Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr 19;15(1):71.
doi: 10.1038/s41408-025-01283-z.

Risk of lymphoid malignancy associated with cancer predisposition genes

Nicholas J Boddicker  1 , Raphael Mwangi  2 , Dennis P Robinson  2 , Cristine Allmer  2 , Allison C Rosenthal  3 , Thomas M Habermann  4 , Andrew L Feldman  5   6 , Lisa M Rimsza  7 , Rebecca L King  5 , Melissa C Larson  2 , Bri J Negaard  2 , Aaron D Norman  8 , Nikhil Rajkumar  9 , Stephen M Ansell  4 , Angela Dispenzieri  4 , David L Murray  6 , Vincent Rajkumar  4   6 , Shaji Kumar  4 , Jithma P Abeykoon  4 ; Regeneron Genetics Center; Grzegorz S Nowakowski  4 , Thomas E Witzig  4 , Anne J Novak  4 , Susan L Slager #  10   4 , Celine M Vachon #  8 , James R Cerhan #  8
Collaborators, Affiliations

Risk of lymphoid malignancy associated with cancer predisposition genes

Nicholas J Boddicker et al. Blood Cancer J. .

Abstract

We investigated the prevalence of rare inherited pathogenic variants (PV) in 19 cancer predisposition genes regularly included on multi-gene panel testing based on NCCN guidelines and their association with the risk of lymphoid malignancies (LM) overall and by common lymphoma subtypes and multiple myeloma. The study population included newly diagnosed LM cases (N = 6990) and unrelated controls (N = 42,632), excluding individuals with a history of hematologic malignancy. Whole exome sequencing was performed on DNA from whole blood. PV were defined as loss-of-function (i.e., nonsense, frameshift, consensus splice sites) or identified as "pathogenic" or "likely pathogenic" in the ClinVar database. A total of 1816 (3.7%) individuals had a PV across the 19 genes, higher in cases (4.7%) than controls (3.5%). In controls, CHEK2 (1.0%), ATM (0.4%), BRCA2 (0.4%), and BRCA1 (0.3%) had the highest prevalence. ATM (odds ratio [OR] = 1.86, 95% confidence interval [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 associated with increased risk of LM overall and were further validated in the UK Biobank. We observed heterogeneity in associations by LM subtype. These results demonstrate that several commonly tested cancer predisposition genes are associated with an increased risk of LM.

PubMed Disclaimer

Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: This study was reviewed and approved by the institutional review board at the Mayo Clinic (IRB# 1870-00). All methods were performed in accordance with the relevant guidelines and regulations. Written informed consent was obtained from all participants for germline genetic studies.

Figures

Fig. 1
Fig. 1. Association between pathogenic variants in cancer predisposition genes and risk of lymphoid malignancy.
Estimates were adjusted for age and sex in the Mayo Clinic study. Univariate analysis was used in the UK Biobank cohort. OR Odds Ratio, CI Confidence Interval.
Fig. 2
Fig. 2. Risk of lymphoid malignancy subtype by cancer predisposition gene.
Data shown for ATM (A), CHEK2 (B), and TP53 (C). Gene selected based on being significantly associated with at least one lymphoid subtype. OR Odds Ratio, CI Confidence Interval. Estimates were adjusted for age and sex. NA denotes not applicable (too few events [<4] to calculate a stable odds ratio). SLL small lymphocytic lymphoma, DLBCL diffuse large B-cell lymphoma, FL follicular lymphoma, HL Hodgkin’s lymphoma, MCL mantle cell lymphoma, MM multiple myeloma, MZL marginal zone lymphoma.
See this image and copyright information in PMC

References

    1. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66:443–59. - PubMed
    1. Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Araujo IBO, Berti E, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022;36:1720–48. - PMC - PubMed
    1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48. - PubMed
    1. Thun MJ, Linet MS, Cerhan JR, Haiman C, Schottenfeld D Schottenfeld and Fraumeni cancer epidemiology and prevention. Fourth edition. ed. New York, NY: Oxford University Press; 2018. xix, 1308 pages p.
    1. Cerhan JR, Slager SL. Familial predisposition and genetic risk factors for lymphoma. Blood. 2015;126:2265–73. - PMC - PubMed