Genetic profile of adult T‐cell leukemia/lymphoma in Okinawa: Association with prognosis, ethnicity, and HTLV‐1 strains

Abstract

Genetic alterations in adult T‐cell leukemia/lymphoma (ATLL), a T‐cell malignancy associated with HTLV‐1, and their clinical impacts, especially from the perspective of viral strains, are not fully elucidated. We employed targeted next‐generation sequencing and single nucleotide polymorphism array for 89 patients with ATLL in Okinawa, the southernmost islands in Japan, where the frequency of HTLV‐1 tax subgroup‐A (HTLV‐1‐taxA) is notably higher than that in mainland Japan, where most ATLL cases have HTLV‐1‐taxB, and compared the results with previously reported genomic landscapes of ATLL in mainland Japan and the USA. Okinawan patients exhibited similar mutation profiles to mainland Japanese patients, with frequent alterations in TCR/NF‐ĸB (eg, PRKCB, PLCG1, and CARD11) and T‐cell trafficking pathways (CCR4 and CCR7), in contrast with North American patients who exhibited a predominance of epigenome‐associated gene mutations. Some mutations, especially GATA3 and RHOA, were detected more frequently in Okinawan patients than in mainland Japanese patients. Compared to HTLV‐1‐taxB, HTLV‐1‐taxA was significantly dominant in Okinawan patients with these mutations (GATA3, 34.1% vs 14.6%, P = .044; RHOA, 24.4% vs 6.3%, P = .032), suggesting the contribution of viral strains to these mutation frequencies. From a clinical viewpoint, we identified a significant negative impact of biallelic inactivation of PRDM1 (P = .027) in addition to the previously reported PRKCB mutations, indicating the importance of integrated genetic analysis. This study suggests that heterogeneous genetic abnormalities in ATLL depend on the viral strain as well as on the ethnic background. This warrants the need to develop therapeutic interventions considering regional characteristics.

C-C Chemokine Receptor 7 in Cancer

“…In adult T-cell leukemia/lymphoma, evidence suggests that both genetic mutations and epigenetic changes are involved in cancer progression. Common CCR7 SNPs were found in Japanese adult T-cell leukemia/lymphoma patients, although CCR7 differences were typically epigenetic changes rather than gene mutations in North American patients [ 249 ]. In addition to SNPs, most of the larger CCR7 mutations in adult T-cell leukemia/lymphoma patients were truncations of the C-terminus cytoplasmic domain, which were likely gain-of-function mutations [ 250 ].…”

“…Adult T-cell leukemia patients with lymphoid involvement were more likely to express CCR7 than patients with no lymphoid association [ 248 ]. Next-generation sequencing was used to investigate single-nucleotide polymorphisms in adult T-cell leukemia/lymphoma patients from different regions of Japan, where it was found that similar mutation profiles occurred, including in the CCR7 gene, likely responsible for T-cell trafficking [ 249 ]. The results, however, contrasted with patient analysis from North America that showed a dominance of epigenetic modifications over genetic mutations [ 249 ].…”

“…Next-generation sequencing was used to investigate single-nucleotide polymorphisms in adult T-cell leukemia/lymphoma patients from different regions of Japan, where it was found that similar mutation profiles occurred, including in the CCR7 gene, likely responsible for T-cell trafficking [ 249 ]. The results, however, contrasted with patient analysis from North America that showed a dominance of epigenetic modifications over genetic mutations [ 249 ]. Most of the CCR7 mutations in adult T-cell leukemia/lymphoma patients were truncations of the C-terminus cytoplasmic domain and were associated with elevated membrane localization of the CCR7 receptor, which the authors suggested was likely a gain-of-function mutation [ 250 ].…”

CCR7 in Blood Cancers – Review of Its Pathophysiological Roles and the Potential as a Therapeutic Target

“…These mutations led to an enhanced ligand-induced chemotaxis and PI3K/AKT signaling (162,163). More recently, CCR7 gene mutations were mutually associated with mutations at phospholipase C gamma 1 (PLCG1) and caspase recruitment domain family member 11 (CARD11) genes, which are frequent alterations in TCR/NF-ĸB signaling (164). The pathological implications of this coexistence in ATLL remain unaddressed.…”

Deconvolution of Adult T-Cell Leukemia/Lymphoma With Single-Cell RNA-Seq Using Frozen Archived Skin Tissue Reveals New Subset of Cancer-Associated Fibroblast

“…Since HTLV-1 infection is endemic in southwestern Japan, ATLL has been mainly reported in the same region ( 3 , 4 ). Recent advances in next-generation sequencing (NGS) technology have provided more detailed information on the unique pathogenesis of ATLL compared to other subtypes of peripheral T-cell lymphoma (PTCL) ( 5 – 7 ). Copy number abnormalities (CNAs) of ATLL are comparable to the PTCL-GATA3 subgroup ( 5 ), and gene expression profiling has been used to define distinct diagnostic and prognostic subtypes of PTCL ( 8 ).…”