The authors review the sparse literature on molecular-genetic aberrations involving the epidermal growth factor receptor family of receptor tyrosine kinases (ERBB1/EGFR, ERBB2, ERBB3, and ERBB4) in uterine mesenchymal tumors, a review that suggests that such tumors may be pathologically heterogeneous. The potential clinical significance of demonstrating a targetable ERBB2/ERBB3 tyrosine kinase mutation or other EGFR family aberrations, as well as its distinctive pathologic profile, supports the segregation of the tumor reported herein as a distinct and emerging entity.

12 months ago

Journal

EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • ALK (Anaplastic lymphoma kinase) • PGR (Progesterone receptor) • FGFR1 (Fibroblast growth factor receptor 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NF1 (Neurofibromin 1) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • ATRX (ATRX Chromatin Remodeler) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • CD34 (CD34 molecule) • NCAM1 (Neural cell adhesion molecule 1) • SOX10 (SRY-Box 10) • CD68 (CD68 Molecule) • MME (Membrane Metalloendopeptidase) • PRAME (Preferentially Expressed Antigen In Melanoma) • MLANA (Melan-A) • NTRK (Neurotrophic receptor tyrosine kinase) • PDGFB (Platelet Derived Growth Factor Subunit B) • STAT6 (Signal transducer and activator of transcription 6) • MITF (Melanocyte Inducing Transcription Factor)

EGFR mutation • HER-2 mutation • CDKN2A deletion • ATRX mutation • ERBB3 mutation • NF1 deletion

1year

Pigment epithelium derived factor drives melanocyte proliferation and migration in neurofibromatosis café au lait macules. (PubMed, Skin Health Dis)

Melanocyte proliferation and migration leading to CALMs in NF1 arises from biallelic NF1 loss, resulting in RAS/MAPK pathway activation, and reduced expression of the tumour suppressor PEDF. Activation of the PI3K/AKT pathway in classical NF1 and NF1 melanoma may facilitate tumour growth.

1 year ago

Journal

NF1 (Neurofibromin 1) • MITF (Melanocyte Inducing Transcription Factor)

NF1 deletion

over1year

CRISPR-Cas9 library screening combined with an exosome-targeted delivery system addresses tumorigenesis/TMZ resistance in the mesenchymal subtype of glioblastoma. (PubMed, Theranostics)

Each of these subtypes exhibits a varying degree of sensitivity to the temozolomide (TMZ) treatment, while the prognosis corresponds to the molecular and genetic characteristics of the tumor cell type...A quadruple combination therapy based on a targeted Exos delivery system demonstrated significantly reduced tumor burden in vivo. Therefore, our study provides new insights and therapeutic approaches for regulating tumor progression and TMZ resistance in the MES-GBM subtype.

over 1 year ago

Journal

KRAS (KRAS proto-oncogene GTPase) • NF1 (Neurofibromin 1) • RASGRP1 (RAS Guanyl Releasing Protein 1)

KRAS mutation • KRAS G12C • KRAS G12 • NF1 deletion • KRAS overexpression

temozolomide

over1year

Generation of heterozygous and homozygous NF1 lines from human-induced pluripotent stem cells using CRISPR/Cas9 to investigate bone defects associated with neurofibromatosis type 1. (PubMed, Front Cell Dev Biol)

In addition, we show that a mono-allelic deletion in NF1 in an isogenic context is sufficient to impair cell differentiation into osteoblasts. Overall, this study highlights the relevance of generating isogenic lines, which may help in genotype-phenotype correlation and provide a human cellular model to understand the molecular mechanisms underlying NF1 and, thus, discover new therapeutic strategies.

over 1 year ago

Journal

NF1 (Neurofibromin 1)

NF1 mutation • NF1 deletion

over1year

Correlation between large rearrangements and patient phenotypes in NF1 deletion syndrome: an update and review. (PubMed, BMC Med Genomics)

In this study, we analysed 22 NF1 deletion patients by genome-wide array-CGH with the aim (1) to correlate deletion length to observed phenotypic features and their severity in NF1 deletion syndrome, and (2) to identify whether the deletion phenotype could also be modulated by copy number variations elsewhere in the genome. We then review the role of co-deleted genes in the 1.4 Mb interval of type-1 deletions, and their possible implication in the main clinical features observed in this high-risk group of NF1 patients.

over 1 year ago

Review • Journal

NF1 (Neurofibromin 1)

NF1 deletion

2years

Droplet digital PCR for fast and accurate characterization of NF1 locus deletions: confirmation of the predominant maternal origin of type-1 deletions. (PubMed, J Mol Diagn)

We propose a fast and efficient ddPCR quantification to allow fine NF1 deletion classification; ddPCR can easily be implemented into routine diagnosis to complement the techniques dedicated to NF1 point variants identification. This new tool may help unravel the genetic basis conditioning phenotypic variability in NF1 deleted patients and offer tailored genetic counselling.

2 years ago

Journal

NF1 (Neurofibromin 1) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)

NF1 deletion

2years

A bedside-to-bench translational analysis demonstrates that NF1 alterations promote CDK4/6 inhibitor (CDK4/6i) resistance in hormone receptor-positive (HR+) metastatic breast cancer (MBC) (SABCS 2023)

MCF7 wild-type (WT) and two NF1-knockout (KO) clones were treated with palbociclib Â± estrogen deprivation, followed by cell viability assays... Using multicenter clinical and real-world evidence, we demonstrate that NF1-MUT is associated with inferior duration and worse outcomes on CDK4/6i in MBC. Pts with baseline pNF1-MUT on 1L CDK4/6i and endocrine therapy had a median PFS below typical responses expected in clinical practice. A link between NF1 loss and CDK4/6i resistance was supported by in vitro experiments in HR+ breast cancer cells.

2 years ago

Metastases

HER-2 (Human epidermal growth factor receptor 2) • NF1 (Neurofibromin 1) • CDK4 (Cyclin-dependent kinase 4)

HR positive • HER-2 negative • HER-2 expression • NF1 mutation • NF1 deletion • CDK4 mutation

Guardant360® CDx

Ibrance (palbociclib)

over2years

Genomic heterogeneity of ALK rearrangements and acquired resistance pathways in ALK+ Advanced non-small cell lung cancer (NSCLC) treated with upfront alectinib: Preliminary results of GALILEO project (ESMO 2023)

Legal entity responsible for the study Fondazione Policlinico Universitario A Gemelli â€“ IRCCS. In post-lorlatinib NGS-assay, 2 pts had ALK-compound mutations, while 4 pts had newly off-target alterations (CDKN2A/B CDKN2B loss, NF1 deletion, DNMT3A/ARID1A/CHECK2 M+). Conclusions Implementation of longitudinal genomic assessment is required in order to provide an extensive overview of resistance mechanisms and clinical outcomes according to current ALK-inhibitors treatment sequences.

over 2 years ago

Preclinical • Metastases

EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • EML4 (EMAP Like 4) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • ARID1A (AT-rich interaction domain 1A) • NF1 (Neurofibromin 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)

ALK rearrangement • EML4-ALK fusion • ALK fusion • ALK mutation • CDKN2A deletion • ALK G1202R • NF1 deletion • ALK I1171N • ALK I1171 • ALK E1210K • CDKN2B deletion • EML4-ALK G1202R

FoundationOne® CDx • FoundationOne® Liquid CDx

Alecensa (alectinib) • Lorbrena (lorlatinib)

over2years

Deregulated expression of polycomb repressive complex 2 target genes in a NF1 patient with microdeletion generating the RNF135-SUZ12 chimeric gene. (PubMed, Neurogenetics)

These results suggest that RNF135-SUZ12 chimera may acquire a gain of function, compared with SUZ12 wild type in the PRC2 complex, and a loss of function relative to RNF135 wild type. Both events may have a role in the early onset of the patient's neurofibromas.

over 2 years ago

Journal

TP53 (Tumor protein P53) • NF1 (Neurofibromin 1) • SUZ12 (SUZ12 Polycomb Repressive Complex 2 Subunit)

NF1 mutation • NF1 deletion • TP53 expression