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2990 Lymphoid Malignancy Risk with Rare Inherited Variants in Known Cancer Predisposition Genes

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational—Molecular and Genetic: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research, epidemiology, Clinical Research
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Nicholas J. Boddicker, PhD1, Raphael Mwangi, M.S.2*, Dennis P. Robinson, PhD3*, Cristine Allmer, BS4*, Allison C. Rosenthal, DO5, Thomas M. Habermann, MD6, Andrew L. Feldman, MD7, Lisa M. Rimsza, MD8, Rebecca King, MD4*, Melissa C. Larson, MS9*, Brianna Gysbers4*, Aaron D. Norman9*, Stephen M Ansell, MD, PhD6, Angela Dispenzieri, MD4, David L Murray, MD, PhD10*, S. Vincent Rajkumar, MD4, Shaji Kunnathu Kumar, MD6, Jithma Prasad Abeykoon, MD11, Grzegorz S. Nowakowski, MD6, Thomas E. Witzig, MD4, Anne J. Novak, PhD4, Celine M. Vachon, PhD9, Susan L. Slager, PhD6 and James R. Cerhan, MD, PhD12

1Division of Computational Biology, Mayo Clinic, Rochester, MN
2Department of Health Sciences Research, Mayo Clinic, Rochester, MN
3Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN
4Mayo Clinic, Rochester, MN
5Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ
6Division of Hematology, Mayo Clinic, Rochester, MN
7Department of Laboratory Medicine and Pathology, Division of Hematopathology, Mayo Clinic, Rochester, MN
8Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ
9Division of Epidemiology, Mayo Clinic, Rochester, MN
10Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
11Mayo Clinic, Boston, MN
12Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN


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.


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.


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.


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.

Disclosures: Habermann: Genentech: Research Funding; sorrento: Research Funding; BMS: Research Funding. Rimsza: Roche: Other: Consulting; NanoString: Other: Licensed intellectual property. Ansell: Seagen Inc: Other: Contracted Research; Regeneron Pharmaceuticals Inc: Other: Contracted Research; Pfizer, Inc: Other: Contracted Research; Bristol-Myers Squibb: Other: Contracted Research; Affirmed: Other: Contracted Research; ADC Therapeutics: Other: Contracted Research; Takeda Pharmaceuticals USA Inc: Other: Contracted Research. Dispenzieri: Oncopeptides, Sorento: Consultancy; Alnylam, Bristol-Myers Squibb, Janssen, Pfizer, Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Murray: Eastman Kodak: Patents & Royalties. Nowakowski: Ryvu Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Zai Lab Limited: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy; Curis: Consultancy; ADC Therapeutics: Consultancy; Selvita Inc: Consultancy; Kymera Therapeutics: Consultancy; MEI Pharma: Consultancy; Seagen: Consultancy; Debiopharm: Consultancy; F Hoffmann-La Roche Limited: Consultancy; Bantam Pharmaceutical LLC: Consultancy; Blueprint Medicines: Consultancy; Celgene Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Incyte: Consultancy; Karyopharm Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy. Witzig: Salarius Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; ADC: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding. Novak: Bristol Myers Squibb: Research Funding. Cerhan: Genmab: Research Funding; NanoString: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Protagonist: Other: Safety Monitoring Committee; Genentech: Research Funding.

*signifies non-member of ASH