PLCG1 mutations in cutaneous T-cell lymphomas
Menée initialement sur une cohorte de 11 patients atteints d'un lymphome T cutané, puis sur une cohorte complémentaire de 42 patients, cette étude identifie des mutations du gène PLCG1 associées à la prolifération des cellules cancéreuses
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, and whose aggressive forms lack effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCR). DNAs from 11 CTCL patients, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection of 524 TCR-signaling related genes. Identified variants were validated by capillary sequencing. Multiple mutations were found that affected several signaling pathways like TCR, NFKB or JAK-STAT, but PLCG1 was found to be mutated in three samples, two of which featured a redundant mutation (c.1034T>C, S345F) in exon 11 that affects the PLCx protein catalytic domain. This mutation was further analyzed by qPCR-genotyping in a new cohort of 42 CTCL patients, where it was found in 19% of samples. Immunohistochemical analysis for NFAT showed that PLCG1-mutated cases exhibited strong NFAT nuclear immunostaining. Functional studies demonstrated that PLCG1 mutants elicited increased downstream signaling towards NFAT activation, and inhibition of this pathway resulted in reduced CTCL cell proliferation and cell viability. Thus, increased proliferative and survival mechanisms in CTCL may partially depend on the acquisition of somatic mutations in PLCG1 and other genes that are essential for normal T-cell differentiation.
Blood 2014