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Letters to the Editor
Figure 2. The results of shared and non-shared mutation analysis combined with the clinicopathological and IgH-clonality characteristics. The shared and non- shared mutations in the paired tumor samples were described separately. The numbers of mutations in each gene were expressed as shades of grey and black. All eight patients with tumor mutations in CD79B and/or MYD88 had non-germinal-center B-cell-like lymphoma (DLBCL). Clonal relationships between the paired tumors, which were determined using immunoglobulin heavy chain PCR analysis, were confirmed in 6 of the 8 patients. No clear trends were observed in the patterns of the non-shared mutations.
chemotherapy once, but be prone to continuous relapse, as observed in our study.
The paired specimens of 2 patients (#8 and #10) were judged to be clonally unrelated based on the IgH clonality analysis. However, patient #8 had shared mutations in the paired specimens that involved CREBBP, KMT2D, MEF2B, and PIM1. Furthermore, FISH analysis using FFPE specimens revealed BCL2/IGH translocations in the paired tumors (data not shown). Abnormalities in the CREBBP, KMT2D, MEF2B, and PIM1 genes are reported- ly associated with lymphomagenesis,8,12-14 and lym- phoma-progenitor cells acquiring these mutations may develop DLBCL with different IgH rearrangements in the same patient. The background of the clonally unrelated relapse could not be determined in patient #10, and a rare second primary DLBCL might occur in this patient.
Our findings suggested that the mechanisms of LR were heterogeneous. The acquired overexpression of MYC or BCL28 might be associated with LR in some patients, although it is not considered specific for LR. We cannot definitively comment on the possibility that recurrent mutations were associated with LR; the two most common non-shared mutations involved PIM1 (five samples) and KMT2D (two samples), although they were not consistently detected at initial diagnosis or LR. At LR, two patients expressed PD-L1, and three had acquired loss of function mutations involving B2M, CD58, or CIITA, which might be associated with an immune eva- sion mechanism related to avoidance of antigen presen- tation.
The present study has several limitations. First, only a small number of patients developed LR. Second, many of the initial tumor specimens were old, which might have affected the results of the genetic analyses. However, the reliability of shared mutations is likely robust, as it is
extremely rare to identify the same mutation in paired samples by chance. Furthermore, we only considered 64 lymphoma-related genes, and other important genetic alterations might be missed. Again, we did not perform the genetic analyses or COO evaluations for all patients with limited-stage DLBCL; thus, it remains unclear whether our findings are truly specific for LR develop- ment.
In conclusion, the present study revealed that patients with limited-stage DLBCL and LR tended to have CD79B and/or MYD88 tumor mutations, the non-GCB type of DLBCL, and extranodal disease at the initial presentation. However, the mechanisms of LR appear to be heteroge- neous, and further studies are needed to confirm our results.
Tomotaka Suzuki,1 Suguru Fukuhara,1 Junko Nomoto,1,4 Satoshi Yamashita,3 Akiko (Miyagi) Maeshima,2 Yuta Ito,1 Shunsuke Hatta,1 Sayako Yuda,1 Shinichi Makita,1 Wataru Munakata,1 Tatsuya Suzuki,1 Dai Maruyama,1 Hirokazu Taniguchi,2 Toshikazu Ushijima,3 Koji Izutsu,1 Kensei Tobinai1 and Yukio Kobayashi1,5
1Department of Hematology, National Cancer Center Hospital; 2Department of Pathology, National Cancer Center Hospital; 3Department of Epigenomics, National Cancer Center Research Institute; 4Institute of Medical Genomics, IUHW, Chiba and 5Department of Hematology, IUHW Mita Hospital, Tokyo, Japan
Correspondence: SUGURU FUKUHARA - sufukuha@ncc.go.jp
doi:10.3324/haematol.2019.235598
Disclosures: TS reports personal fees from Chugai Pharmaceutical, outside the submitted work; DM reports grants and personal fees from Chugai, grants and personal fees from Takeda, during the conduct of the study; grants from Sanofi, grants and personal fees from Janssen, grants and personal fees from Eisai, grants and personal fees from Celegene, grants and personal fees from Kyowa Hakko Kirin,
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