volume constraint of 0.5 mL was utilized (MIM Software, Inc., Cleveland OH, USA) with manual input as needed. Functional splines analysis determined SUVmax and TMTV threshold for analysis. Results: 131 patients had complete PET-CT data (N=79 prDLBCL, N=52 erDLBCL). Baseline median TMTV and SUVmax were 767.4 cm3 (range 0.9-6840.4) and 20.5 (2.0-52.6), respectively. At a median follow up of 77.6 months, 81 patients had died. 2-year OS rate was 53% (95% CI: 42-67) for patients with a PET2 ΔSUVmax decline ≥65% compared to 15% (95% CI: 7-29) for patients with a PET2 ΔSUVmax decline <65%(p<0.001). PrDLBCL had a 2-year OS rate of 48% (95% CI: 31-74) for a ΔSUVmax ≥65% compared to 7% (95% CI: 2-21) for a ΔSUVmax <65%(p<0.001), which captured 58% of prDLBCL patients (N=46). Two-year OS rate was 43% (95% CI: 34-54) for patients with a ΔTMTV ≥75% compared to 5% (95% CI: 1-35) for patients with ΔTMTV <75% (p<0.001). All patients with a ΔTMTV <75% had prDLBCL. PrDLBCL had a 2-year OS rate of 28% (95% CI: 18-44) for a ΔTMTV ≥75%. The outcomes for ΔSUVmax <65% and ΔTMTV <75% at PET2 remained significant in a cox regression model adjusted for IPI and bulky disease (>10cm)(Table). Conclusions: A ΔTMTV decline <75% or a ΔSUVmax decline <65% at PET2 identified an ultra-high-risk subgroup of DLBCL with particularly poor outcomes, that captured a high percentage of prDLBCL patients, and was significant after adjusting for IPI and bulky baseline disease. These patients may benefit from clinical trials evaluating alternative PET-adapted treatment strategies, but further evaluation among all patients with DLBCL is needed. [Table: see text]

Abstract Non‐follicular low‐grade B‐cell lymphomas (LGBCL) are biologically diverse entities that share clinical and histologic features that make definitive pathologic categorization challenging. While most patients with LGBCL have an indolent course, some experience aggressive disease, highlighting additional heterogeneity across these subtypes. To investigate the potential for shared biology across subtypes, we performed RNA sequencing and applied machine learning approaches that identified five clusters of patients that grouped independently of subtype. One cluster was characterized by inferior outcome, upregulation of cell cycle genes, and increased tumor immune cell content. Integration of whole exome sequencing identified novel LGBCL mutations and enrichment of TNFAIP3 and BCL2 alterations in the poor survival cluster. Building on this, we further refined a transcriptomic signature associated with early clinical failure in two independent cohorts. Taken together, this study identifies unique clusters of LGBCL defined by novel gene expression signatures and immune profiles associated with outcome across diagnostic subtypes.

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults worldwide. Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying CLL susceptibility, the potential use of GWAS-identified risk variants to predict disease progression and patient survival remains unexplored. Here, we evaluated whether 41 GWAS-identified risk variants for CLL could influence overall survival (OS) and disease progression, defined as time to first treatment (TTFT) in a cohort of 1039 CLL cases ascertained through the CRuCIAL consortium. Although this is the largest study assessing the effect of GWAS-identified susceptibility variants for CLL on OS, we only found a weak association of ten single nucleotide polymorphisms (SNPs) with OS (p < 0.05) that did not remain significant after correction for multiple testing. In line with these results, polygenic risk scores (PRSs) built with these SNPs in the CRuCIAL cohort showed a modest association with OS and a low capacity to predict patient survival, with an area under the receiver operating characteristic curve (AUROC) of 0.57. Similarly, seven SNPs were associated with TTFT (p < 0.05); however, these did not reach the multiple testing significance threshold, and the meta-analysis with previous published data did not confirm any of the associations. As expected, PRSs built with these SNPs showed reduced accuracy in prediction of disease progression (AUROC = 0.62). These results suggest that susceptibility variants for CLL do not impact overall survival and disease progression in CLL patients.