Association of Cancer Predisposition Genes with Risk of Lymphoid Malignancies

Overview

This study investigates the association between pathogenic variants (PVs) in 19 cancer predisposition genes and the risk of lymphoid malignancies (LM) and their subtypes using a large clinic-based case-control cohort. The findings suggest that rare PVs in known cancer predisposition genes, particularly those involved in DNA damage repair, may contribute to LM susceptibility.

Background

Lymphoid malignancies are a heterogeneous group of cancers arising from lymphatic tissues, encompassing over 100 subtypes such as diffuse large B-cell lymphoma and Hodgkin lymphoma. Established risk factors include family history, infections, immune dysregulation, and environmental exposures. While genome-wide association studies have identified common susceptibility variants with small effects, the role of rare pathogenic variants in cancer predisposition genes in LM risk remains less understood. Prior evidence indicates increased lymphoma incidence in hereditary cancer syndromes like Li Fraumeni and Lynch syndrome, highlighting the need for large-scale genetic studies.

Data Highlights

The study utilized germline DNA sequencing from lymphoma cases (excluding CLL and MM) enrolled in the Mayo Molecular Epidemiology Resource and multiple myeloma cases from Mayo Clinic, compared to controls from the Mayo Clinic Biobank. Sequencing was performed using high-throughput exome capture and Illumina NovaSeq technology, achieving >20× read depth in over 95% of samples. Pathogenic variants were defined as loss-of-function mutations including nonsense, frameshift, and splice site alterations.

Key Findings

• Pathogenic variants in DNA damage repair genes such as BRCA1, BRCA2, ATM, and TP53 are associated with increased risk of lymphoid malignancies.
• Family history of hematologic malignancies is a significant risk factor, with subtype-specific familial clustering observed.
• Rare pathogenic variants confer higher risk compared to common single nucleotide polymorphisms identified in GWAS.
• Genetic testing criteria based on known cancer predisposition genes may be applicable to LM patients to guide risk assessment and management.
• Large clinic-based case-control studies provide robust data supporting the contribution of inherited genetics to LM etiology.

Clinical Implications

Clinicians should consider genetic testing for pathogenic variants in cancer predisposition genes in patients with lymphoid malignancies, especially those with a family history of hematologic cancers. Identification of such variants can inform personalized treatment strategies and enable risk assessment for family members. Integrating genetic information into clinical practice may improve outcomes through targeted surveillance and prevention.

Conclusion

This study underscores the importance of rare pathogenic variants in cancer predisposition genes in the risk of lymphoid malignancies and supports the integration of genetic testing into clinical evaluation. Further research is warranted to refine risk estimates and optimize management strategies for affected individuals and their families.

References

1. Molecular Epidemiology Resource and Mayo Clinic Biobank Studies
2. NCCN Guidelines on Genetic Testing for Cancer Predisposition Genes
3. Genome-wide Association Studies of Lymphoid Malignancies
4. Studies on Li Fraumeni and Lynch Syndromes and Lymphoma Risk