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<p>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 (<i>N</i> = 6990) and unrelated controls (<i>N</i> = 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, <i>CHEK2</i> (1.0%), <i>ATM</i> (0.4%), <i>BRCA2</i> (0.4%), and <i>BRCA1</i> (0.3%) had the highest prevalence. <i>ATM</i> (odds ratio [OR] = 1.86, 95% confidence interval [CI]: 1.36–2.49), <i>CHEK2</i> (OR = 1.74, 95% CI: 1.42–2.13) and <i>TP53</i> (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.</p>

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Risk of lymphoid malignancy associated with cancer predisposition genes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月19日

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  • Nicholas J. Boddicker,
  • Raphael Mwangi,
  • Dennis P. Robinson,
  • Cristine Allmer,
  • Allison C. Rosenthal,
  • Thomas M. Habermann,
  • Andrew L. Feldman,
  • Lisa M. Rimsza,
  • Rebecca L. King,
  • Melissa C. Larson,
  • Bri J. Negaard,
  • Aaron D. Norman,
  • Nikhil Rajkumar,
  • Stephen M. Ansell,
  • Angela Dispenzieri,
  • David L. Murray,
  • Vincent Rajkumar,
  • Shaji Kumar,
  • Jithma P. Abeykoon,
  • GNoncalo Abecasis,
  • Aris Baras,
  • Michael Cantor,
  • Giovanni Coppola,
  • Andrew Deubler,
  • Aris Economides,
  • Luca A. Lotta,
  • John D. Overton,
  • Jeffrey G. Reid,
  • Katherine Siminovitch,
  • Alan Shuldiner,
  • Christina Beechert,
  • Caitlin Forsythe,
  • Erin D. Fuller,
  • Zhenhua Gu,
  • Michael Lattari,
  • Alexander Lopez,
  • Maria Sotiropoulos Padilla,
  • Manasi Pradhan,
  • Kia Manoochehri,
  • Thomas D. Schleicher,
  • Louis Widom,
  • Sarah E. Wolf,
  • Ricardo H. Ulloa,
  • Amelia Averitt,
  • Nilanjana Banerjee,
  • Dadong Li,
  • Sameer Malhotra,
  • Ob Deepika Sharma,
  • Jeffrey Staples,
  • Xiaodong Bai,
  • Suganthi Balasubramanian,
  • Suying Bao,
  • Boris Boutkov,
  • Siying Chen,
  • Gisu Eom,
  • Lukas Habegger,
  • Alicia Hawes,
  • Shareef Khalid,
  • Olga Krasheninina,
  • Rouel Lanche,
  • Adam J. Mansfield,
  • Evan K. Maxwell,
  • George Mitra,
  • Mona Nafde,
  • Sean O’Keeffe,
  • Max Orelus,
  • Razvan Panea,
  • Tommy Polanco,
  • Ayesha Rasool,
  • William Salerno,
  • Jeffrey C. Staples,
  • Kathie Sun,
  • Goncalo Abecasis,
  • Joshua Backman,
  • Amy Damask,
  • Lee Dobbyn,
  • Manuel Allen Revez Ferreira,
  • Arkopravo Ghosh,
  • Christopher Gillies,
  • Lauren Gurski,
  • Eric Jorgenson,
  • Hyun Min Kang,
  • Michael Kessler,
  • Jack Kosmicki,
  • Alexander Li,
  • Nan Lin,
  • Daren Liu,
  • Adam Locke,
  • Jonathan Marchini,
  • Anthony Marcketta,
  • Joelle Mbatchou,
  • Arden Moscati,
  • Charles Paulding,
  • Carlo Sidore,
  • Eli Stahl,
  • Kyoko Watanabe,
  • Bin Ye,
  • Blair Zhang,
  • Andrey Ziyatdinov,
  • Ariane Ayer,
  • Aysegul Guvenek,
  • George Hindy,
  • Jan Freudenberg,
  • Jonas Bovijn,
  • Kavita Praveen,
  • Manav Kapoor,
  • Mary Haas,
  • Moeen Riaz,
  • Niek Verweij,
  • Olukayode Sosina,
  • Parsa Akbari,
  • Priyanka Nakka,
  • Sahar Gelfman,
  • Sujit Gokhale,
  • Tanima De,
  • Veera Rajagopal,
  • Gannie Tzoneva,
  • Juan Rodriguez-Flores,
  • Esteban Chen,
  • Marcus B. Jones,
  • Michelle G. LeBlanc,
  • Jason Mighty,
  • Lyndon J. Mitnaul,
  • Nirupama Nishtala,
  • Nadia Rana,
  • Jaimee Hernandez,
  • Grzegorz S. Nowakowski,
  • Thomas E. Witzig,
  • Anne J. Novak,
  • Susan L. Slager,
  • Celine M. Vachon,
  • James R. Cerhan

摘要

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.