Inherited BRCA2 Mutations Linked to Risk of Non-Hodgkin’s Lymphoma in Children

Inherited mutations in the DNA repair gene BRCA2 — a well-known risk factor for breast and ovarian cancers in adults — also show a significant association with non-Hodgkin’s lymphoma in children and adolescents, a new study found.

Survivors of childhood lymphoma, particularly those with a family history of BRCA2-associated cancers, should be offered the option of genetic testing and counseling due to their risk of other cancers in adulthood, its researchers said.

The study, ”Association of Germline BRCA2 Mutations With the Risk of Pediatric or Adolescent Non-Hodgkin Lymphoma” was published in JAMA Oncology.

“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,” Zhaoming Wang, PhD, the study’s lead author, said in a press release. Wang is an associate member of the St. Jude departments of Epidemiology and Cancer Control and Computational Biology.

People who inherit harmful mutations in the BRCA1 or BRCA2 genes are significantly more likely to develop breast and ovarian cancer during their lives than those in the general population. These patients are also at an increase risk for other adult-onset cancers, including melanoma, pancreatic cancer, prostate cancer.

Looking at survivors of childhood cancers included in the St Jude Lifetime (SJLIFE) study, researchers came to a surprise finding: mutations in BRCA2 ranked third in frequency, and were particularly common in survivors of childhood lymphoma.

These findings suggested that BRCA2 mutations predispose children and teenagers to lymphoma.

To further investigate, scientists at St. Jude Children’s Research Hospital examined the genome from 1,380 childhood lymphoma survivors included in the SLIFE study and in the Childhood Cancer Survivor Study, both of which examine the long-term effects of cancer and therapy.

Participants had Hodgkin’s lymphoma (815) or non-Hodgkin’s lymphoma (565) during their childhood, and had been cancer free for at least five years. They were diagnosed at a median age of 13 years, and most were male (54.2%) and white (81%–84%).

Looking at each patient’s genome, investigators identified a total of 13 disease-linked mutations in the BRCA2 gene: five mutations in survivors of Hodgkin’s lymphoma and eight mutations in non-Hodgkin’s lymphoma survivors — all of whom were males.

Patients with these mutations were diagnosed at a similar age (12.8 years) compared to non-carriers (13.5%). Comparing these people to non-cancer controls included in the Genome Aggregation Database (gnomAD) — a data set of genomes from multiple sequencing projects — they found the chances of lymphoma to be three times higher in people with a BRCA2 mutation.

Looking at this association by lymphoma type, it remained significant only for non-Hodgkin’s lymphoma, with BRCA2 mutations increasing the risk for this childhood cancer by five-fold.

A genetic counselor was able to obtain the cancer family history for seven of the eight non-Hodgkin’s lymphoma survivors. Six of these survivors had a family history of cancer, including breast, prostate, pancreas and melanoma, “all within the BRCA2-associated cancer spectrum,” the researchers wrote.

Overall, these results suggest childhood non-Hodgkin’s lymphoma survivors, particularly those which have a family history of cancers associated with BRCA2 mutations, should be given genetic counseling and BRCA2 genetic testing.

“Survivors whose test results are positive for mutation should be offered surveillance for BRCA2-associated cancers, such as breast and ovarian, and counseled about cancer risk–reducing strategies,” the researchers wrote.

“Understanding inherited risk helps childhood cancer survivors and it enables conversations among relatives who can then make decisions about their own health management strategies,” said Kim Nichols, a study author and director of the St. Jude Cancer Predisposition Division.

“The more we know about the biology that drives a particular cancer, the more a patient’s care can be precisely tailored,” said Leslie Robison, the study’s senior author and chair of the St. Jude Department of Epidemiology and Cancer Control. “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.”