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Germline BRCA2 Mutations Linked to Pediatric Non-Hodgkin Lymphoma Risk

NEW YORK – Inherited BRCA2 mutations may also increase a person's risk of developing pediatric lymphoma, according to a new analysis.

Inherited mutations in BRCA1 and BRCA2 are most typically associated with an increased risk of developing breast and ovarian cancer, but a previous study from St. Jude Children's Research Hospital hinted that BRCA2 mutations might also be prevalent among some lymphoma survivors.

In a new analysis, St Jude's researchers have now examined germline sequencing data from 1,380 survivors of childhood lymphoma from two cohorts. As compared to controls with no history of cancer, non-Hodgkin lymphoma survivors were more likely to harbor pathogenic or likely pathogenic variants in BRCA2, suggesting there could be a link between the variants and non-Hodgkin lymphoma risk.

"The BRCA family of genes are known to be linked to risk for breast and ovarian cancer as well as several other types of adult onset cancers, but our study shows a relationship between BRCA2 and non-Hodgkin lymphoma diagnosed in childhood," corresponding author Zhaoming Wang, an associate member of St. Jude's departments of epidemiology and cancer control and computational biology, said in a statement. The study appears online this week in JAMA Oncology.

The researchers analyzed data collected by the St. Jude Lifetime Cohort and Childhood Cancer Survivors Study, both of which are studying the health of adult survivors of pediatric cancers to minimize any later-life effects. Germline whole-genome sequencing, reaching 30-fold coverage, was obtained for both groups, either from peripheral blood or from buccal or saliva samples.

From this data, the researchers identified 13 pathogenic or likely pathogenic mutations in BRCA2 in survivors of Hodgkin lymphoma and eight in survivors of non-Hodgkin lymphoma. The researchers then compared the prevalence of these mutations in the lymphoma survivors to their prevalence among a control group of more than 59,000 people without a history of cancer amassed from the Genome Aggregation Database (gnomAD).

In their cohort, they found a statistically significant association between lymphoma and mutations in BRCA2. When they stratified the patients by disease type, they found that the statistical significance held for a link between BRCA2 mutations and non-Hodgkin lymphoma, though not for Hodgkin lymphoma.

Additionally, six of the seven childhood non-Hodgkin lymphoma survivors for whom the researchers were able to get family histories had family histories of BRCA2-related cancers like breast, prostate, pancreatic, and melanoma cancer.

This suggested to the researchers that pediatric or adolescent non-Hodgkin lymphoma could possibly be included in the list of cancers associated with germline BRCA2 mutations. Further, they argued that non-Hodgkin lymphoma survivors could possibly benefit from increased surveillance for other BRCA2-linked cancers.

"The more we know about the biology that drives a particular cancer, the more a patient's care can be precisely tailored," co-senior author Leslie Robison, chair of St. Jude's department of epidemiology and cancer control, said in a statement. "This includes cancer prevention and cancer screening, where an understanding of inherited mutations can help us put in place strategies to care for that patient and family long-term."

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