Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma
| Autor: | Masashi Sanada, Arunrat Pirunsarn, June Takeda, Hiromichi Suzuki, Kenichi Yoshida, Noppacharn Uaprasert, Ponlapat Rojnuckarin, Hiroko Tanaka, Kenichi Chiba, Satoru Miyano, Sunisa Kongkiatkamon, Chatphatai Moonla, Hideki Makishima, Yuichi Shiraishi, Nobuyuki Kakiuchi, Panisinee Lawasut, Seishi Ogawa, Chantana Polprasert, Nobuhiro Akita, Kitsada Wudhikarn, Udomsak Bunworasate, Thamathorn Assanasen, Yasuhito Nannya, Wimonmas Sitthi, Yoichi Fujii, Yasuhide Takeuchi |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Panniculitis Biology medicine.disease_cause Compound heterozygosity Lymphoma T-Cell Germline Epigenesis Genetic Young Adult Germline mutation Subcutaneous Panniculitis-Like T-Cell Lymphoma medicine Missense mutation Humans Hepatitis A Virus Cellular Receptor 2 Exome sequencing Alleles Germ-Line Mutation Hemophagocytic lymphohistiocytosis Mutation Lymphoid Neoplasia Hematology Middle Aged medicine.disease Child Preschool Cancer research |
| Popis: | Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger patients and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole-exome sequencing. All cases were Asians and were phenotypically sporadic with no family history of SPTCL. Consistent with a recent report, germline mutations in HAVCR2, encoding T-cell immunoglobulin mucin 3 (TIM3), were identified in 11 of 13 (85%) cases. All mutated cases were primary SPTCL, whereas the 2 cases without mutation were secondary SPTCL associated with underlying diseases, including viral infection and autoimmune disease. Ten patients harbored homozygous p.Y82C mutations, and 1 showed compound heterozygous mutations (p.Y82C and p.T101I). Both missense mutations altered highly conserved residues located in the extracellular immunoglobulin variable–like domain. According to the Genome Aggregation Database of >138 500 general individuals, both mutations were documented with minor allele frequencies < 0.007, indicating remarkable enrichment of these HAVCR2 alleles in SPTCL. SPTCL cells also harbored somatic mutations (6.2 per patient) that are frequently identified in genes associated with epigenetic regulation and signal transduction. In conclusion, individuals harboring biallelic HAVCR2 (TIM3) germline mutations were highly susceptible to sporadic SPTCL, which was also associated with clonal somatic mutations. |
| Databáze: | OpenAIRE |
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