Frequent BCOR aberrations in extranodal NK/T‐Cell lymphoma, nasal type

Abstract

Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK-STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer-related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples. Several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%), and MIR17HG (8%) were identified. The pattern of BCOR aberrations (1 nonsense and 5 frame-shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. The literature was reviewed and the public data on BCOR aberrations was reanalyzed and it was found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene.

Frequent Mutations in Natural Killer/T Cell Lymphoma

“…Another study of a Chinese population revealed an similar frequency of 12% (three of 25) [65]. This frequency was found to be higher in Korea (26.4%, nine of 34) [66] and slightly lower in Japan (8%, two of 25) [18]. STAT3 mutations were found to occur at several (Fig.…”

“…Traditional Sanger sequencing technology revealed very high mutation frequencies of TP53 in NKTCL, specifically, 63% (17 of 27 cases) in Indonesia [13], 40% (eight of 20 cases) in China [14], 18.9% (six of 32 cases) and 62% (36 of 58 cases) in Japan [15,16], and 31% (13 of 42 cases) in Korea [15]. These high frequencies were detected using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) followed by direct sequencing.…”

“…This method can detect mutant DNA in as little as 3% of the total gene copies in a PCR mixture [17]. Recently, TP53 mutations in NKTCL were also studied by NGS, but the frequencies were relatively lower at 13.3% (14 of 105 cases) among the Chinese population [11], and 16% (four of 25) and 20% (one of five) in Japanese and Korean cohorts [18,19], respectively. There is thus an apparent discrepancy in reported frequencies between the two methods.…”

“…DDX3X has been reported to be a tumor suppressor in medulloblastoma and its dysregulation is thought to be involved in tumorigenesis [35]. A study of 25 Japanese individuals identified three (12%) DDX3X alterations in NKTCL by traditional Sanger sequencing [18]. However, another larger-scale study [11], comprising 105 samples in China and using NGS, revealed a higher frequency (20%; 21 of 105 cases).…”

“…Recently, MGA mutations were identified in NKTCL by NGS. Specifically, these were reported in two of 25 cases (8%) in Japan [18], and nine of 105 cases (8.6%) in China [11]. However, the details regarding these mutations are not available, and their underlying significance in NKTCL have not been reported to date.…”