BRCA2 mutations linked with non-Hodgkin's lymphoma in children

By Marilynn Larkin

NEW YORK (Reuters Health) - 31/7/2019

BRCA2 mutations increase the risk for pediatric non-Hodgkin's lymphoma (NHL), researchers say, and survivors should be offered genetic counseling.

A previous report from the St. Jude Lifetime (SJLIFE) study found that BRCA2 was the third most frequently mutated gene among survivors of childhood cancer, with the highest number observed among survivors of lymphoma.

To investigate further, Dr. Zhaoming Wang of St. Jude Children's Research Hospital in Memphis and colleagues analyzed additional survivors from SJLIFE and from the Childhood Cancer Survivor cohorts using whole-genome sequencing data.

"Compared to control individuals, we found that pathogenic germline variants in the BRCA2 gene were associated with a 3-fold increased risk of developing childhood or adolescent lymphoma and a 5-fold increased risk of developing childhood or adolescent NHL," Dr. Wang told Reuters Health by email.

"Genetic counseling and possible BRCA2 genetic testing should be offered to survivors of pediatric or adolescent NHL, particularly those with a family history of BRCA2-associated cancers," he said.

Specifically, the team studied 1,380 survivors: 565 of NHL and 815 of Hodgkin's lymphoma; 54.2% were male, and the median age at diagnosis was 13.4 years.

As reported online July 25 in JAMA Oncology, 13 P/LP (pathogenic or likely pathogenic) mutations in BRCA2 were identified: eight (1.4%) in NHL survivors and five (0.6%) in survivors of Hodgkin's lymphoma. Mutation carriers were indistinguishable from noncarriers on the basis of median age at lymphoma diagnosis.

"Notably, all eight survivors of childhood or adolescent NHL who carried pathogenic germline variants in BRCA2 were male," Dr. Wang noted. "The reasons for this finding remain unknown."

Compared with controls, when stratified by diagnosis, the association was statistically significant for NHL (OR, 5.0) but not for Hodgkin's lymphoma (OR, 2.1).

Six of the NHL survivors carrying a P/LP BRCA2 mutation had family histories of BRCA2-associated cancers, including breast, prostate, pancreas and melanoma.

"These findings support inclusion of pediatric or adolescent NHL in the spectrum of BRCA2-associated cancers," Dr. Wang said. "We are currently investigating the genetic alterations in tumor samples from NHL survivors to better understand how pathogenic germline BRCA2 variants lead to lymphoma development."

Dr. Catherine Diefenbach, Director of Hematology Translational Research at NYU Langone's Perlmutter Cancer Center in New York City, commented by email, "This study showed a small statistically significant association between patients with mutations in BRCA2 and the development of NHL."

"The study does not further stratify the NHL patients into subtypes to elucidate whether the BRCA2 mutation is associated with specific NHL histologies or subtypes such as B or T cell, or aggressive versus indolent," she told Reuters Health.

"Guidelines recommend that patients who are BRCA2 mutation carriers be offered surveillance for BRCA2-associated-cancers such as breast or ovarian," she noted. "However, the majority of lymphoma patients do not have BRCA2 mutations - i.e., the incidence in the study lymphoma population was 1.4%."

"Moreover," she added, "there is currently no standard for lymphoma-specific screening which can reduce lymphoma risk or has been known to improve lymphoma specific survival."

SOURCE: http://bit.ly/2YuwuVv

JAMA Oncol 2019.

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