Whole exome sequencing identifies recessive germline mutations in FAM160A1 in familial NK/T cell lymphoma

Chan, Jason Yongsheng; Ng, Alvin Yu Jin; Cheng, Chee Leong; Nairismagi, Maarja-Liisa; Venkatesh, Byrappa; Cheah, Daryl Ming Zhe; Li, Shao-Tzu; Chan, Sock Hoai; Ngeow, Joanne; Laurensia, Yurike; Lim, Jing Quan; Pang, Jane Wan Lu; Nagarajan, Sanjanaa; Song, Tongxing; Chia, Burton K.; Tan, Jian; Huang, Dachuan; Goh, Yeow Tee; Poon, Eileen; Somasundaram, Nagavalli; Tao, Miriam; Quek, Richard; Farid, Mohamad; Khor, Chiea Chuen; Bei, Jin‐Xin; Tan, Soo Yong; Lim, Soon Thye; Ong, Choon Kiat; Tang, Tiffany

doi:10.1038/s41408-018-0149-5

Cited by 6 publications

(5 citation statements)

References 12 publications

(17 reference statements)

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“…In the past decade, however, several oncogenic pathways, including Janus kinase (JAK)—signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), AKT, and NF-κB signaling pathways, have been identified in the development of NKTCL by gene expression profiling 15–20 . Recently, DDX3X , STAT3 , JAK3 , BCOR , and TP53 have been revealed as novel genes mutated in NKTCL by high-throughput sequencing studies 21–28 .…”

Section: Introductionmentioning

confidence: 99%

Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Zhang

Xue

et al. 2019

Nat Commun

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Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.

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Section: Introductionmentioning

confidence: 99%

Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Zhang

Xue

et al. 2019

Nat Commun

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“…Se encontró la mutación de la línea germinal del FAM1600AL en los casos de LNKTE nasal familiar, así como en otros cánceres. 14 Pese a los avances científicos, la predisposición genética como factor de riesgo es desconocida y la presencia de familiares con linfoma NK/T son extremadamente raros. 15 En el caso que se presenta, el paciente tuvo un hermano menor que fue diagnosticado con LNKTE nasal, recibió tratamiento y obtuvo mejoría, sin embargo, dos años después falleció por recidiva de la enfermedad.…”

Section: Discussionunclassified

Linfoma NK/T extranodal diagnosticado como celulitis orbitaria refractaria a tratamiento

Tito-Eusebio¹,

Gil-Clares²,

Pimentel³

2021

spmi

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Varón de 60 años, con antecedente familiar de hermano fallecido con diagnóstico de linfoma de células Natural Killer/T extranodales (LNKTE) tipo nasal, presentó un cuadro clínico compatible con celulitis orbitaria izquierda y, posteriormente, deterioro del estado general e insuficiencia hepática. Sin adecuada respuesta a los antibióticos, la biopsia del párpado reveló un LNKTE. Recibió tratamiento con quimioterapia y falleció un mes después del diagnóstico.

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“…Homozygous deletion of RASGRPI, leading to defective activation of the MAPK pathway and impaired immune response to EBV, is also documented as an inherited susceptibility to EBV infection and EBV-driven LPD such as ENKTCL [54]. In addition, homozygous germline mutation in FAM160A1 leading to alterations in the microenvironment is related to ENKTCL familiar susceptibility [55]. The geographic distribution of ENKTCL is characteristic with higher incidence among Native Americans, Hispanic and Asian ethnic groups [36].…”

Section: Enktcl Geographic Distributionmentioning

confidence: 99%

EBV and the Pathogenesis of NK/T Cell Lymphoma

Montes-Mojarro

Fend

Quintanilla-Martı́nez

2021

Cancers

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Epstein-Barr virus (EBV) is a ubiquitous gamma herpes virus with tropism for B cells. EBV is linked to the pathogenesis of B cell, T cell and NK cell lymphoproliferations, with extranodal NK/T cell lymphoma, nasal type (ENKTCL) being the prototype of an EBV-driven lymphoma. ENKTCL is an aggressive neoplasm, particularly widespread in East Asia and the native population of Latin America, which suggests a strong genetic predisposition. The link between ENKTCL and different populations has been partially explored. EBV genome sequencing analysis recognized two types of strains and identified variants of the latent membrane protein 1 (LMP1), which revealed different oncogenic potential. In general, most ENKTCL patients carry EBV type A with LMP1 wild type, although the LMP1 variant with a 30 base pair deletion is also common, especially in the EBV type B, where it is necessary for oncogenic transformation. Contemporary high-throughput mutational analyses have discovered recurrent gene mutations leading to activation of the JAK-STAT pathway, and mutations in other genes such as BCOR, DDX3X and TP53. The genomic landscape in ENKTCL highlights mechanisms of lymphomagenesis, such as immune response evasion, secondary to alterations in signaling pathways or epigenetics that directly or indirectly interfere with oncogenes or tumor suppressor genes. This overview discusses the most important findings of EBV pathogenesis and genetics in ENKTCL.

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Whole exome sequencing identifies recessive germline mutations in FAM160A1 in familial NK/T cell lymphoma

Cited by 6 publications

References 12 publications

Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Linfoma NK/T extranodal diagnosticado como celulitis orbitaria refractaria a tratamiento

EBV and the Pathogenesis of NK/T Cell Lymphoma

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