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Table 1.  
Characteristics of the Study Population
Characteristics of the Study Population
Table 2.  
Comparison of Cancer Risk Associated With BRCA2 Mutations Among Survivors and Controls
Comparison of Cancer Risk Associated With BRCA2 Mutations Among Survivors and Controls
1.
Wang  Z, Wilson  CL, Easton  J,  et al.  Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer.  J Clin Oncol. 2018;36(20):2078-2087. doi:10.1200/JCO.2018.77.8589PubMedGoogle ScholarCrossref
2.
Hudson  MM, Ehrhardt  MJ, Bhakta  N,  et al.  Approach for classification and severity grading of long-term and late-onset health events among childhood cancer survivors in the St. Jude lifetime cohort.  Cancer Epidemiol Biomarkers Prev. 2017;26(5):666-674. doi:10.1158/1055-9965.EPI-16-0812PubMedGoogle ScholarCrossref
3.
Robison  LL, Armstrong  GT, Boice  JD,  et al.  The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research.  J Clin Oncol. 2009;27(14):2308-2318. doi:10.1200/JCO.2009.22.3339PubMedGoogle ScholarCrossref
4.
Zhang  J, Walsh  MF, Wu  G,  et al.  Germline mutations in predisposition genes in pediatric cancer.  N Engl J Med. 2015;373(24):2336-2346. doi:10.1056/NEJMoa1508054PubMedGoogle ScholarCrossref
5.
Kalia  SS, Adelman  K, Bale  SJ,  et al.  Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.  Genet Med. 2017;19(2):249-255. doi:10.1038/gim.2016.190PubMedGoogle ScholarCrossref
6.
Moran  A, O’Hara  C, Khan  S,  et al.  Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations.  Fam Cancer. 2012;11(2):235-242. doi:10.1007/s10689-011-9506-2PubMedGoogle ScholarCrossref
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Research Letter
July 25, 2019

Association of Germline BRCA2 Mutations With the Risk of Pediatric or Adolescent Non–Hodgkin Lymphoma

Author Affiliations
  • 1Department of Epidemiology and Cancer Control, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 2Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 3Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee
JAMA Oncol. 2019;5(9):1362-1364. doi:10.1001/jamaoncol.2019.2203

In a previous report from the St Jude Lifetime (SJLIFE) study, BRCA2 (GenBank U43746 .1) was the third most frequently mutated gene (14 occurrences) among 3006 survivors of childhood cancer, with the highest number observed among survivors of lymphoma (7 [1.2%] of 586).1 To further investigate BRCA2 as a potential predisposition gene for pediatric or adolescent lymphoma, we analyzed 794 additional survivors of lymphoma from the SJLIFE study2 and Childhood Cancer Survivor Study3 cohorts, using whole-genome sequencing data.

Methods

Participants included 5-year survivors of pediatric or adolescent lymphomas. Germline whole-genome sequencing (30-fold coverage) was performed using DNA extracted from peripheral blood (SJLIFE study) or buccal or saliva samples (Childhood Cancer Survivor Study). This present study was approved by the institutional review board of St Jude Children’s Research Hospital. Study participants provided written informed consent at the time of sample collection.

Germline single-nucleotide variants and small insertions and deletions were detected by whole-genome sequencing.4 Genetic variants were annotated, and pathogenicity was classified according to the American College of Medical Genetics and Genomics guidelines,5 with the processing pipeline previously used in the SJLIFE study cohort.1

We downloaded 177 putative loss-of-function BRCA2 mutations (excluding those with low confidence), which passed quality controls from the whole-exome sequencing source, from gnomAD (Genome Aggregation Database) noncancer set, version 2.1. The final numbers of BRCA2 mutation carriers and noncarriers were scaled according to the proportion of 3-way admixture coefficients of the study population (data from African, East Asian, and white participants in the 1000 Genomes Project were used as references).

The lymphoma-mutation associations were quantified as odds ratios (ORs), and their statistical significance was evaluated by Fisher exact test. Statistical significance was defined by a 2-sided P = .05. Age-distribution differences were assessed by Wilcoxon rank sum test. R software, version 3.5.2 (R Foundation for Statistical Computing), was used for statistical analysis.

Results

The 1380 total survivors comprised 815 survivors of Hodgkin lymphoma and 565 survivors of non–Hodgkin lymphoma; of whom, 748 (54.2%) were male, and the median (range) age at diagnosis was 13.4 (1.1–22.7) years (Table 1). Most participants were white (604 [81.0%] in the SJLIFE study and 533 [84.1%] in the Childhood Cancer Survivor Study) and had a similar median (range) age at lymphoma diagnosis (13.5 [1.1-22.7] years and 13.3 [1.2-21.0] years). We identified 13 P/LP (pathogenic or likely pathogenic) mutations in BRCA2 (5 mutations [0.6%] in survivors of Hodgkin lymphoma, and 8 mutations [1.4%] in survivors of non–Hodgkin lymphoma). Mutation carriers were indistinguishable from noncarriers on the basis of median (range) age at lymphoma diagnosis (12.8 [6.0-17.7] years vs 13.5 [1.1-22.7] years; P = .40). All 8 survivors of non–Hodgkin lymphoma with BRCA2 mutations were male.

In a comparison with controls without cancer from the gnomAD (Table 2), we found a statistically significant association between lymphoma and mutations in BRCA2 (OR, 3.3; 95% CI, 1.7-5.8). When stratified by diagnosis, the association was statistically significant for non–Hodgkin lymphoma (OR, 5.0; 95% CI, 2.1-10.2) but did not achieve statistical significance for Hodgkin lymphoma (OR, 2.1; 95% CI, 0.7-5.1). A genetic counselor obtained cancer-focused family histories for 7 of the 8 survivors of non–Hodgkin lymphoma carrying a P/LP BRCA2 mutation. Six survivors had family histories of cancers, including breast, prostate, pancreas, and melanoma, all within the BRCA2-associated cancer spectrum.

Discussion

In addition to being at risk for breast and ovarian cancers, heterozygous BRCA2 mutation carriers are at an increased risk for other adult-onset malignant neoplasms, including pancreatic cancer, prostate cancer, and melanoma.6 The increased non–Hodgkin lymphoma risk observed among BRCA2 mutation carriers supports the inclusion of pediatric or adolescent non–Hodgkin lymphoma in the spectrum of cancers associated with germline BRCA2 mutations.

Genetic counseling and the option of BRCA2 genetic testing should be offered to survivors of pediatric or adolescent non–Hodgkin lymphoma, particularly those with a family history of BRCA2-associated cancers. 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. Currently, it remains unclear whether surveillance for non–Hodgkin lymphoma is associated with early detection of lymphomas or with other medical advantages. Future investigation of the prevalence of P/LP BRCA2 mutations among populations of newly diagnosed pediatric or adolescent patients with non–Hodgkin lymphoma and the penetrance within mutation-positive individuals will determine whether these recommendations should be extended to all pediatric or adolescent patients with a non-Hodgkin lymphoma diagnosis.

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Article Information

Accepted for Publication: June 28, 2019.

Corresponding Author: Zhaoming Wang, PhD, Department of Epidemiology and Cancer Control, St Jude Children’s Research Hospital, 262 Danny Thomas Pl, MS 735, Memphis, TN 38105 (zhaoming.wang@stjude.org).

Published Online: July 25, 2019. doi:10.1001/jamaoncol.2019.2203

Author Contributions: Drs Wang and Robison had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Wang, Nichols, and Robison contributed equally as senior investigators.

Concept and design: Wang, Armstrong, Hudson, Zhang, Nichols, Robison.

Acquisition, analysis, or interpretation of data: Wang, Wilson, Hudson, Zhang, Robison.

Drafting of the manuscript: Wang.

Critical revision of the manuscript for important intellectual content: Wilson, Armstrong, Hudson, Zhang, Nichols, Robison.

Statistical analysis: Wang, Wilson.

Obtained funding: Hudson, Zhang, Robison.

Administrative, technical, or material support: Hudson, Zhang, Robison.

Supervision: Wang, Zhang, Nichols, Robison.

Conflict of Interest Disclosures: None.

Funding/Support: This study was funded by a grant to St Jude Children’s Research Hospital from the American Lebanese Syrian Associated Charities and by grants CA021765 and CA195547 to St Jude Children’s Research Hospital from the National Institutes of Health.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The authors thank the following individuals for their contributions to this study: Chimene A. Kesserwan, MD, Roya Mostafavi, MSc, Ti-Cheng Chang, PhD, Nan Li, PhD, Todd M. Gibson, PhD, Na Qin, MD, John Easton, PhD, Heather Mulder, BS, Gang Wu, PhD, Michael N. Edmonson, BA, Michael C. Rusch, BA, James R. Downing, MD, and Yutaka Yasui, PhD, all from St Jude Children’s Research Hospital, as well as Smita Bhatia, MD, from University of Alabama at Birmingham. These individuals received no compensation for their contributions.

Additional Information: BAM files and gVCF files for 1380 survivors of pediatric/adolescent lymphoma are accessible through the St Jude Cloud (https://stjude.cloud) under accession numbers SJC-DS-1002 and SJC-DS-1005.

References
1.
Wang  Z, Wilson  CL, Easton  J,  et al.  Genetic risk for subsequent neoplasms among long-term survivors of childhood cancer.  J Clin Oncol. 2018;36(20):2078-2087. doi:10.1200/JCO.2018.77.8589PubMedGoogle ScholarCrossref
2.
Hudson  MM, Ehrhardt  MJ, Bhakta  N,  et al.  Approach for classification and severity grading of long-term and late-onset health events among childhood cancer survivors in the St. Jude lifetime cohort.  Cancer Epidemiol Biomarkers Prev. 2017;26(5):666-674. doi:10.1158/1055-9965.EPI-16-0812PubMedGoogle ScholarCrossref
3.
Robison  LL, Armstrong  GT, Boice  JD,  et al.  The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research.  J Clin Oncol. 2009;27(14):2308-2318. doi:10.1200/JCO.2009.22.3339PubMedGoogle ScholarCrossref
4.
Zhang  J, Walsh  MF, Wu  G,  et al.  Germline mutations in predisposition genes in pediatric cancer.  N Engl J Med. 2015;373(24):2336-2346. doi:10.1056/NEJMoa1508054PubMedGoogle ScholarCrossref
5.
Kalia  SS, Adelman  K, Bale  SJ,  et al.  Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.  Genet Med. 2017;19(2):249-255. doi:10.1038/gim.2016.190PubMedGoogle ScholarCrossref
6.
Moran  A, O’Hara  C, Khan  S,  et al.  Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations.  Fam Cancer. 2012;11(2):235-242. doi:10.1007/s10689-011-9506-2PubMedGoogle ScholarCrossref
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