Mutational Landscape of Relapsed or Refractory Extranodal Natural Killer (NK)/T-Cell Lymphoma in Chinese Patients

Introduction:

Extranodal natural killer/T-cell lymphoma (ENKTL), which is a very aggressive disease with poor prognosis, is prevalent in East Asian populations and accounts for 5-10% of all lymphomas in the Chinese population. The pathogenesis and molecular characteristics of different subgroups of ENKTL have largely remained elusive.

Methods:

Samples from 12 patients, aged 13 to 79, who were diagnosed with ENKTL in southwest China and received chemotherapy as first-line therapy, were collected for whole-exome sequencing (WES). Samples included 5 relapsed/refractory (rel/ref) patients and 7 treatment effective patients. The inclusion criteria for rel/ref group were that the patient progressed after 2 cycles of standard or conventional first-line treatment, or failed to achieve complete remission after 4 cycles (complete response (CR), or CR after treatment, but relapsed within 1 year after treatment). The inclusion criteria for the treatment effective group were that patient achieved CR after treatment, confirmed by long-term survival and no recurrence found after follow-up. In the rel/ref group, 3 cases occurred in the nasal cavity and 2 cases occurred outside the nasal cavity. In the treatment effective group, 3 cases occurred in the nasal cavity and 4 cases occurred outside the nasal cavity. The median overall survival (OS) in the rel/ref group and treatment effective group was 36 weeks and 80 weeks, respectively. Genomic DNA of tumors was extracted from the formalin-fixed, paraffin-embedded (FFPE) samples by using QIAamp DNA FFPE Tissue Kit. Along with virus infection status, somatic genomic alterations, including single nucleotide variations (SNV), short and long insertions and deletions (Indel), copy number variations (CNV), and gene rearrangements, were analyzed.

Results:

Common gene mutations (frequencies ≥25%) that occurred in both the rel/ref and treatment effective group included TP53, CD274, CSMD2, CUL9, EPPK1, PCDHA6, PCSK5, PKHD1, SDK1, STAT3 and TNXB. Relatively specific genes to the rel/ref group were ABCA13, COL22A1, NOTCH1, NDN, OBSL1, PPFIA2, SDK2, ZFP36L2, and ZNF860. In addition, we found that the most frequently mutated genes were different in patients with ENKTL occurring in the nasal cavity compared to those outside the nasal cavity. The high frequency mutated genes relatively specific to ENKTL in the nasal cavity were TP53 (50% vs. 17%), PKHD1 (50% vs. 0%), SDK1 (50% vs. 0%) and TNXB (50% vs. 0%), while in ENKTL outside the nasal cavity, EPPK1 (0% vs. 50%) was the most mutated gene. Meanwhile, we detected the wildly concerned biomarker CD274 (33% vs. 17%) and CHD8 (33% vs. 0%) in ENKTL occurring in the nasal cavity, and STAT3 (17% vs. 33%) in ENKTL outside the nasal cavity. Furthermore, we revealed that gene rearrangements were more common in the treatment effective group than in the rel/ref group (43% vs. 20%, respectively). A CD274 rearrangement and two TARP rearrangement were detected in 3/7 treatment effective patients, however, in the rel/ref ENKTL group, only a CD274 rearrangement was found. In this cohort, one ENKTL patient (1/12) exhibited a high tumor mutational burden (TMB) (15.4 Muts/Mb).

Conclusion:

Our findings revealed the molecular characteristics of different ENKTL subgroups, especially in the rel/ref subgroup, which might provide useful information for targeted/immunotherapy of ENKTL patients.