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Letters to the Editor
Differences in other patient characteristics may also explain the discordance (e.g., patients with HLH in Singapore had stage III or IV disease, while most patients with HLH in Wen et al.’s cohort had early stage disease).
In summary, our data from multiple cohorts do not support the risk effect of ECSIT-T419 mutation (SNP rs145036301) on HLH in NKTCL. Furthermore, this is a germline rather than somatic mutation that appears in SNP database (dbSNP v153) and has now been flagged as a common polymorphic variant by Catalogue of Somatic Mutations in Cancer (COSMIC v90) databases.7,8 Additionally, there were no differences in clinical charac- teristics or prognosis between NKTCL patients with and without ECSIT-T419 mutation. One limitation of our study is not being able to examine whether germline vari- ants in genes associated with familial HLH are enriched in patients with NKTCL-associated HLH. However, recent studies have not shown an association of biallelic pathogenic variants in HLH-associated genes with adult HLH, albeit in cohorts that comprise a mixture of lym- phoma and non-lymphoma subtypes.9,10 Ultimately, addi- tional efforts to define disruptive variants in a larger num- ber of genes, in expanded cohorts of adults with lym- phoma associated HLH, may further refine our under- standing and treatment of this devastating condition.
Shin Yeu Ong,1* Jing Quan Lim,2,3* Nicholas Grigoropoulos,1 Yurike Laurensia,2 Dachuan Huang,2,3 Burton Kuan Hui Chia,2 Daryl Cheah Ming Zhe,2 Sahil Ajit Saraf,4 Chee Leong Cheng,4 Wen-Yu Chuang,5 Ming-Chung Kuo,6 Yi-Jiun Su,6 Colin Phipps,1 Chandramouli Nagarajan,1 Yuh Shan Lee,1 Daryl Tan Chen Lung,1 Lee-Yung Shih,6 Yeow Tee Goh,1 Soon Thye Lim2,3# and Choon Kiat Ong2,3,7#
Received: August 12, 2020.
Accepted: September 30, 2020. Pre-published: October 13, 2020. Disclosures: no conflicts of interest to disclose.
Contributions: CKO conceived the project and designed the study; SYO drafted the initial manuscript; CCL, SAS, and WYC performed pathological studies; YL performed sequencing studies; JQL and BKHC performed the bioinformatics analysis; SYO, JQL, DCH, DCMZ, CP, CN, YSL, DTCL, STL, MCK, YJS, and LYS recruit- ed participants, managed subject information and tissue samples, and contributed to data analysis; CKO, JQL, NG and YTG participated in critical revision of the manuscript.
Funding: the study was supported by grants from the Singapore Ministry of Health’s National Medical Research Council (NMRC-OFLCG-18May0028 and NMRC-ORIRG16nov090), Tanoto Foundation Professorship in Medical Oncology, New Century International Pte Ltd, Ling Foundation, and Chang Gung Memorial Hospital (OMRPG3C0021), Taiwan.
References
1. Jin Z, Wang Y, Wang J, et al. Multivariate analysis of prognosis for patients with natural killer/T cell lymphoma-associated hemo- phagocytic lymphohistiocytosis. Hematology. 2018;23(4):228-234.
2. Wen H, Ma H, Cai Q, et al. Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma. Nat Med. 2018; 24(2):154-164.
3. Jiang L, Gu ZH, Yan ZX, et al. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nat Genet. 2015;47(9):1061-1066.
4. Kim S, Scheffler K, Halpern AL, et al. Strelka2: fast and accurate call- ing of germline and somatic variants. Nat Methods. 2018;15(8):591-
1Department of Haematology, Singapore General Hospital, 594.
Singapore; 2National Cancer Center, Singapore; 3Duke-NUS Medical School, Singapore; 4Department of Pathology, Singapore General Hospital, Singapore; 5Department of Pathology, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, Taiwan; 6Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, and Chang Gung University, Taoyuan, Taiwan and 7Genome Institute of Singapore, A*STAR, Singapore.
*SYO and JQL contributed equally as co-first authors. #STL and CKO contributed equally as co-senior authors.
Correspondence:
CHOON KIAT ONG - cmrock@nccs.com.sg SOON THYE LIM - lim.soon.thye@singhealth.com.sg doi:10.3324/haematol.2020.269209
5. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and thera- peutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131.
6. Daver N, McClain K, Allen CE, et al. A consensus review on malig- nancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer. 2017;123(17):3229-3240.
7. Smigielski EM, Sirotkin K, Ward M, et al. dbSNP: a database of sin- gle nucleotide polymorphisms. Nucleic Acids Res. 2000;28(1):352- 355.
8. Tate JG, Bamford S, Jubb HC, et al. COSMIC: the Catalogue of Somatic Mutations In Cancer. Nucleic Acids Res. 2019; 47(D1):D941-D947.
9. Miller PG, Niroula A, Ceremsak JJ, et al. Identification of germline variants in adults with hemophagocytic lymphohistiocytosis. Blood Adv. 2020;4(5):925-929.
10. Carvelli J, Piperoglou C, Farnarier C, et al. Functional and genetic testing in adults with HLH reveals an inflammatory profile rather than a cytotoxicity defect. Blood. 2020;136(5):542-552.
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