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Article ; Online: Histo-Molecular Factors of Response to Combined Chemotherapy and Immunotherapy in Non-Small Cell Lung Cancers.

Marchal, Marine / Leroy, Vincent / Behal, Hélène / Dansin, Eric / Paris, Nicolas / Bordier, Soraya / Humez, Sarah / Escande, Fabienne / Gauvain, Clément / Cortot, Alexis B

Targeted oncology

2023 Volume 18, Issue 6, Page(s) 927–939

Abstract: Background: Chemo-immunotherapy (CIT) is the standard of care for advanced non-small cell lung cancer (NSCLC), but the impact of routinely available histo-molecular biomarkers on its efficacy has not yet been fully assessed.: Objective: The purpose ... ...

Abstract	Background: Chemo-immunotherapy (CIT) is the standard of care for advanced non-small cell lung cancer (NSCLC), but the impact of routinely available histo-molecular biomarkers on its efficacy has not yet been fully assessed. Objective: The purpose of this multicenter study was to evaluate the clinical activity of CIT according to oncogenic drivers, STK11 and TP53 mutations, and MET overexpression. Patients and methods: Patients receiving CIT for advanced NSCLC with available comprehensive molecular profile were included. The primary endpoint was progression-free survival (PFS), adjusted on main confounding factors, and secondary endpoints were overall survival (OS) and objective response rate. Results: Among the 195 patients included between September 2018 and October 2021, 88 (41%) had a KRAS mutation, 16 (8.2%) an EGFR mutation or an ALK, ROS1, or RET rearrangement, 11 (5.6%) a BRAF mutation, 6 (3.1%) a MET exon 14 mutation or MET amplification, and 5 (2.6%) a HER2 mutation. Seventy-seven patients (39.5%) had none of these alterations. The median PFS was 6.4 months (95% CI 5.3-7.3). Per subgroup, the median PFS was 7.1 months (5.4-8.9) for KRAS, 5.5 months (2.5-15.3) for EGFR/ALK/ROS1/RET, 12.9 months (2.6-not reached [NR]) for BRAF, 1.5 months (0.6-NR) for MET, 3.9 months (2.6-NR) for HER2, and 5.6 months (4.7-7.8) for patients without any oncogenic alteration. No difference in PFS was observed between the KRAS, BRAF, EGFR/ALK/ROS1/RET, and no-driver subgroups. STK11 mutations were associated with poor PFS (HR 1.59 [95% CI 1.01-2.51]) whereas TP53 mutations had no impact. MET overexpression was associated with longer PFS (HR 0.59 [95% CI 0.35-0.99]). Conclusion: This study suggests that the efficacy of combining pembrolizumab with pemetrexed and platinum-based chemotherapy differs according to the histo-molecular biomarkers, which may help to identify patients liable to benefit from CIT.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/genetics ; Lung Neoplasms/genetics ; Protein-Tyrosine Kinases/genetics ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins/genetics ; Mutation ; Receptor Protein-Tyrosine Kinases/genetics ; ErbB Receptors/genetics ; Biomarkers ; Immunotherapy
Chemical Substances	Protein-Tyrosine Kinases (EC 2.7.10.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Proto-Oncogene Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Biomarkers
Language	English
Publishing date	2023-11-03
Publishing country	France
Document type	Multicenter Study ; Journal Article
ZDB-ID	2222136-0
ISSN	1776-260X ; 1776-2596
ISSN (online)	1776-260X
ISSN	1776-2596
DOI	10.1007/s11523-023-01009-w
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Article: Pursuit or discontinuation of anti-PD1 after 2 years of treatment in long-term responder patients with non-small cell lung cancer.

Ardin, Camille / Humez, Sarah / Leroy, Vincent / Ampere, Alexandre / Bordier, Soraya / Escande, Fabienne / Turlotte, Amélie / Stoven, Luc / Nunes, David / Cortot, Alexis / Gauvain, Clément

Therapeutic advances in medical oncology

2023 Volume 15, Page(s) 17588359231195600

Abstract: Background: The optimal duration of immune checkpoint inhibitor (ICI) treatment for patients with advanced non-small cell lung cancer (NSCLC) remains to be determined. Treatment durations in cornerstone phase 3 clinical trials vary between a fixed 2- ... ...

Abstract	Background: The optimal duration of immune checkpoint inhibitor (ICI) treatment for patients with advanced non-small cell lung cancer (NSCLC) remains to be determined. Treatment durations in cornerstone phase 3 clinical trials vary between a fixed 2-year duration and pursuit until disease progression. Clinical practices may thus differ according to the attending physician. Objectives: Here we provide real-world data about treatment decisions at 2 years, with subsequent clinical outcomes. Design and methods: This multicentric observational study included patients with advanced NSCLC whose disease was controlled after 2 years of pembrolizumab or nivolumab. The primary outcome was the decision to discontinue ICI treatment or not, along with factors motivating this decision. Secondary outcomes included progression-free survival (PFS) (according to treatment continuation or not) and adverse events. Results: A total of 91 patients were included, of which 60 (66%) had been pre-treated. The programmed death-ligand 1 expression level was ⩾50% in 43 patients (47%). In 61 patients (67%), ICI was continued after 2 years of treatment. This decision was significantly associated with the care center ( Conclusion: The decision to continue ICI or not after 2 years of treatment depends mainly on the care center and does not seem to impact survival. Larger, randomized data sets are required to confirm this result.
Language	English
Publishing date	2023-09-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2503443-1
ISSN	1758-8359 ; 1758-8340
ISSN (online)	1758-8359
ISSN	1758-8340
DOI	10.1177/17588359231195600
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Article ; Online: Clinicopathological and molecular characterization of a case classified by DNA‑methylation profiling as "CNS embryonal tumor with BRD4-LEUTX fusion".

Lebrun, Laetitia / Allard-Demoustiez, Sacha / Gilis, Nathalie / Van Campenhout, Claude / Rodesch, Marine / Roman, Celine / Calò, Pierluigi / Lolli, Valentina / David, Philippe / Fricx, Christophe / De Witte, Olivier / Escande, Fabienne / Maurage, Claude-Alain / Salmon, Isabelle

Acta neuropathologica communications

2023 Volume 11, Issue 1, Page(s) 46

Abstract: Central Nervous System (CNS) embryonal tumors represent a heterogeneous group of highly aggressive tumors occurring preferentially in children but also described in adolescents and adults. In 2021, the CNS World Health Organization (WHO) classification ... ...

Abstract	Central Nervous System (CNS) embryonal tumors represent a heterogeneous group of highly aggressive tumors occurring preferentially in children but also described in adolescents and adults. In 2021, the CNS World Health Organization (WHO) classification drastically changed the diagnosis of the other CNS embryonal tumors including new histo-molecular tumor types. Here, we report a pediatric case of a novel tumor type among the other CNS embryonal tumors classified within the methylation class "CNS Embryonal Tumor with BRD4-LEUTX Fusion". The patient was a 4-year girl with no previous history of disease. For a few weeks, she suffered from headaches, vomiting and mild fever associated with increasing asthenia and loss of weight leading to a global deterioration of health. MRI brain examination revealed a large, grossly well-circumscribed tumoral mass lesion located in the left parietal lobe, contralateral hydrocephalus and midline shift. Microscopic examination showed a highly cellular tumor with a polymorphic aspect. The majority of the tumor harbored neuroectodermal features composed of small cells with scant cytoplasm and hyperchromatic nuclei associated with small "medulloblastoma-like" cells characterized by syncytial arrangement and focally a streaming pattern. Tumor cells were diffusely positive for Synaptophysin, CD56, INI1 and SMARCA4 associated with negativity for GFAP, OLIG-2, EMA, BCOR, LIN28A and MIC-2. Additional IHC features included p53 protein expression in more than 10% of the tumor's cells and very interestingly, loss of H3K27me3 expression. The Heidelberg DNA-methylation classifier classified this case as "CNS Embryonal Tumor with BRD4:LEUTX Fusion". RNA-sequencing analyses confirmed the BRD4 (exon 13)-LEUTX (exon 2) fusion with no other molecular alterations found by DNA sequencing. Our case report confirmed that a new subgroup of CNS embryonal tumor with high aggressive potential, loss of H3K27me3 protein expression, BRDA4-LEUTX fusion, named "Embryonal CNS tumor with BRD4-LEUTX fusion", has to be considered into the new CNS WHO classification.
MeSH term(s)	Female ; Humans ; Brain Neoplasms/diagnostic imaging ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Cell Cycle Proteins/metabolism ; Central Nervous System Neoplasms/genetics ; Cerebellar Neoplasms/genetics ; DNA/metabolism ; DNA Helicases/genetics ; DNA Methylation ; Histones/genetics ; Neoplasms, Germ Cell and Embryonal ; Neuroectodermal Tumors, Primitive/genetics ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Child, Preschool
Chemical Substances	BRD4 protein, human ; Cell Cycle Proteins ; DNA (9007-49-2) ; DNA Helicases (EC 3.6.4.-) ; Histones ; LEUTX protein, human ; Nuclear Proteins ; SMARCA4 protein, human (EC 3.6.1.-) ; Transcription Factors
Language	English
Publishing date	2023-03-18
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01549-2
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Article ; Online: Progestin-related WHO grade II meningiomas behavior-a single-institution comparative case series.

Devalckeneer, Antoine / Aboukais, Rabih / Faisant, Maxime / Bourgeois, Philippe / Quentin, Vannod-Michel / Maurage, Claude-Alain / Escande, Fabienne / Lejeune, Jean-Paul

Neurosurgical review

2021 Volume 45, Issue 2, Page(s) 1691–1699

Abstract: WHO grade II progestin-related meningiomas have been reported in recent series but we found no previous study describing their long-term outcome. Our study aimed to evaluate patients operated on for high-grade intracranial meningioma and who underwent ... ...

Abstract	WHO grade II progestin-related meningiomas have been reported in recent series but we found no previous study describing their long-term outcome. Our study aimed to evaluate patients operated on for high-grade intracranial meningioma and who underwent long-term exposure to high dose of cyproterone acetate, nomegestrol acetate, and chlormadinone acetate. Our study retrospectively included 9 patients with high-grade progestin-related intracranial meningioma between December 2006 and September 2021. In each patient, clinico-radiological follow-up was performed every 6 months after diagnosis and treatment withdrawal recommendation. The mean progestative exposure was 11.4 years. Edema existence or absence of cleft sign on MRI were the key factors for surgical indication. All patients underwent surgery. Adjuvant radiotherapy was indicated in 1 patient, and Gamma Knife radiosurgery was proposed in 2 other patients for a second location of meningioma. Six patients harbored a grade II chordoid meningioma subtype with 100% PR expression and 3 patients a grade II atypical meningioma subtype with lower PR expression. The mean follow-up was 8.1 years and none of the 9 patients presented with a recurrence. Patients with grade II progestin-related meningiomas have less tumor recurrence after surgery than patients with sporadic grade II meningiomas, especially after progestin withdrawal. The presence/appearance of peri-meningioma edema and the absence of cleft sign before volumetric change should suggest the existence of an underlying WHO grade II meningiomas. In these cases, surgical resection may immediately be considered and adjuvant radiotherapy should be reserved for proven recurrence cases.
MeSH term(s)	Child ; Humans ; Meningeal Neoplasms/pathology ; Meningioma/diagnosis ; Progestins/therapeutic use ; Retrospective Studies ; World Health Organization
Chemical Substances	Progestins
Language	English
Publishing date	2021-11-30
Publishing country	Germany
Document type	Journal Article
ZDB-ID	6907-3
ISSN	1437-2320 ; 0344-5607
ISSN (online)	1437-2320
ISSN	0344-5607
DOI	10.1007/s10143-021-01708-w
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Article ; Online: Split hand/foot malformation with long bone deficiency associated with BHLHA9 gene duplication: a case report and review of literature.

Paththinige, Chamara Sampath / Sirisena, Nirmala Dushyanthi / Escande, Fabienne / Manouvrier, Sylvie / Petit, Florence / Dissanayake, Vajira Harshadeva Weerabaddana

BMC medical genetics

2019 Volume 20, Issue 1, Page(s) 108

Abstract: Background: Split hand/foot malformation (SHFM) is a group of congenital skeletal disorders which may occur either as an isolated abnormality or in syndromic forms with extra-limb manifestations. Chromosomal micro-duplication or micro-triplication ... ...

Abstract	Background: Split hand/foot malformation (SHFM) is a group of congenital skeletal disorders which may occur either as an isolated abnormality or in syndromic forms with extra-limb manifestations. Chromosomal micro-duplication or micro-triplication involving 17p13.3 region has been described as the most common cause of split hand/foot malformation with long bone deficiency (SHFLD) in several different Caucasian and Asian populations. Gene dosage effect of the extra copies of BHLHA9 gene at this locus has been implicated in the pathogenesis of SHFLD. Case presentation: The proband was a female child born to non-consanguineous parents. She was referred for genetic evaluation of bilateral asymmetric ectrodactyly involving both hands and right foot along with right tibial hemimelia. The right foot had fixed clubfoot deformity with only 2 toes. The mother had bilateral ectrodactyly involving both hands, but the rest of the upper limbs and both lower limbs were normal. Neither of them had any other congenital malformations or neurodevelopmental abnormalities. Genetic testing for rearrangement of BHLHA9 gene by quantitative polymerase chain reaction confirmed the duplication of the BHLHA9 gene in both the proband and the mother. Conclusions: We report the first Sri Lankan family with genetic diagnosis of BHLHA9 duplication causing SHFLD. This report along with the previously reported cases corroborate the possible etiopathogenic role of BHLHA9 gene dosage imbalances in SHFM and SHFLD across different populations.
MeSH term(s)	Basic Helix-Loop-Helix Transcription Factors/genetics ; Chromosome Duplication ; Chromosomes, Human, Pair 17/genetics ; Comparative Genomic Hybridization ; Ectromelia ; Female ; Foot Deformities, Congenital/genetics ; Gene Dosage ; Gene Duplication ; Gene Rearrangement/genetics ; Genetic Association Studies ; Genetic Loci ; Genetic Predisposition to Disease ; Hand Deformities, Congenital/genetics ; Humans ; Infant, Newborn ; Limb Deformities, Congenital/diagnostic imaging ; Limb Deformities, Congenital/genetics ; Limb Deformities, Congenital/physiopathology ; Tibia/abnormalities ; Tibia/diagnostic imaging ; Tibia/physiopathology
Chemical Substances	BHLHA9 protein, human ; Basic Helix-Loop-Helix Transcription Factors
Language	English
Publishing date	2019-06-14
Publishing country	England
Document type	Case Reports ; Journal Article ; Review
ISSN	1471-2350
ISSN (online)	1471-2350
DOI	10.1186/s12881-019-0839-2
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Article ; Online: Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival.

Duhamel, Marie / Drelich, Lauranne / Wisztorski, Maxence / Aboulouard, Soulaimane / Gimeno, Jean-Pascal / Ogrinc, Nina / Devos, Patrick / Cardon, Tristan / Weller, Michael / Escande, Fabienne / Zairi, Fahed / Maurage, Claude-Alain / Le Rhun, Émilie / Fournier, Isabelle / Salzet, Michel

Nature communications

2022 Volume 13, Issue 1, Page(s) 6665

Abstract: Molecular heterogeneity is a key feature of glioblastoma that impedes patient stratification and leads to large discrepancies in mean patient survival. Here, we analyze a cohort of 96 glioblastoma patients with survival ranging from a few months to over ... ...

Abstract	Molecular heterogeneity is a key feature of glioblastoma that impedes patient stratification and leads to large discrepancies in mean patient survival. Here, we analyze a cohort of 96 glioblastoma patients with survival ranging from a few months to over 4 years. 46 tumors are analyzed by mass spectrometry-based spatially-resolved proteomics guided by mass spectrometry imaging. Integration of protein expression and clinical information highlights three molecular groups associated with immune, neurogenesis, and tumorigenesis signatures with high intra-tumoral heterogeneity. Furthermore, a set of proteins originating from reference and alternative ORFs is found to be statistically significant based on patient survival times. Among these proteins, a 5-protein signature is associated with survival. The expression of these 5 proteins is validated by immunofluorescence on an additional cohort of 50 patients. Overall, our work characterizes distinct molecular regions within glioblastoma tissues based on protein expression, which may help guide glioblastoma prognosis and improve current glioblastoma classification.
MeSH term(s)	Humans ; Glioblastoma/metabolism ; Proteome ; Brain Neoplasms/metabolism ; Proteomics/methods ; Spatial Analysis ; Survival Analysis
Chemical Substances	Proteome
Language	English
Publishing date	2022-11-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-34208-6
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Article ; Online: Comprehensive study of nine novel cases of TFEB-amplified renal cell carcinoma: an aggressive tumour with frequent PDL1 expression.

Kammerer-Jacquet, Solène-Florence / Gandon, Camille / Dugay, Frederic / Laguerre, Brigitte / Peyronnet, Benoit / Mathieu, Romain / Verhoest, Grégory / Bensalah, Karim / Leroy, Xavier / Aubert, Sebastien / Vermaut, Catherine / Escande, Fabienne / Verkarre, Virginie / Compérat, Eva / Ambrosetti, Damien / Pedeutour, Florence / Belaud-Rotureau, Marc-Antoine / Rioux-Leclercq, Nathalie

Histopathology

2022 Volume 81, Issue 2, Page(s) 228–238

Abstract: Aims: First described in 2014, renal cell carcinoma (RCC) with TFEB amplification (6p21) is a rare molecular subgroup whose diagnosis is challenging. The prognosis and therapeutic implications remain unclear.: Methods: We report here the clinical, ... ...

Abstract	Aims: First described in 2014, renal cell carcinoma (RCC) with TFEB amplification (6p21) is a rare molecular subgroup whose diagnosis is challenging. The prognosis and therapeutic implications remain unclear. Methods: We report here the clinical, histological, immunohistochemical, and genetic features of nine novel cases. The pathological and immunohistochemical features were centrally reviewed by expert uropathologists. Fluorescence in situ hybridisation (FISH) confirmed the diagnosis and comparative genomic hybridisation (CGH) was performed to determine quantitative genomic alterations. We also performed an exhaustive review of the literature and compiled our data. Results: TFEB-amplified RCC were locally advanced, with initial lymph node involvement in one case and liver metastasis in another case. They were high-grade eosinophilic tumours with papillary/pseudopapillary architecture, frequent positivity for melanocytic markers, and frequent PDL1 expression. FISH demonstrated high-level TFEB amplification in six cases. One case showed concomitant TFEB translocation. CGH analysis identified complex alterations with frequent losses of 1p, 2q, 3p, 6p, and frequent 6p and 8q gains. VEGFA coamplification was identified in all cases with a lower level than TFEB. The prognosis was poor, with five patients having lymph node or distant metastases. Conclusion: TFEB-amplified RCC is a rare molecular subgroup with variable morphology whose diagnosis is confirmed by FISH analysis. The complex alterations identified by CGH are consistent with an aggressive clinical behaviour. The coamplification of VEGFA and the expression of PDL1 could suggest a potential benefit from antiangiogenics and targeted immunotherapy in combination for these aggressive tumours.
MeSH term(s)	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Biomarkers, Tumor/analysis ; Biomarkers, Tumor/genetics ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/pathology ; Humans ; In Situ Hybridization, Fluorescence ; Kidney Neoplasms/genetics ; Kidney Neoplasms/pathology ; Translocation, Genetic
Chemical Substances	Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Biomarkers, Tumor ; TFEB protein, human
Language	English
Publishing date	2022-06-13
Publishing country	England
Document type	Journal Article
ZDB-ID	131914-0
ISSN	1365-2559 ; 0309-0167
ISSN (online)	1365-2559
ISSN	0309-0167
DOI	10.1111/his.14683
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Zs.A 1328: Show issues

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Article ; Online: Split hand/foot malformation associated with 20p12.1 deletion: A case report.

Ruaud, Lyse / Flöttmann, Ricarda / Spielmann, Malte / Escande, Fabienne / Van Maldergem, Lionel / Mundlos, Stefan / Piard, Juliette

European journal of medical genetics

2019 Volume 63, Issue 4, Page(s) 103805

Abstract: Split hand/foot malformation (SHFM) or ectrodactyly is a rare congenital disorder affecting limb development characterized by clinical and genetic heterogeneity. SHFM is usually inherited as an autosomal dominant trait with incomplete penetrance. ... ...

Abstract	Split hand/foot malformation (SHFM) or ectrodactyly is a rare congenital disorder affecting limb development characterized by clinical and genetic heterogeneity. SHFM is usually inherited as an autosomal dominant trait with incomplete penetrance. Isolated and syndromic forms are described. The extent of associated malformations is highly variable and multiple syndromes with clinical and genetic overlap have been described. We report here a 28 year-old man presenting with SHFM, sparse hair and widespread freckles. Array-CGH identified a 450 kb de novo 20p12.1 microdeletion encompassing three exons (exon 6 to 8) of MACROD2. Although MACROD2 mutations have not been associated with limb malformation until now, it is located next to KIF16B, which is involved in fibroblast growth factor receptor (FGFR) signaling. Additionally, the deletion encompassed a histone modification H3K27ac mark, known as a provider of quantitative readout of promoter and enhancer activity during human limb development. Altogether, these findings suggest that the 20p12.1 CNV is causative of SHFM in the present case through disturbance of regulatory elements functioning.
MeSH term(s)	Adult ; Chromosomes, Human, Pair 20/genetics ; DNA Repair Enzymes/genetics ; Histone Code ; Humans ; Hydrolases/genetics ; Kinesin/genetics ; Limb Deformities, Congenital/genetics ; Male ; Mutation
Chemical Substances	KIF16B protein, human ; MACROD2 protein, human ; Hydrolases (EC 3.-) ; Kinesin (EC 3.6.4.4) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2019-11-04
Publishing country	Netherlands
Document type	Case Reports ; Journal Article
ZDB-ID	2184135-4
ISSN	1878-0849 ; 1769-7212
ISSN (online)	1878-0849
ISSN	1769-7212
DOI	10.1016/j.ejmg.2019.103805
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Article: Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling

Dufour, William / Alawbathani, Salem / Jourdain, Anne-Sophie / Asif, Maria / Baujat, Geneviève / Becker, Christian / Budde, Birgit / Gallacher, Lyndon / Georgomanolis, Theodoros / Ghoumid, Jamal / Höhne, Wolfgang / Lyonnet, Stanislas / Ba-Saddik, Iman Ali / Manouvrier-Hanu, Sylvie / Motameny, Susanne / Noegel, Angelika A. / Pais, Lynn / Vanlerberghe, Clémence / Wagle, Prerana /

White, Susan M. / Willems, Marjolaine / Nürnberg, Peter / Escande, Fabienne / Petit, Florence / Hussain, Muhammad Sajid

American College of Medical Genetics and Genomics Genetics in medicine. 2022 Apr. 20,

2022

Abstract: LEF1 encodes a transcription factor acting downstream of the WNT-β-catenin signaling pathway. It was recently suspected as a candidate for ectodermal dysplasia in 2 individuals carrying 4q35 microdeletions. We report on 12 individuals harboring LEF1 ... ...

Abstract	LEF1 encodes a transcription factor acting downstream of the WNT-β-catenin signaling pathway. It was recently suspected as a candidate for ectodermal dysplasia in 2 individuals carrying 4q35 microdeletions. We report on 12 individuals harboring LEF1 variants. High-throughput sequencing was employed to delineate the genetic underpinnings of the disease. Cellular consequences were characterized by immunofluorescence, immunoblotting, pulldown assays, and/or RNA sequencing. Monoallelic variants in LEF1 were detected in 11 affected individuals from 4 unrelated families, and a biallelic variant was detected in an affected individual from a consanguineous family. The phenotypic spectrum includes various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia. Depending on the type and location of LEF1 variants, the inheritance of this novel Mendelian condition can be either autosomal dominant or recessive. Our functional data indicate that 2 molecular mechanisms are at play: haploinsufficiency or loss of DNA binding are responsible for a mild to moderate phenotype, whereas loss of β-catenin binding caused by biallelic variants is associated with a severe phenotype. Transcriptomic studies reveal an alteration of WNT signaling. Our findings establish mono- and biallelic variants in LEF1 as a cause for a novel syndrome comprising limb malformations and ectodermal dysplasia.
Keywords	DNA ; RNA ; ectoderm ; fluorescent antibody technique ; haploinsufficiency ; immunoblotting ; medicine ; phenotype ; transcription factors ; transcriptomics
Language	English
Dates of publication	2022-0420
Publishing place	Elsevier Inc.
Document type	Article
Note	Pre-press version
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1016/j.gim.2022.04.022
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 5059: Show issues

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Article ; Online: Alterations in the PI3K Pathway Drive Resistance to MET Inhibitors in NSCLC Harboring MET Exon 14 Skipping Mutations.

Jamme, Philippe / Fernandes, Marie / Copin, Marie-Christine / Descarpentries, Clotilde / Escande, Fabienne / Morabito, Angela / Grégoire, Valérie / Jamme, Matthieu / Baldacci, Simon / Tulasne, David / Kherrouche, Zoulika / Cortot, Alexis B

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

2020 Volume 15, Issue 5, Page(s) 741–751

Abstract: Hepatocyte growth factor receptor (MET) tyrosine kinase inhibitors (MET TKIs) have been found to have efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response ... ...

Abstract	Hepatocyte growth factor receptor (MET) tyrosine kinase inhibitors (MET TKIs) have been found to have efficacy against advanced NSCLC with mutations causing MET exon 14 skipping (METex14 mutations), but primary resistance seems frequent, as response rates are lower than those for targeted TKIs of other oncogene-addicted NSCLCs. Given the known interplay between MET and phosphoinositide 3-kinases (PI3K), we hypothesized that in METex14 NSCLC, PI3K pathway alterations might contribute to primary resistance to MET TKIs. We reviewed clinical data from 65 patients with METex14 NSCLC, assessing PI3K pathway alterations by targeted next-generation sequencing (mutations) and immunohistochemistry (loss of phosphatase and tensin homolog [PTEN]). Using a cell line derived from a patient with primary resistance to a MET TKI and cell lines harboring both a METex14 mutation and a PI3K pathway alteration, we assessed sensitivity to MET TKIs used alone or with a PI3K inhibitor and investigated relevant signaling pathways. We found a phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutation in two of 65 samples (3%) and loss of PTEN in six of 26 samples (23%). All three of the MET TKI-treated patients with a PI3K pathway alteration had been found to have progressive disease at first assessment. Likewise, MET TKIs had no effect on the proliferation of METex14-mutated cell lines with a PI3K pathway alteration, including the PTEN-lacking patient-derived cell line. Treatment combining a MET TKI with a PI3K inhibitor caused inhibition of both PI3K and MAPK signaling and restored sensitivity to MET TKIs. PI3K pathway alterations are common in METex14 NSCLC and may confer primary resistance to MET TKIs. In preclinical models, PI3K inhibition restores sensitivity to MET TKIs.
MeSH term(s)	Drug Resistance, Neoplasm/genetics ; Exons ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Mutation ; Phosphatidylinositol 3-Kinases/genetics ; Protein Kinase Inhibitors/pharmacology
Chemical Substances	Protein Kinase Inhibitors
Language	English
Publishing date	2020-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2432037-7
ISSN	1556-1380 ; 1556-0864
ISSN (online)	1556-1380
ISSN	1556-0864
DOI	10.1016/j.jtho.2020.01.027
Database	MEDical Literature Analysis and Retrieval System OnLINE

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