RHOA – Angioimmunoblastic T-cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell neoplasm derived from follicular helper T cells, characterized clinically by generalized lymphadenopathy and B symptoms, including night sweats and weight loss. Somatic mutations in the RHOA gene, encoding a small GTPase, have emerged as a molecular hallmark in AITL alongside recurrent alterations in epigenetic regulators such as TET2 and IDH2. Precise molecular profiling of RHOA mutations refines diagnostic classification and informs targeted management strategies.

Genetic evidence for RHOA in AITL is robust. Multi-patient studies demonstrate that the p.Gly17Val variant (c.50G>T (p.Gly17Val)) occurs in approximately 56–68% of AITL cases across independent cohorts, with no detection in reactive or other T-cell lymphomas ([PMID:27158755], [PMID:24413737]). In a series of 18 formalin-fixed tissue samples, RHOA G17V was identified in 10 cases (56%) by three sequencing methods, correlating with distinctive follicular helper T-cell immunophenotypes ([PMID:27158755]). Larger sequencing of 92 cases confirmed RHOA p.Gly17Val in 68% of AITL and its confinement to tumor cells, often co-occurring with TET2 mutations ([PMID:24413737]).

The variant spectrum in RHOA-mutated AITL is dominated by the c.50G>T (p.Gly17Val) hotspot, reflecting a gain-of-function phenotype in diffuse gastric cancer but a dominant-negative effect in AITL. Rare mutations at Lys18Asn, Arg68His, Cys83Tyr, and Gly17del are also reported at low frequency, underscoring the selectivity of Gly17 for AITL pathogenesis.

Functional studies reveal that the Gly17Val substitution abrogates GTP binding and impairs intrinsic GTPase activity, while paradoxically augmenting adaptor interactions with VAV1. G17V-RHOA binds VAV1, enhances its Tyr174 phosphorylation, and accelerates T-cell receptor signaling, promoting Tfh specification and lymphomagenesis in vitro ([PMID:28832024]). These mechanistic insights link RHOA mutation to deregulated TCR signaling and follicular helper T-cell differentiation.

Clinically, detection of RHOA G17V by sensitive PCR-based assays or deep sequencing supports early and accurate differentiation of AITL from mimickers such as peripheral T-cell lymphoma, not otherwise specified. Presence of RHOA G17V correlates with increased microvessel density, B symptoms, splenomegaly, and poorer progression-free survival, highlighting its value as a prognostic biomarker ([PMID:27158755]). Furthermore, the RHOA–VAV1 axis represents a potential therapeutic target, with kinase inhibitors shown to block downstream signaling in preclinical models.

In summary, the strong, recurrent association of RHOA c.50G>T (p.Gly17Val) with AITL, combined with concordant functional data on impaired GTPase activity and enhanced TCR signaling, supports a classification of "Strong" clinical validity under ClinGen criteria. Somatic RHOA genotyping is essential for precise diagnosis, prognostic stratification, and development of targeted interventions. Key Take-home: RHOA mutation testing is a critical component of AITL workup, informing diagnosis, prognosis, and future precision-medicine trials.

References

• The American journal of surgical pathology • 2016 • Clinicopathologic Analysis of Angioimmunoblastic T-cell Lymphoma With or Without RHOA G17V Mutation Using Formalin-fixed Paraffin-embedded Sections. PMID:27158755
• Nature genetics • 2014 • Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. PMID:24413737
• Leukemia • 2018 • Activation of RHOA-VAV1 signaling in angioimmunoblastic T-cell lymphoma. PMID:28832024

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