Cutaneous T-cell lymphoma in SHOC2 mutation-associated Noonan-like syndrome with loose anagen hair

Avery, Alexandria; Metcalf, John S.; Maize, John C.; Swanson, Leah A.

doi:10.1016/j.jdcr.2022.04.009

Cited by 5 publications

(2 citation statements)

References 11 publications

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“…The role of Shoc2 in cancer progression has been explored as well. Even though there is not enough evidence to suggest that NSLH Shoc2 mutations cause pediatric cancers, instances of neuroblastoma and cutaneous T-cell lymphoma have been reported in patients heterozygous for the c.4A>G Shoc2 variant (5,74). Several studies have suggested that Shoc2 could be an independent prognostic marker for breast, lung, and other cancers (75) or have evaluated Shoc2's feasibility as a therapeutic target for pancreatic, lung, and colorectal tumors (76)(77)(78).…”

Section: Discussionmentioning

confidence: 99%

The expression of congenital Shoc2 variants induces AKT-dependent feedback activation of the ERK1/2 pathway

Wilson,

Abdelmoti,

Gao

et al. 2023

Preprint

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The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary mutations in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these mutations affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. We found that, in cells expressing the Shoc2 NSLH mutants, the AKT signaling pathway triggers the PAK activation, followed by phosphorylation and Raf-1/MEK1/2 /ERK1/2 signaling axis activation. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide evidence for the Shoc2 role as a “gatekeeper” in controlling the selection of downstream effectors within the EGFR signaling network.

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Section: Discussionmentioning

confidence: 99%

The expression of congenital Shoc2 variants induces AKT-dependent feedback activation of the ERK1/2 pathway

Wilson,

Abdelmoti,

Gao

et al. 2023

Preprint

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“…The majority of cancers reported in NSML and NSLH have been case reports and therefore specific estimates of cancer incidence are not well described. Rare hematologic malignancies, such as myelofibrosis and T‐cell lymphoma, have been reported in NSLH (Avery, Metcalf, Maize, & Swanson, 2022; Gripp et al, 2013). Additionally, there have been cases of neuroblastoma in individuals with SHOC2 variants (Garavelli et al, 2015).…”

Section: Noonan Syndrome With Multiple Lentigines and Noonan Syndrome...mentioning

confidence: 99%

Cancer incidence and surveillance strategies in individuals withRASopathies

Ney

Gross

Livinski

et al. 2022

American J of Med Genetics Pt C

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RASopathies are a set of clinical syndromes that have molecular and clinical overlap.Genetically, these syndromes are defined by germline pathogenic variants in RAS/MAPK pathway genes resulting in activation of this pathway. Clinically, their common molecular signature leads to comparable phenotypes, including cardiac anomalies, neurologic disorders and notably, elevated cancer risk. Cancer risk in individuals with RASopathies has been estimated from retrospective reviews and cohort studies. For example, in Costello syndrome, cancer incidence is significantly elevated over the general population, largely due to solid tumors. In some forms of Noonan syndrome, cancer risk is also elevated over the general population and is enriched for hematologic malignancies. Thus, cancer surveillance guidelines have been developed to monitor for the occurrence of such cancers in individuals with some RASopathies. These include abdominal ultrasound and urinalyses for individuals with Costello syndrome, while complete blood counts and splenic examination are recommended in Noonan syndrome. Improved cancer risk estimates and refinement of surveillance recommendations will improve the care of individuals with RASopathies.

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RAS Family Interactions: The SHOC2-MRAS-PP1 Complex in Noonan Syndrome

Boned del Rio,

Rodriguez-Viciana

2024

The RASopathies

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Cutaneous T-cell lymphoma in SHOC2 mutation-associated Noonan-like syndrome with loose anagen hair

Cited by 5 publications

References 11 publications

The expression of congenital Shoc2 variants induces AKT-dependent feedback activation of the ERK1/2 pathway

The expression of congenital Shoc2 variants induces AKT-dependent feedback activation of the ERK1/2 pathway

Cancer incidence and surveillance strategies in individuals withRASopathies

RAS Family Interactions: The SHOC2-MRAS-PP1 Complex in Noonan Syndrome

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