Clay‐Gilmour, Alyssa

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive and rare B-cell non-Hodgkin lymphoma with poor prognosis, even with treatment. Despite its clinical importance, the etiology of MCL remains largely unknown. Some studies have reported a positive association with family history, suggesting that genetic factors could contribute to risk. Methods: To identify germline genetic variants associated with risk, we conducted the first genome-wide association studies (GWAS) and GWAS meta-analysis for MCL, comprising 1,163 cases and 61,271 controls. The most significant loci were taken forward for replication in three independent studies, including 576 cases and 771,773 controls. To identify potential target genes and pathways of discovered loci, we conducted F-MAGMA, colocalization, and transcriptome-wide association study (TWAS) analyses. To gain insight into underlying regulatory mechanisms, we performed integrative epigenomic analyses using DNase I hotspots and histone mark ChIP-seq data across diverse cell types applying the FORGE2 framework. Results: In the joint analyses, we identified eight genome-wide significant loci (P<5x10-8) associated with MCL risk, several of which were located near genes with known DNA repair (ATM), telomere (TERT), or RNA-binding functions (RBM20). Further analyses using F-MAGMA, which uses DNase-seq data to prioritize genes from GWAS, identified genes that were significantly associated with risk, including SP140, a chromatin reader and immune regulator of pathogen response. This gene also displayed strong colocalization with our lead variant in whole blood (COLOC posterior probability PP4=0.97). TWAS demonstrated significant associations with SP140 and ACTA2, which has been linked to cell proliferation (P<3x10-6). Enrichment for DNase I hotspots was observed in B and T lymphocytes (q-value<0.05), providing evidence for a role in immune cell-specific regulatory regions. Enrichment for enhancer-associated histone mark H3K4me1 was observed in B cells (q-value<0.01), highlighting a role for immune cell-specific enhancers. Transcription factor (TF) motif enrichment analysis pointed to TFs critical for B-cell development and differentiation, notably TCF3 and EP300 (q<0.01 for both), suggesting an association between B-cell lineage regulation and MCL risk. Finally, genome-wide SNP-based heritability was estimated to be 17%, underscoring the importance of common variants in MCL risk. Conclusion: Our study provides novel insight into the inherited susceptibility of MCL by identifying eight significant loci and estimating substantial common variant heritability. These findings highlight a role for several distinct biological pathways -specifically DNA repair, telomerase function, and B-cell differentiation- in the etiology of MCL, offering new targets for mechanistic investigation. Citation Format: Charles E. Breeze, Alyssa Clay-Gilmour, Hanla A. Park, Ólafur B. Davíðsson, Angelica Macauda, Brenda M. Birmann, Elizabeth E. Brown, Murat Güler, Michelle A. T. Hildebrandt, Alexandra Nieters, Krystle Ong, Jojo Biel-Nielsen Dietz, Karin E. Smedby, Karl Smith-Byrne, Rosalie Griffin, Sophia S. Wang, Susan Slager, James R. Cerhan, Jonathan N. Hofmann, Qing Lan, Nathaniel Rothman, Ingrid Glimelius, Henrik Hjalgrim, James Mckay, Sonja I. Berndt. Genome-wide association study of mantle cell lymphoma identifies novel loci suggesting a critical role for B-cell chromatin readers and DNA repair mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3602.

Abstract Background. Genome-wide association studies (GWAS) have identified 35 genetic susceptibility single-nucleotide polymorphisms (SNPs) for multiple myeloma (MM) in individuals of European ancestry (EA) and shown strong genetic correlation between MM and its precursor, monoclonal gammopathy of undetermined significance (MGUS). We evaluate the contribution of the 35 MM variants to MGUS susceptibility overall and by prognostic subgroups. Methods. The study included 20,756 participants (14,486 controls, 1,883 with MGUS, and 2,163 with MM) from the Mayo Clinic. Logistic regression assuming an additive model estimated odds ratios (ORs) and 95% confidence intervals (CIs) for individual SNPs and for the MM-PRS, adjusted for age, sex, study, and principal components. The PRS was a weighted sum of 35 SNPs with effect estimates from the largest MM GWAS and was modeled continuously (per SD) and by quintiles (Q1-Q5). SNPnexus annotated variants that replicated in MGUS (P < 0.05 and OR > 1.01) versus those that did not (P > 0.05 and OR < 1.01). Results. The 35-SNP MM-PRS was strongly associated with MM risk and modestly with MGUS. Compared with the middle quintile (Q3), MM odds rose from OR=0.55 (CI=0.46-0.65, P=2.2e-11) in Q1 to OR = 1.82 (CI=1.59-2.09, P=6.2e-18) in Q5. MGUS showed a similar, attenuated pattern (Q1 OR = 0.74, CI=0.64-0.84, P=6.4e-6 / Q5 OR=1.36, CI=1.21-1.53, P=3.4e-7). Each SD increase in PRS corresponded to OR=1.52 (CI=1.45-1.59, P=1.3e-66) for MM and OR = 1.22 (CI=1.18-1.27, P=1.0e-23) for MGUS. Higher PRS values were linked to larger M-protein ((0.1-1.5 g/dL: OR=1.40, CI=1.18-1.65, P=5.8e-12) vs <0.1 g/dL: OR = 1.19, CI=1.13-1.24, P=5.8e-12)) and abnormal free light chain (FLC) ratio ((OR = 1.33, CI=1.21-1.46, P=1.0e-9) vs normal ratio (OR=1.19, CI=1.14-1.25, P=1.4e-13)). Ten risk loci replicated in MGUS, mapping to genes involved in plasma-cell function, immune regulation, and DNA repair and enriched for Rho GTPase signaling, NF-κB-mediated apoptosis, and RNA polymerase II transcription, implicating early plasma-cell activation and transcriptional control. The 12 non-replicating loci, including PHC3, ATG5, and NFIC, mapped to genes involved in chromatin remodeling, autophagy, and SUMOylation, suggesting roles in stress response and genomic maintenance. Conclusions. The MM-PRS captures shared heritability between MM and MGUS and correlates with MGUS subtype and severity. Replicating variants highlight immune and cell-cycle pathways relevant to MGUS onset, whereas non-replicating loci cluster in DNA-repair and stress-response processes, underscoring their potential role in progression. Citation Format: Alyssa Ione Clay-Gilmour, Angelica Macauda, Cristine Allmer, Danelle Moonen, Aaron D. Norman, Nicholas Boddicker, Janet E. Olson, Elizabeth E. Brown, Vincent S. Rajkumar, Esteban Braggio, David Murray, Susan Slager, Shaji Kunnathu Kumar, Celine Vachon. Implications of multiple myeloma polygenic risk scores (PRS) for MGUS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3603.

Summary Evidence for an association between insulin‐like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF‐I concentrations and risk of MM by combining baseline serological data among UK Biobank participants ( n = 444 187; 732 incident MM) with a two‐sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF‐I and IGF‐binding protein 3 (IGFBP‐3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF‐I level was positively associated with MM risk Hazard ratio‐HR‐per one standard deviation‐SD‐increase (HR 1‐SD = 1.11, 95% confidence interval [CI]: 1.01–1.22; p ‐value = 0.03), especially closer to diagnosis. Genetically inferred IGF‐I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05–1.54) but not with any other LNs. Genetically inferred IGFBP‐3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF‐I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR 1‐SD in obese male = 1.36, 95% CI: 1.14–1.61). Our serological and MR analyses suggest a contributing role of IGF‐I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex‐specific adiposity.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy‐related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy‐related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood‐derived immune cell subsets and 103 circulating immunological proteins. Meta‐analysis revealed a genome‐wide significant association between the ULK4 rs6599175C allele and increased MGUS risk ( p = 3.35 × 10 −8 ). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p = .0038 and p = .0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p = .0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B‐cell differentiation. Additionally, the CDKN2A rs2811710 variant showed a suggestive association with MGUS risk ( p = 2.17 × 10 −4 ), affecting transcription factor binding involved in B‐cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome‐wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B‐cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.

Abstract Background: Monoclonal B-cell lymphocytosis (MBL), a precursor to chronic lymphocytic leukemia (CLL), is an understudied yet common premalignant condition present in ~8 million adults in the United States. Based on flow cytometry, MBL can be classified into two immunophenotypes: CLL-type (CD5, CD23, and CD20 co-expression) and non-CLL-type (CD5-negative). While the majority of the data to date pertains to CLL-type MBL, the available evidence indicates non-CLL-type MBL is also associated with an increased risk of hematologic malignancies. Clonal hematopoiesis of indeterminate potential (CHIP) is another precursor condition associated with hematologic malignancies. The relationship between non-CLL-type MBL and CHIP and their combined effect remains unknown. Herein, we report findings on these two precursor conditions in the largest screening cohort to date. Methods: Using flow cytometry, we screened for MBL in the Mayo Clinic Biobank participants who were 40 years or older with no prior history of hematologic cancers. Using whole-exome sequencing of whole-blood DNA, CHIP was screened on 291 genes related to myeloid (56 genes) or lymphoid malignancies (235 genes). Incident hematologic malignancies were detected during follow-up using International Classification of Diseases (ICD) codes in the medical record. All diagnoses were manually reviewed for confirmation. Multivariable logistic regression was used to evaluate the association between non-CLL-type MBL and CHIP. Time to incident hematologic malignancy was calculated from date of MBL screening to the earliest date of incident malignancy, withdrawal, death, last medical visit, or study end. Overall survival (OS) was calculated from date of MBL screening to date of death or last known alive. Multivariable Cox regression, adjusted for age, sex and residency, was used to investigate associations between non-CLL-type MBL and CHIP with clinical outcomes; with results reported using hazard ratios (HR) and 95% confidence intervals (CI). Results: In total, 8,802 individuals with MBL screening and CHIP data were analyzed. Non-CLL-type MBL was detected in 249 (2.8%) individuals; 121 (49%) were male, and median age was 78 years (range, 47-95). We identified 757 (8.6%) individuals with CHIP in at least one of the 291 genes tested. The most frequently mutated CHIP genes were DNMT3A, TET2, ASXL1, PPM1D, and TP53. A total of 47 (0.5%) individuals had both non-CLL-type MBL and CHIP; the four genes with the highest number of CHIP variants in these individuals were DNMT3A (n=16), TET2 (n=10), ASXL1 (n=3), and ATM (n=3). An association between non-CLL-type MBL and any CHIP (OR=1.6, 95%CI:1.2-2.3, P=0.006) was observed. When analyzing CHIP in genes related to myeloid malignancies, the association with non-CLL-type MBL was also significant (OR=1.6, 95%CI:1.1-2.3, P=0.012); however, the association was not statistically significant for genes related to lymphoid malignancies (OR=1.6, 95%CI:0.8-3.3, P=0.165). With a median follow-up of 5.4 years, 104 individuals developed incident hematologic malignancies (66 lymphoid and 38 myeloid malignancies). Non-CLL-type MBL (HR=3.5, 95%CI:1.9-6.5, P<0.001) and CHIP (HR=3.2, 95%CI:2.1-5.1, P<0.001) were each associated with increased risk of incident hematologic malignancies. Co-existence of both precursor conditions was associated with a substantially higher risk of incident hematologic malignancies (HR=10.3, 95%CI:4.0-26.2, P<0.001) compared to individuals with neither precursor condition. Among individuals with non-CLL-like MBL, any CHIP was a borderline significant predictor for incident hematologic malignancy (HR=3.6, 95%CI:1.0-12.9, P=0.049). Compared to individuals with no precursor conditions, OS was not significantly different in those with non-CLL-type MBL-only (HR=1.1, 95%CI:0.8-1.5, P=0.40), those with CHIP-only (HR=1.2, 95%CI:0.99-1.4, P=0.06), or those with both CHIP and non-CLL-type MBL (HR=1.3, 95%CI:0.8-2.1, P=0.39). Conclusions: In the largest screening cohort to date evaluating the relationship of CHIP and non-CLL-type MBL, we found that non-CLL-type MBL and CHIP are associated with each other. Individuals with non-CLL-type MBL were more likely to have CHIP variants in DNMT3A, TET2, ASXL1, and ATM. Among individuals with non-CLL-type MBL, the presence of any CHIP was associated with increased risk of developing hematologic malignancy.

Background/Objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis. Methods:Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander–Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, and 21 unaffected). Genome-wide linkage was evaluated using 12,946 independent single-nucleotide variants (linkage disequilibrium r2 < 0.05). Results: Significant linkage was observed at chromosome 6q22.33–q24.2 by the non-parametric model (logarithm-of-odds (LOD) = 3.3) and suggestive linkage by the dominant parametric model (heterogeneity LOD (HLOD) = 2.5). Fourteen rare variants within this region were prioritized using family-specific partial LOD scores and in silico functional prediction tools. Nine of these variants, REPS1, THEMIS, TAAR6, AHI1, VNN1, VNN3, MTFR2/FAM54A, LAMA2, and PHACTR2, overlapped immune-regulatory regions in blood cell lines and were not previously identified in GWASs. Conclusions: This study demonstrates the utility of applying a linkage analysis framework to familial WES data for identifying genomic regions and candidate genes that may contribute to MM/MGUS predisposition. These findings provide new insight into the inherited risk and etiology of familial MM and MGUS.

Abstract We investigated the influence of 55 583 autophagy-related single-nucleotide polymorphisms (SNPs) on chronic lymphocytic leukemia (CLL) risk across 4 independent populations comprising 5472 CLL cases and 726 465 controls. We also examined their impact on overall survival (OS), time to first treatment (TTFT), autophagy flux, and immune responses. A meta-analysis of the 4 populations identified, to our knowledge, for the first time, significant associations between CDKN2A (rs3731204) and BCL2 (rs4940571, rs12457371, and rs1026825) SNPs and CLL risk, with CDKN2A showing the strongest association (P = 1.57 × 10−12). We also validated previously reported associations for FAS, BCL2, and BAK1 SNPs with CLL risk (P = 4.73 × 10−21 to 3.39 × 10−9). The CDKN2Ars3731204 and FASrs1926194 SNPs associated with increased CDKN2A and ACTA2 messenger RNA expression levels in the whole blood and/or lymphocytes (P = 5.1 × 10−7, P = 1.58 × 10−21, and P = 7.8 × 10−41), although no significant effect on autophagy flux was observed. However, associations were found between CDKN2A, BCL2, and FAS SNPs and various T-cell subsets, cytokine production, and circulating concentrations of interferon gamma, tumor necrosis factor–related apoptosis-inducing ligand, CD40, chemokine ligand 20, and interleukin-2 receptor subunit β proteins (P ≤ .005). No significant association was detected between autophagy variants and OS or TTFT, suggesting that these variants drive disease initiation rather than progression. In conclusion, this study identified 4 novel associations for CLL and provided insights into the biological pathways that influence CLL development.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM). Clonal hematopoiesis of indeterminate potential (CHIP) is a precursor to either myeloid or lymphoid malignancy, depending on whether the mutation is in a gene associated with lymphoid (L-CHIP) or myeloid (M-CHIP) outcome. Little is known about the association between CHIP and MGUS and their combined effect on risk of MM. We examined this question within Mayo Clinic Biobank cohort of participants aged 50 years or older with no prior history of hematological malignancies. Using whole blood, individuals were screened for MGUS using a matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry assay. M-CHIP and L-CHIP were defined based on mutations in 56 genes associated with myeloid malignancies or mutations in 235 genes associated with lymphoid malignancies, respectively, using whole-exome-sequencing. Incident MM was identified using International Classification of Diseases (ICD) codes and confirmed via medical record review. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals for the association of CHIP and MGUS. Cox proportional hazards regression was used to estimate hazard ratios (HR), with time defined as date between blood sample and the first incident MM, date of death, or 12/31/2023. All models were adjusted for age and sex. Of the 16, 479 individuals (median age 65 years, 45% male) screened, 12.3% were positive for MGUS, 9.8% were positive for M-CHIP, and 1.5% were positive for L-CHIP. There was no evidence of an association between M-CHIP and MGUS (OR=0.97, 95% CI:0.83-1.12) nor L-CHIP and MGUS (OR=1.12, 95% CI:0.78-1.57), including with any MGUS isotype (IgA, IgG, or IgM; P-values&gt;0.22). Next, we investigated the association of these precursors on risk of MM. Median follow-up was 11.7 years (range 0.1-15.1), and 46 individuals developed incident MM. Both MGUS (HR=29.7, 95% CI: 14.1-62.4) and L-CHIP (HR=4.1, 95% CI: 1.3-13.2) were significantly associated with incident MM, but not M-CHIP (HR-1.0, 95% CI: 0.4-2.5). Investigating the combined effect of MGUS and L-CHIP, we found those with MGUS alone had a 27.5-fold (95% CI: 13.0-58.2) increased risk of incident MM compared to those with no precursors. No individuals with L-CHIP only developed MM, but those with both L-CHIP and MGUS had a 129.4-fold (95% CI: 34.4-486.4) increased risk of incident MM. In the largest cohort with screened MGUS and CHIP, we found no evidence of an association between either definition of CHIP with MGUS. However, individuals with both L-CHIP and MGUS were at the highest risk of developing MM. Citation Format: Nicholas J. Boddicker, Cristine Allmer, Danelle H. Moonen, Aaron D. Norman, Angelica Macauda, Alyssa Clay-Gilmour, Janet E. Olson, Mrinal S. Patnaik, Vincent Rajkumar, Esteban Braggio, David L. Murray, Shaji Kumar, Susan L. Slager, Celine M. Vachon. The association between MGUS and CHIP and their impact on multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4917.

Abstract Introduction: With over 80, 000 new cases of non-Hodgkin's lymphoma (NHL) diagnosed annually, modifiable risk factors remain unclear. Circadian disruption, linked to cancers like breast and prostate, affects immune cells (e.g., natural killer cells and T-helper cells) by altering their trafficking and proliferation. Some studies (PMID: 30566672, 27611440) suggest long sleep may increase overall NHL risk, including a Mendelian randomization (MR) study (PMID: 32895918). However, no research has examined the causal relationship between sleep traits, including long sleep, and NHL risk, by subtypes. We hypothesize that sleep traits are causally associated with NHL subtypes in European populations, testing this using MR with data from the International Lymphoma Epidemiology Consortium (InterLymph). Methods: We conducted two-sample MR using genome-wide association studies (GWAS) summary data for sleep traits and NHL subtypes. Only independent, genome-wide significant (p &lt; 5×10-8) Single Nucleotide Polymorphisms (SNPs) were selected as valid instruments, sourced from the UK Biobank. Sleep traits included chronotype (153 SNPs), insomnia (48 SNPs), sleep duration (78 SNPs), excessive daytime sleepiness (37 SNPs), short sleep (27 SNPs), and long sleep (8 SNPs). NHL subtype data were from InterLymph: follicular lymphoma (6, 508 cases / 64, 183 controls), mantle cell lymphoma (1, 169 cases / 61, 603 controls), Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL: 1, 697 cases / 59, 333 controls), and chronic lymphocytic leukemia (8, 522 cases / 67, 653 controls). The primary analysis used inverse-variance weighted (IVW) random-effects, with MR-Egger for pleiotropy adjustment. Results: Using the IVW method, we did not identify any statistically significant causal association between sleep traits and the risk of NHL subtypes, but did yield several intriguing trends. Long sleep (sleep duration &gt;= 9 h per night) showed a marginally increased NHL risk [Odds ratio (OR) range: 1.51 - 247.9] across each subtype. Short sleep (sleep duration &lt; 7 h per night) showed a similar trend [OR range: 1.25 - 1.81], except for WM/LPL, where we noticed a negative trend. The confidence limit for long sleep was imprecise due to the small number of variants. We did not notice any significant directional horizontal pleiotropy or weak instrument bias. Conclusions: We found no conclusive evidence of a relationship between sleep traits and four NHL subtypes. However, we see suggestive trends of long and short sleep associated with higher risk of some NHL subtypes. These findings align with the previous studies, which showed long sleep was associated with higher risk of NHL overall. Future directions include expanding our analysis to additional NHL subtypes, generating polygenic risk scores, and conducting stratified analyses. Citation Format: Pankhil Shah, Brittany Crawford, Anwar Merchant, Brenda Birmann, Angelica Macauda, Michelle A. Hildebrandt, Aaron Norman, Neil E. Caporaso, Meredith Yeager, Michael Dean, Immaculata De Vivo, Lynn Goldin, Nicola J. Camp, Rosalie Griffin, Delphine Casabonne, Federico Canzian, Pelin Unal, Elad Ziv, Catherine R. Marinac, Alexandra Nieters, Stephen J. Chanock, Mitchell J. Machiela, Michael Conry, Charlie Zhong, Hanla A. Park, Simon Cheah, Jonathan N. Hofmann, Elizabeth E. Brown, Celine Vachon, Susan Slager, Sonja Berndt, Sophia S. Wang, Vijai Joseph, James McKay, Henrik Hjalgrim, Lara Sucheston-Campbell, Karl Smith-Byrne, Alyssa Clay-Gilmour. Association between sleep traits and risk of non-Hodgkin's lymphoma subtypes: a mendelian randomization study in the International Lymphoma Epidemiology (InterLymph) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7415.