Association of Germline BRCA2 Mutations with The

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Benjamin J. Resio, MD BRCA2 as a potential predisposition gene for pediatric or ado- Jessica R. Hoag, PhD lescent lymphoma, we analyzed 794 additional survivors of Alexander S. Chiu, MD lymphoma from the SJLIFE study2 and Childhood Cancer Sur- Andres Monsalve, MD vivor Study3 cohorts, using whole-genome sequencing data. Tejas Sathe, BS Xiao Xu, PhD Methods | Participants included 5-year survivors of pediatric or Daniel J. Boffa, MD adolescent lymphomas. Germline whole-genome sequencing (30-fold coverage) was performed using DNA extracted Author Affiliations: Section of Thoracic Surgery, Department of Surgery, Yale from peripheral blood (SJLIFE study) or buccal or saliva School of Medicine, New Haven, Connecticut (Resio, Hoag, Chiu, Monsalve, samples (Childhood Cancer Survivor Study). This present study Boffa); Yale School of Medicine, New Haven, Connecticut (Sathe); Yale Center for Outcomes Research and Evaluation, New Haven, Connecticut (Xu). was approved by the institutional review board of St Jude Chil- Accepted for Publication: April 14, 2019. dren’s Research Hospital. Study participants provided writ- Published Online: July 11, 2019. doi:10.1001/jamaoncol.2019.1808 ten informed consent at the time of sample collection. Correction: This article was corrected on September 12, 2019, to fix errors in Germline single-nucleotide variants and small insertions the Results section and Table. In the first sentence of the Results section, the and deletions were detected by whole-genome sequencing.4 number of patients should be 73 680 not 2729. The P value for the last row of Genetic variants were annotated, and pathogenicity was clas- the Table (ie, All procedures) should be .06 not .10. sified according to the American College of Medical Genetics Corresponding Author: Daniel J. Boffa, MD, Section of Thoracic Surgery, and Genomics guidelines,5 with the processing pipeline pre- Department of Surgery, Yale School of Medicine, 330 Cedar St. BB205, PO Box 1 208062, New Haven, CT 06520-8062 ([email protected]). viously used in the SJLIFE study cohort. Author Contributions: Drs Resio, Hoag, and Boffa had full access to all of the We downloaded 177 putative loss-of-function BRCA2 mu- data in the study and takes responsibility for the integrity of the data and the tations (excluding those with low confidence), which passed accuracy of the data analysis. quality controls from the whole-exome sequencing source, Study concept and design: Resio, Chiu, Boffa. from gnomAD (Genome Aggregation Database) noncancer set, Acquisition, analysis, or interpretation of data: Resio, Hoag, Chiu, Monsalve, Sathe, Xu. version 2.1. The final numbers of BRCA2 mutation carriers and Drafting of the manuscript: Resio, Boffa. noncarriers were scaled according to the proportion of 3-way Critical revision of the manuscript for important intellectual content: All authors. admixture coefficients of the study population (data from Afri- Statistical analysis: Resio, Hoag, Chiu, Sathe. Obtained funding: Boffa. can, East Asian, and white participants in the 1000 Genomes Administrative, technical, or material support: Resio, Hoag. Project were used as references). Study supervision: Hoag, Boffa. The lymphoma-mutation associations were quantified as Conflict of Interest Disclosures: Dr Xu reported other from Centers for odds ratios (ORs), and their statistical significance was evaluated Medicare & Medicaid Services outside the submitted work. Dr Boffa reported by Fisher exact test. Statistical significance was defined by a nonfinancial support from Epic Sciences outside the submitted work. No other disclosures were reported. 2-sided P = .05. Age-distribution differences were assessed by 1. Gombeski WR Jr, Claypool JO, Karpf M, et al. Hospital affiliations, Wilcoxon rank sum test. R software, version 3.5.2 (R Foundation co-branding, and consumer impact. Health Mark Q. 2014;31(1):65-77. doi:10. for Statistical Computing), was used for statistical analysis. 1080/07359683.2014.874873 2. Chiu AS, Resio B, Hoag JR, et al. US public perceptions about cancer care Results | The 1380 total survivors comprised 815 survivors of provided by smaller hospitals associated with large hospitals recognized for Hodgkin lymphoma and 565 survivors of non–Hodgkin lym- specializing in cancer care. JAMA Oncol. 2018;4(7):1008-1009. doi:10.1001/ jamaoncol.2018.1400 phoma; of whom, 748 (54.2%) were male, and the median 3. Chiu AS, Resio B, Hoag JR, et al. Why travel for complex cancer surgery? (range) age at diagnosis was 13.4 (1.1–22.7) years (Table 1). Most Americans react to ‘brand-sharing’ between specialty cancer hospitals and their participants were white (604 [81.0%] in the SJLIFE study and affiliates. Ann Surg Oncol. 2019;26(3):732-738. doi:10.1245/s10434-018-6868-9 533 [84.1%] in the Childhood Cancer Survivor Study) and had 4. Hoag JR, Resio BJ, Monsalve AF, et al. Differential safety between a similar median (range) age at lymphoma diagnosis (13.5 [1.1- top-ranked cancer hospitals and their affiliates for complex cancer surgery. 22.7] years and 13.3 [1.2-21.0] years). We identified 13 P/LP JAMA Netw Open. 2019;2(4):e191912. doi:10.1001/jamanetworkopen.2019.1912 (pathogenic or likely pathogenic) mutations in BRCA2 (5 mu- 5. Birkmeyer JDSY, Sun Y, Wong SL, Stukel TA. Hospital volume and late survival after cancer surgery. Ann Surg. 2007;245(5):777-783. doi:10.1097/01.sla. tations [0.6%] in survivors of Hodgkin lymphoma, and 8 0000252402.33814.dd mutations [1.4%] in survivors of non–Hodgkin lymphoma). Mu- 6. Sheetz KH, Ryan AM, Ibrahim AM, Dimick JB. Association of hospital tation carriers were indistinguishable from noncarriers on the network participation with surgical outcomes and Medicare expenditures. Ann basis of median (range) age at lymphoma diagnosis (12.8 [6.0- Surg. 2018;(April). doi:10.1097/SLA.0000000000002791 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. Association of Germline BRCA2 Mutations In a comparison with controls without cancer from the With the Risk of Pediatric or Adolescent gnomAD (Table 2), we found a statistically significant asso- Non–Hodgkin Lymphoma ciation between lymphoma and mutations in BRCA2 (OR, 3.3; In a previous report from the St Jude Lifetime (SJLIFE) study, 95% CI, 1.7-5.8). When stratified by diagnosis, the association BRCA2 (GenBank U43746.1) was the third most frequently mu- was statistically significant for non–Hodgkin lymphoma (OR, tated gene (14 occurrences) among 3006 survivors of child- 5.0; 95% CI, 2.1-10.2) but did not achieve statistical signifi- hood cancer, with the highest number observed among sur- cance for Hodgkin lymphoma (OR, 2.1; 95% CI, 0.7-5.1). A ge- vivors of lymphoma (7 [1.2%] of 586).1 To further investigate netic counselor obtained cancer-focused family histories for

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Table 1. Characteristics of the Study Population

Survivors of Pediatric or Adolescent Lymphoma, No. (%) Hodgkin Lymphoma Non–Hodgkin Lymphoma All Lymphomas Variable SJLIFE CCSS SJLIFE CCSS SJLIFE CCSS Combined No. of survivors 467 348 279 286 746 634 1380 Sex Male 251 (53.8) 148 (42.5) 182 (65.2) 167 (58.4) 433 (58.0) 315 (49.7) 748 (54.2) Female 216 (46.2) 200 (57.5) 97 (34.8) 119 (41.6) 313 (42.0) 319 (50.3) 632 (45.8) Race/ethnicity White, non-Hispanic 380 (81.4) 298 (85.6) 224 (80.3) 235 (82.2) 604 (81.0) 533 (84.1) 1137 (82.39) Black, non-Hispanic 73 (15.6) 8 (2.3) 47 (16.9) 9 (3.2) 120 (16.1) 17 (2.7) 137 (9.9) Hispanic 8 (1.7) 33 (9.5) 2 (0.72) 18 (6.3) 10 (1.3) 51 (8.0) 61 (4.4) Other/unknown 6 (1.3) 9 (2.6) 6 (2.2) 24 (8.4) 12 (1.6) 33 (5.2) 45 (3.3) Age at primary diagnosis, y 0-4 11 (2.4) 4 (1.2) 38 (13.6) 48 (16.8) 49 (6.6) 52 (8.2) 101 (7.3) 5-9 70 (15.0) 45 (12.9) 93 (33.3) 75 (26.2) 163 (21.9) 120 (18.9) 283 (20.5) 10-14 168 (36.0) 148 (42.5) 89 (31.9) 96 (33.6) 257 (34.5) 244 (38.5) 501 (36.3) ≥15 218 (46.7) 151 (43.4) 59 (21.2) 67 (23.4) 277 (37.1) 218 (34.4) 495 (35.9) Median (range) 14.6 (3.0-22.7) 14.4 (2.0-21.0) 10.3 (1.1-19.9) 11 (1.2-20.9) 13.5 (1.1-22.7) 13.3 (1.2-21.0) 13.4 (1.1-22.7)

Abbreviations: CCSS, Childhood Cancer Survivor Study3; SJLIFE, St Jude Lifetime Cohort Study.2

Table 2. Comparison of Cancer Risk Associated With BRCA2 Mutations Among Survivors and Controls

No. Lymphoma Survivors Controls From gnomAD Cancer Riska Lymphoma Diagnosis Carriers Noncarriers Carriers Noncarriers OR (95% CI) P Value Hodgkin lymphoma and non–Hodgkin lymphoma 13 1367 170 59 175 3.3 (1.7-5.8) <.001 Hodgkin lymphoma 5 810 169 58 681 2.1 (0.7-5.1) .09 Non–Hodgkin lymphoma 8 557 171 59 902 5.0 (2.1-10.2) <.001

Abbreviations: gnomAD, Genome Aggregation Database; OR, odds ratio. a Cancer risk was calculated by Fisher exact test.

7 of the 8 survivors of non–Hodgkin lymphoma carrying a P/LP non–Hodgkin lymphoma and the penetrance within mutation- BRCA2 mutation. Six survivors had family histories of can- positive individuals will determine whether these recommen- cers, including breast, prostate, pancreas, and melanoma, all dations should be extended to all pediatric or adolescent pa- within the BRCA2-associated cancer spectrum. tients with a non-Hodgkin lymphoma diagnosis.

Discussion | In addition to being at risk for breast and ovarian Zhaoming Wang, PhD cancers, heterozygous BRCA2 mutation carriers are at an Carmen L. Wilson, PhD increased risk for other adult-onset malignant neoplasms, in- Gregory T. Armstrong, MD cluding pancreatic cancer, prostate cancer, and melanoma.6 Melissa M. Hudson, MD The increased non–Hodgkin lymphoma risk observed among Jinghui Zhang, PhD BRCA2 mutation carriers supports the inclusion of pediatric Kim E. Nichols, MD or adolescent non–Hodgkin lymphoma in the spectrum of Leslie L. Robison, PhD cancers associated with germline BRCA2 mutations. Genetic counseling and the option of BRCA2 genetic test- Author Affiliations: Department of Epidemiology and Cancer Control, St Jude Children’s Research Hospital, Memphis, Tennessee (Wang, Wilson, Armstrong, ing should be offered to survivors of pediatric or adolescent Hudson,Robison); DepartmentofComputationalBiology,StJudeChildren’sResearch non–Hodgkin lymphoma, particularly those with a family his- Hospital, Memphis, Tennessee (Wang, Zhang); Department of Oncology, St Jude tory of BRCA2-associated cancers. Survivors whose test re- Children’s Research Hospital, Memphis, Tennessee (Hudson, Nichols). sults are positive for mutation should be offered surveillance Accepted for Publication: June 28, 2019. for BRCA2-associated cancers, such as breast and ovarian, and Corresponding Author: Zhaoming Wang, PhD, Department of Epidemiology counseled about cancer risk–reducing strategies. Currently, and Cancer Control, St Jude Children’s Research Hospital, 262 Danny Thomas Pl, MS 735, Memphis, TN 38105 ([email protected]). it remains unclear whether surveillance for non–Hodgkin Published Online: July 25, 2019. doi:10.1001/jamaoncol.2019.2203 lymphoma is associated with early detection of lymphomas or with other medical advantages. Future investigation of 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 the prevalence of P/LP BRCA2 mutations among populations of the data analysis. Drs Wang, Nichols, and Robison contributed equally as of newly diagnosed pediatric or adolescent patients with senior investigators.

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Concept and design: Wang, Armstrong, Hudson, Zhang, Nichols, Robison. mitotic catastrophe. Mean time to the next mitosis after a pre- Acquisition, analysis, or interpretation of data: Wang, Wilson, Hudson, vious mitosis for NSCLC is likely longer than 10 weeks. The Zhang, Robison. Drafting of the manuscript: Wang. NSCLC mean doubling time was more than 100 days in 1 large 3 Critical revision of the manuscript for important intellectual content: Wilson, review. In vitro, radiobiology researchers do not examine Armstrong, Hudson, Zhang, Nichols, Robison. irradiated cells under the microscope to determine cell sur- Statistical analysis: Wang, Wilson. vival after RT; irradiated cells are cultured to count what pro- Obtained funding: Hudson, Zhang, Robison. Administrative, technical, or material support: Hudson, Zhang, Robison. portion of irradiated cells give rise to daughter cells (the plat- Supervision: Wang, Zhang, Nichols, Robison. ing efficiency). Hematoxylin and eosin staining of irradiated Conflict of Interest Disclosures: None. cells as done at 10 weeks in the study by Palma et al2 is mostly Funding/Support: This study was funded by a grant to St Jude Children’s meaningless to determine irradiated cells’ mitotic ability and Research Hospital from the American Lebanese Syrian Associated Charities patients’ ultimate future. and by grants CA021765 and CA195547 to St Jude Children’s Research Hospital In a study of rectal adenocarcinomas, when tumor speci- from the National Institutes of Health. mens were examined at more than 13 weeks vs 6 weeks or less Role of the Funder/Sponsor: The funders had no role in the design and 4 conduct of the study; collection, management, analysis, and interpretation of after RT, pCR rates more than doubled. This phenomenon of the data; preparation, review, or approval of the manuscript; and decision to increased pCR rate with passage of time (eg, over many months’ submit the manuscript for publication. time) has been seen in many settings. More time after RT equals Additional Contributions: The authors thank the following individuals for their more mitotic catastrophe. Furthermore, the pCR/local con- contributions to this study: Chimene A. Kesserwan, MD, Roya Mostafavi, MSc, trol (LC) correlation has not ever been reported using a 1-to-1 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, ratio—especially in early time frames—so it is inappropriate that Michael C. Rusch, BA, James R. Downing, MD, and Yutaka Yasui, PhD, all from Palma et al2 hypothesized a 1-to-1 ratio. There are no data to St Jude Children’s Research Hospital, as well as Smita Bhatia, MD, from suggest that the pCR behavior of NSCLC after RT would be University of Alabama at Birmingham. These individuals received much different than that seen in other cancers. The best indi- no compensation for their contributions. cator of LC may be measurement of local failure (ie, progres- Additional Information: BAM files and gVCF files for 1380 survivors of pediatric/adolescent lymphoma are accessible through the St Jude Cloud sion) after local therapy over time using time-failure analyses (https://stjude.cloud) under accession numbers SJC-DS-1002 and SJC-DS-1005. like Kaplan-Meier plots. 1. Wang Z, Wilson CL, Easton J, et al. Genetic risk for subsequent neoplasms There is a plethora of data on stereotactic ablative radio- among long-term survivors of childhood cancer. J Clin Oncol. 2018;36(20): therapy indicating very high LC rates, that irradiated cells take 2078-2087. doi:10.1200/JCO.2018.77.8589 a long time to reveal “death” from RT, and that microscopy- 2. Hudson MM, Ehrhardt MJ, Bhakta N, et al. Approach for classification and assessed pCR rates increase over time after RT. Per the media, severity grading of long-term and late-onset health events among childhood cancer survivors in the St. Jude lifetime cohort. Cancer Epidemiol Biomarkers Prev. the 60% pCR for stereotactic ablative radiotherapy at 10 weeks 2017;26(5):666-674. doi:10.1158/1055-9965.EPI-16-0812 reported by Palma et al2 is “eye-popping[ly]” bad.5 It is not. 3. Robison LL, Armstrong GT, Boice JD, et al. The Childhood Cancer Survivor For RT, early pCR rates are noninstructive. A 10-week 60% Study: a National Cancer Institute-supported resource for outcome and pCR rate is pretty good all things considered, although clini- intervention research. J Clin Oncol. 2009;27(14):2308-2318. doi:10.1200/JCO. cally superfluous. It is a radiobiological sin to think a 10-week 2009.22.3339 pCR after local RT is clinically informative. 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/ NEJMoa1508054 Todd J. Scarbrough, MD 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): Author Affiliation: Alabama Cancer Care and Northeast Alabama Regional apolicystatementoftheAmericanCollegeofMedicalGeneticsandGenomics. Genet Medical Center, Anniston. Med. 2017;19(2):249-255. doi:10.1038/gim.2016.190 Corresponding Author: Todd J. Scarbrough, MD, Alabama Cancer Care and 6. Moran A, O’Hara C, Khan S, et al. Risk of cancer other than breast or ovarian Northeast Alabama Regional Medical Center, 171 Town Center Dr, Anniston, AL in individuals with BRCA1 and BRCA2 mutations. Fam Cancer. 2012;11(2):235-242. 36205 ([email protected]). doi:10.1007/s10689-011-9506-2 Published Online: July 3, 2019. doi:10.1001/jamaoncol.2019.1879 Conflict of Interest Disclosures: None reported. COMMENT & RESPONSE 1. Ebert R. Review of The Passion of the Christ directed by Mel Gibson. February 24, 2004. https://www.rogerebert.com/reviews/the-passion-of-the-christ- Analysis of Pathologic Complete Response 10 Weeks 2004. Accessed March 2, 2019. After Radiotherapy—A Radiobiological Sin 2. Palma DA, Nguyen TK, Louie AV, et al. Measuring the integration of To the Editor In 2004, the late, great Roger Ebert penned one stereotactic ablative radiotherapy plus surgery for early-stage non–small cell lung cancer: a phase 2 clinical trial [published online February 21, 2019]. JAMA 1 of his best reviews for Mel Gibson’s The Passion of the Christ. Oncol. 2019. doi:10.1001/jamaoncol.2018.6993 Ebert posited how Christians violate their own beliefs if they 3. Detterbeck FC, Gibson CJ. Turning gray: the natural history of lung cancer argue that Jews killed Jesus; all men (via their sin), Ebert ar- over time. J Thorac Oncol. 2008;3(7):781-792. doi:10.1097/JTO.0b013e31817c9230 gued, killed Jesus. To count how many non–small cell lung 4. Macchia G, Gambacorta MA, Masciocchi C, et al. Time to surgery and cancer (NSCLC) cells radiotherapy killed (ie, the pathologic pathologic complete response after neoadjuvant chemoradiation in rectal complete response [pCR]) at 10 weeks after radiotherapy (RT) cancer: a population study on 2094 patients. Clin Transl Radiat Oncol. 2017;4: 8-14. doi:10.1016/j.ctro.2017.04.004 violates radiobiological beliefs.2 5. Harrison P. 'Eye-popping' pCR rate with SABR alone in early lung cancer. Cells are (almost) never immediately killed after RT. Irra- https://www.medpagetoday.com/hematologyoncology/lungcancer/78181. diated cells die after attempting mitosis in a process termed Accessed March 2, 2019.

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