Publications by authors named "Veronique Haddad"

23 Publications

  • Page 1 of 1

Outcomes of patients with metastatic gastrointestinal stromal tumors (GIST) treated with multi-kinase inhibitors other than imatinib as first-line treatment.

ESMO Open 2020 11;5(6):e001082

Sarcoma Group, Gustave Roussy, Villejuif, France.

Background: Imatinib is the standard first-line therapy in metastatic gastrointestinal stromal tumours (GIST). Investigational multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result either in increased survival or in early emergence of resistance to approved MKIs.

Methods: To assess whether using MKIs other than imatinib in first line decreases imatinib efficacy in second line for patients with GIST, a retrospective chart review was performed from 2005 to 2011 in two French tertiary centres of patients with GIST who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by imatinib as second line.

Results: Of 46 patients, (55% women, median age 55 years (range 24-81)), 22 (47%) had a exon 11 mutation, 1 a exon 9 mutation (2%), 1 a mutation (2%). Out of 46 patients, 21 (46%) received masitinib, 17 (37%) received dasatinib and 8 (17%) received nilotinib as first-line treatment with a median progression-free survival of 18.0 months (95% CI: 8.5 to 25.5). Median time to imatinib failure was 19.7 months (95% CI: 13.5 to 29.0). Median time to second relapse was 48.7 months (95% CI: 31.2 to 72.0). Median overall survival from time of initial metastasis diagnosis was 5.7 years (95% CI: 4.5 to 7.4).

Conclusions: Patients with GIST who received investigational MKIs as first-line treatment and imatinib as second line had a time to second relapse longer than that observed historically with imatinib in first line, suggesting that using MKIs other than imatinib in first line does not decrease the efficacy of subsequent treatment lines.
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http://dx.doi.org/10.1136/esmoopen-2020-001082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703411PMC
November 2020

Cutaneous Melanocytic Tumors With Concomitant NRASQ61R and IDH1R132C Mutations: A Report of 6 Cases.

Am J Surg Pathol 2020 10;44(10):1398-1405

Department of Biopathology, Centre Léon Bérard.

We report a series of 6 melanocytic proliferations harboring both NRAS and IDH1 hotspot mutations. Clinically, there was no specific sex-ratio, ages ranged from 18 to 85 years, and the trunk and limbs were the most affected localizations. In half of the cases, progressive modification of a pre-existing nevus was reported. Morphologically, all tumors were predominantly based in the dermis and the most striking pathologic finding was the presence of a background architecture of congenital-type nevi with a superimposed biphasic pattern formed by dendritic pigmented melanocytes surrounding areas of nevoid melanocytes. This finding was further underscored by HMB45 staining, which was positive in the dendritic cells and negative in the nevoid melanocytes. Four cases displayed increased cellularity and 1 case showed increased dermal mitotic activity. DNA and RNA sequencing revealed NRAS and IDH1 comutations in all 6 cases, with homogenous expression data according to unsupervised clustering analysis. Array-comparative genomic hybridization revealed no copy number alteration for the 2 most cellular and mitogenic cases. All were surgically excised, available follow-up for 2 patients showed no relapse nor metastases. We hypothesize that the IDH1 mutation is a secondary event in a pre-existing NRAS-mutated nevus and could be in part responsible for the emergence of a pigmented dendritic dermal component. So far, such comutations have been reported in one benign melanocytic nevus and several melanomas. This combination could represent a new subgroup of intermediate prognosis (melanocytoma) with a distinctive morphology. Further acquisition of genomic anomalies could progressively lead to malignant transformation.
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http://dx.doi.org/10.1097/PAS.0000000000001500DOI Listing
October 2020

Detailed overview on rare malignant ovarian tumors.

Bull Cancer 2020 Mar 27;107(3):385-390. Epub 2020 Feb 27.

Department of Medical Oncology, centre Léon-Bérard, University Claude Bernard (UCBL Lyon1), Lyon, France. Electronic address:

The group of rare malignant ovarian tumors includes the group of germ cell tumors, sex cords stromal ovarian tumors, small cell carcinoma, malignant Brenner tumors, rare epithelial tumors such as mucinous carcinoma, clear cell carcinoma, or low-grade serous carcinoma, as well as ovarian carcinosarcoma. Together they comprise about 10% of all ovarian tumors. Due to their low prevalence and their heterogeneity, data and treatment recommendations are limited. Even though all ovarian tumors are staged according to the FIGO staging of epithelial ovarian tumors, treatment differs especially in germ cell tumors and sex cords stromal ovarian tumors. Non-epithelial ovarian tumors can arise from a variety of ovarian precursor cells such as germ cells, granulosa cells, theca cells, or stromal fibroblasts. As can be expected already due to their divergent precursor lesions, these malignancies are substantially different but united by their rarity. This overview article gives a comprehensive summary on the pathology and clinical presentation, as well as therapy recommendations of a selection of those rare ovarian tumors, based on the latest national guidelines and related important publications.
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http://dx.doi.org/10.1016/j.bulcan.2020.01.011DOI Listing
March 2020

Compound blue nevus: a reappraisal of the concept in the genomic era.

Virchows Arch 2020 Mar 21;476(3):439-443. Epub 2019 Nov 21.

Department of Biopathology, Center Léon Bérard, 28, Rue Laennec, 69008, Lyon, France.

We report a series of 21 compound blue nevi, a rare variant in the vast clinical and morphological spectrum of blue melanocytic proliferations. Clinically, they presented in young adults, with a slight female predominance. One-third were located on the dorsum of the foot. Morphologically, all cases displayed large dendritic melanocytes restricted to the deep layers of the epidermis. The compound component was central and evenly distributed. Melanocytic density ranged from scarce isolated cells to a confluent lentiginous architecture. In 12 of the 21 cases, junctional nests of small, bland, weakly pigmented melanocytes were associated. These nests became confluent in the most cellular cases. In all cases, a dermal component was immediately present underneath, mainly of cellular blue nevus-type. All cases were genetically confirmed to harbor either a GNAQ or GNA11 hotspot mutation. This study expands the morphological spectrum of blue nevi that should not be restricted to a strictly intradermal melanocytic proliferation.
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http://dx.doi.org/10.1007/s00428-019-02667-wDOI Listing
March 2020

Clinical Efficacy of Osimertinib in a Patient Presenting a Double EGFR L747S and G719C Mutation.

J Thorac Oncol 2019 07;14(7):e151-e153

Department of Pulmonology and Oncology, Hospital of Villefranche sur Saône, Plateau d'Ouilly Gleizé, Villefranche sur Saône, France. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2019.02.034DOI Listing
July 2019

Compliance to regional recommendations for molecular analyses and management of advanced lung cancer patients.

Future Oncol 2019 Jun 12;15(18):2139-2149. Epub 2019 Jun 12.

Department of Medical Oncology, Institut Lucien Neuwirth, 42270, Saint-Priest-en-Jarez, France.

We performed a clinical audit of the management of patients with mutations, 1 year after the introduction of tyrosine kinase inhibitor (-TKI) in first-line treatment. Compliance was defined by tumor molecular profiling for stage IIIB and IV non-small-cell lung cancer and first-line treatment as recommended by the French guidelines. Among the 169 -mutated patients, compliance was 76.4%. The most common noncompliance criterion was chemotherapy given in first-line treatment instead of -TKI. No dedicated multidisciplinary meeting and type of institutions were independent unfavorable predictors for compliance. Compliance to guidelines was significantly correlated with time-to-first subsequent treatment improvement (2.5 vs 9.1 months; p < 0.0001). Implementation of new standards of care is challenging. Our results reinforce the role of multidisciplinary meetings to provide a better access to innovating therapeutics.
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http://dx.doi.org/10.2217/fon-2018-0943DOI Listing
June 2019

Malignant melanoma with areas of rhabdomyosarcomatous differentiation arising in a giant congenital nevus with RAF1 gene fusion.

Pigment Cell Melanoma Res 2019 09 21;32(5):708-713. Epub 2019 Apr 21.

Department of Biopathology, Centre Léon Bérard, Lyon, France.

A girl, born with a posterior  lumbosacral giant congenital nevus, developed a central nodule that expanded over a period of 14 months into a 10-cm pedunculated mass. Histological analysis of the mass revealed melanoma of myxoid, small round-cell type with areas of  rhabdomyosarcomatous  transformation confirmed by immunohistochemistry. RNA sequencing identified an in-frame SASS6(e14)-RAF1(e8) fusion in both components and the nevus. A RAF1 FISH break-apart test found a balanced rearrangement pattern in the nevus and an unbalanced pattern in the malignant areas. Wild-type status of NRAS and BRAF was confirmed by NGS techniques. The array-CGH profile displayed copy number alterations commonly found in rhabdomyosarcomas. Despite intensive treatment, widespread metastatic evolution of the melanomatous component was observed.
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http://dx.doi.org/10.1111/pcmr.12785DOI Listing
September 2019

β-Catenin nuclear expression discriminates deep penetrating nevi from other cutaneous melanocytic tumors.

Virchows Arch 2019 May 12;474(5):539-550. Epub 2019 Feb 12.

Departement de Biopathologie, Centre Léon Bérard, 28, rue Laennec, 69008, Lyon, France.

Recent advances in genomics have improved the molecular classification of cutaneous melanocytic tumors. Among them, deep penetrating nevi (DPN) and plexiform nevi have been linked to joint activation of the MAP kinase and dysregulation of the β-catenin pathways. Immunohistochemical studies have confirmed cytoplasmic and nuclear expression of β-catenin and its downstream effector cyclin D1 in these tumors. We assessed nuclear β-catenin immunohistochemical expression in a large group of DPN as well as in the four most frequent differential diagnoses of DPN: "blue" melanocytic tumors, Spitz tumors, nevoid and SSM melanomas, and pigmented epithelioid melanocytomas (PEM). Nuclear β-catenin expression was positive in 98/100 DPN and 2/16 of melanomas (one SSM and one nevoid melanoma with a plexiform clone) and was negative in all 30 Spitz, 26 blue, and 6 PEM lesions. In 41% DPN, β-catenin expression was positive in more than 30% nuclei. No differences were observed in cytoplasmic and nuclear cyclin D1 expression between these tumor groups, suggesting alternate, β-catenin-independent, activation pathways. We have subsequently studied nuclear β-catenin expression in a set of 13 tumors with an ambiguous diagnosis, for which DPN was part of the differential diagnosis. The three out of four patients showing canonical DPN mutation profiles were the only β-catenin-positive cases. We conclude that nuclear β-catenin expression, independently from CCND1 expression, in a dermal melanocytic tumor is an argument for its classification as DPN. In ambiguous cases and in early combined DPN lesions, this antibody can be helpful as a screening tool. β-Catenin is also potentially expressed in a subset of malignant melanomas with CTNNB1 mutations.
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http://dx.doi.org/10.1007/s00428-019-02533-9DOI Listing
May 2019

Activity of cabozantinib in radioresistant brain metastases from renal cell carcinoma: two case reports.

J Med Case Rep 2018 Nov 25;12(1):351. Epub 2018 Nov 25.

Department of Radiation Therapy, Centre Léon Bérard, Lyon, France.

Background: Renal cell carcinoma represents 3-5% of adult malignant tumors. Metastases are found in 30-40% of patients and brain metastases occurred in more than 10% of them. Despite significant progress in medical treatment, patients with brain metastases still have a limited survival. Cabozantinib, a tyrosine kinase inhibitor directed against vascular endothelial growth factor receptors, was recently registered for the treatment of metastatic renal cell carcinoma. Almost no data are, however, available on patients with brain metastases.

Case Presentation: Case 1 is a 51-year-old man of North African origin; Case 2 is a 55-year-old European man. Case 1 and Case 2 had metastases of renal carcinoma at initial diagnosis and were treated with vascular endothelial growth factor receptors tyrosine kinase inhibitors. Case 1 had clear cell renal carcinoma and underwent nephrectomy; he then received several lines of tyrosine kinase inhibitor directed against vascular endothelial growth factor receptors and the mTor complex. During the second treatment a brain metastasis was diagnosed and treated with radiosurgery with rapid efficacy. Two years later he received nivolumab, an antibody directed against the programmed death-1 and programmed death-ligand 1 complex, but disease progression was observed with the reappearance of the brain metastasis together with neurologic symptoms. Cabozantinib was administered and induced a rapid clinical improvement as well as tumor regression in all sites including his brain. Sequencing of his tumor evidenced a mutation of the MET gene. Case 2 had a papillary renal carcinoma with brain metastases at time of diagnosis. After radiation of the brain tumors, a vascular endothelial growth factor receptor tyrosine kinase inhibitor was administered for 3 years. The disease was under control in all sites except in his brain; several new brain metastases requiring new radiation treatments developed. The disease finally progressed at all metastatic sites including his brain and he had several neurological symptoms. Cabozantinib was administered and rapidly induced a clinical improvement; a further computed tomography scan and brain magnetic resonance imaging showed significant tumor regressions. No MET gene mutation or amplification was observed in the tumor analysis.

Conclusions: These case reports indicate that cabozantinib was able, first, to reach brain tumors and second, to induce significant regressions in renal carcinoma brain metastases that were resistant to radiation as well as to previous systemic vascular endothelial growth factor receptor tyrosine kinase inhibitors.
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http://dx.doi.org/10.1186/s13256-018-1875-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260776PMC
November 2018

Cutaneous Melanocytoma With CRTC1-TRIM11 Fusion: Report of 5 Cases Resembling Clear Cell Sarcoma.

Am J Surg Pathol 2018 03;42(3):382-391

Departement of Biopathology, Centre Léon Bérard, Lyon, France.

We report 5 cases of primary intradermal nodular unpigmented tumors with a melanocytic immunophenotype associated with a novel CRTC1-TRIM11 fusion. Clinically, the cutaneous nodules were slowly growing in 3 women and 2 men (25 to 82 y old, median, 28 y) with no specific topography. Lesion size ranged from 4 to 12 mm (median, 5 mm). The tumors were strictly located in the dermis with a nodular pattern. The cells were arranged in confluent nests and fascicules. Central fibronecrotic areas were present in 2 cases. Cells were medium to large, sometimes multinucleated, and presented a spindled and epithelioid cytology with prominent nucleoli. Cytonuclear atypia was constant, and mitotic activity in hotspot areas ranged from 1 to 5/mm². Immunohistochemistry found a constant positivity with S100, MiTF, and Sox10, and a heterogenous staining by MelanA or HMB45. NTRK1 was strongly positive in 3 cases. In all cases, RNA sequencing found an invariable CRTC1(e1)-TRIM11(e2) fusion, confirmed by fluorescent in situ hybridization techniques with a TRIM11 break-apart probe. In 4/4 cases, nuclear TRIM11 expression was positive by immunohistochemistry. Fluorescent in situ hybridization techniques showed no rearrangement of NTRK1 or EWSR1, and array-comparative genomic hybridization displayed no alteration (1 case) or only a whole chromosome 7 gain (2 cases) when performed. No relapse or metastatic event was observed during follow-up [3 to 72 months (median, 14 mo)]. Cutaneous clear cell sarcoma was the main differential diagnosis. Overlapping morphologic features previously described in primary dermal melanomas and paraganglioma-like melanocytic tumors were present. The CRTC1-TRIM11 fusion appears to be specific of an unpigmented nodular tumor combining a melanocytic phenotype and low-grade tumor behavior.
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http://dx.doi.org/10.1097/PAS.0000000000000996DOI Listing
March 2018

Combined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi.

Nat Commun 2017 09 21;8(1):644. Epub 2017 Sep 21.

Department of Biopathology, Centre Léon Bérard, Lyon, 69008, France.

Deep penetrating nevus (DPN) is characterized by enlarged, pigmented melanocytes that extend through the dermis. DPN can be difficult to distinguish from melanoma but rarely displays aggressive biological behavior. Here, we identify a combination of mutations of the β-catenin and mitogen-activated protein kinase pathways as characteristic of DPN. Mutations of the β-catenin pathway change the phenotype of a common nevus with BRAF mutation into that of DPN, with increased pigmentation, cell volume and nuclear cyclin D1 levels. Our results suggest that constitutive β-catenin pathway activation promotes tumorigenesis by overriding dependencies on the microenvironment that constrain proliferation of common nevi. In melanoma that arose from DPN we find additional oncogenic alterations. We identify DPN as an intermediate stage in the step-wise progression from nevus to melanoma. In summary, we delineate specific genetic alterations and their sequential order, information that can assist in the diagnostic classification and grading of these distinctive neoplasms.Deep penetrating nevi (DPN) are unusual melanocytic neoplasms with unknown genetic drivers. Here the authors show that majority of DPN harbor activating mutations in the β-catenin and the MAP-kinase pathways; this characteristic can help in the classification and grading of these distinctive neoplasms.
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http://dx.doi.org/10.1038/s41467-017-00758-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608693PMC
September 2017

Primary leptomeningeal melanocytic tumour with a plaque-like blue nevus in a patient with ocular albinism.

Eur J Dermatol 2016 Oct;26(5):496-498

Department of Biopathology, University Hospital, 80 av Augustin Fliche, 34295 Montpellier Cedex 5,, Tumorotheque of Biopathology, University Hospital, 80 av Augustin Fliche, 34295, Montpellier Cedex 5, France.

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http://dx.doi.org/10.1684/ejd.2016.2828DOI Listing
October 2016

Agminated Spitz nevus arising in normal skin with redundant HRAS mutation.

Eur J Dermatol 2017 Feb;27(1):73-74

Department of Biopathology, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France.

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http://dx.doi.org/10.1684/ejd.2016.2894DOI Listing
February 2017

Three Rounds of External Quality Assessment in France to Evaluate the Performance of 28 Platforms for Multiparametric Molecular Testing in Metastatic Colorectal and Non-Small Cell Lung Cancer.

J Mol Diagn 2016 Mar 2;18(2):205-14. Epub 2016 Jan 2.

Unit of Constitutional and Somatic Genetics, Genetics Department, Institut Curie, Paris, France.

Personalized medicine has gained increasing importance in clinical oncology, and several clinically important biomarkers are implemented in routine practice. In an effort to guarantee high quality of molecular testing in France, three subsequent external quality assessment rounds were organized at the initiative of the National Cancer Institute between 2012 and 2014. The schemes included clinically relevant biomarkers for metastatic colorectal (KRAS, NRAS, BRAF, PIK3CA, microsatellite instability) and non-small cell lung cancer (EGFR, KRAS, BRAF, PIK3CA, ERBB2), and they represent the first multigene/multicancer studies throughout Europe. In total, 56 laboratories coordinated by 28 regional molecular centers participated in the schemes. Laboratories received formalin-fixed, paraffin-embedded samples and were asked to use routine methods for molecular testing to predict patient response to targeted therapies. They were encouraged to return results within 14 calendar days after sample receipt. Both genotyping and reporting were evaluated separately. During the three external quality assessment rounds, mean genotype scores were all above the preset standard of 90% for all biomarkers. Participants were mainly challenged in case of rare insertions or deletions. Assessment of the written reports showed substantial progress between the external quality assessment schemes on multiple criteria. Several essential elements such as the clinical interpretation of test results and the reason for testing still require improvement by continued external quality assessment education.
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http://dx.doi.org/10.1016/j.jmoldx.2015.09.004DOI Listing
March 2016

Melanomas Associated With Blue Nevi or Mimicking Cellular Blue Nevi: Clinical, Pathologic, and Molecular Study of 11 Cases Displaying a High Frequency of GNA11 Mutations, BAP1 Expression Loss, and a Predilection for the Scalp.

Am J Surg Pathol 2016 Mar;40(3):368-77

*Department of Biopathology, Leon Berard Center, Lyon †Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia ‡Department of Dermatology, Lyon Sud Hospital Center, Pierre-Benite, CRCL and CHU of Lyon, Lyon §Department of Dermatology, CHU Besançon, Besançon ∥Department of Medical Oncology, Eugene Marquis Center, Rennes ¶Department of Dermatology, Robert Debre´ University Hospital, Reims #Department of Dermatology, CHU of Dijon, Dijon **Department of Dermatology CHRU of Lille, Lille ††Department of Dermatology, Institut Gustave Roussy, Villejuif ‡‡Department of Dermatocancerology, Hotel Dieu, Nantes §§Department of Pathology, Lyon Sud Hospital Center, Pierre-Benite ∥∥Department of Pathology, CHU of Bordeaux, Hospital Haut-Leveque, Pessac, France.

Melanomas associated with blue nevi (MABN) or mimicking cellular blue nevi (MMCBN) represent exceptional variants of malignant cutaneous melanocytic tumors. Uveal and leptomeningeal melanomas frequently have somatic mutations of GNAQ or GNA11, which are believed to be early driver mutations. In uveal melanomas, monosomy 3, linked to the BAP1 gene, is an adverse prognostic factor. We have studied the clinical, histologic, BAP1 expression profile, and molecular data of 11 cases of MABN/MMCBN and 24 cellular blue nevi. Most of the cases of MABN/MMCBN occurred on the scalps of adult patients and presented as rapidly growing nodules, typically >1 cm, often arising at the site of a preexisting melanocytic lesion. The MABN/MMCBN were composed of dense nests of large dermal atypical melanocytes, in some cases lying adjacent to a blue nevus. Four patients developed metastatic disease, and 2 died from their disease. A GNA11 mutation was found in 8/11 cases and a GNAQ mutation in 1 case. Seven of 11 cases showed loss of nuclear BAP1 immunohistochemical (IHC) expression in the malignant component, sparing the adjacent nevus. Array comparative genomic hybridization revealed recurrent deletions of chromosomes 1p, 3p, 4q, 6q, 8p, 16q, and 17q and recurrent gains of chromosomes 6p, 8q, and 21q. The 24 cases of cellular blue nevi frequently occurred on the sacrum, had GNAQ mutations, and showed normal positive IHC staining for BAP1. These results underscore overlapping features in all blue-like malignant melanocytic tumors. Loss of BAP1 IHC expression was restricted to melanomas, including all metastatic cases.
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http://dx.doi.org/10.1097/PAS.0000000000000568DOI Listing
March 2016

DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study.

Histopathology 2016 Jan 21;68(2):279-85. Epub 2015 Jul 21.

U1052 Inserm, UMR CNRS 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Centre Léon Bérard, Lyon, France.

Aims: FOXL2 mutation has been consistently identified in adult granulosa cell tumours (A-GCTs). DICER1 mutations have been described predominantly in Sertoli-Leydig cell tumours (SLCTs). The prognostic implication of these mutations remains uncertain, as moderately sized studies have yielded variable outcomes. Our aim was to determine the implications of DICER1 and FOXL2 mutations in 156 ovarian sex cord-stromal tumours (SCSTs).

Methods And Results: FOXL2 mutations were found in 94% of pathologically confirmed A-GCTs (95/101), in one of eight juvenile granulosa cell tumours (J-GCTs), and in two of 19 SLCTs. DICER1 mutations in the RNase IIIb domain were found in six of 19 SLCTs, two of eight J-GCTs, and one of 12 undifferentiated SCSTs (Und-SCSTs). Comparison of DICER1-mutated SLCTs with DICER1-non-mutated SLCTs showed that patient age at diagnosis was lower and oestrogen receptor expression was more frequent in DICER1-mutated tumours. With a median follow-up of 22 months, two of five DICER1-mutated SLCTs relapsed, in contrast to none of eight DICER1-non-mutated tumours.

Conclusions: Our results suggest that, in contrast to FOXL2 mutations in A-GCT, DICER1 mutations in SLCT might be more useful for prognosis than for diagnosis. However, study of a larger cohort of patients is necessary to establish this. Identification of genetic alterations in SCST offers promising therapeutic options.
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http://dx.doi.org/10.1111/his.12747DOI Listing
January 2016

Primary leptomeningeal melanoma is part of the BAP1-related cancer syndrome.

Acta Neuropathol 2015 Jun 22;129(6):921-3. Epub 2015 Apr 22.

Département de Biopathologie, Centre Léon Bérard, 28 rue Laennec, 69 373, Lyon Cedex 08, France,

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http://dx.doi.org/10.1007/s00401-015-1423-2DOI Listing
June 2015

Refinement of genotype-phenotype correlation in 18 patients carrying a 1q24q25 deletion.

Am J Med Genet A 2015 May 25;167A(5):1008-17. Epub 2015 Feb 25.

Hospices Civils de Lyon, Service de Génétique, Laboratoire de Cytogénétique Constitutionnelle, Bron, France.

Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype.
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http://dx.doi.org/10.1002/ajmg.a.36856DOI Listing
May 2015

Tumor homogeneity between primary and metastatic sites for BRAF status in metastatic melanoma determined by immunohistochemical and molecular testing.

PLoS One 2013 20;8(8):e70826. Epub 2013 Aug 20.

Department of Dermatology, CHU Bordeaux, Bordeaux, France.

BRAF inhibitors have demonstrated improvement of overall survival in patients with metastatic melanoma and BRAF(V600) mutations. In order to evaluate BRAF tumor heterogeneity between primary and metastatic site, we have evaluated the performance of immunohistochemistry (IHC) with an anti-BRAF(V600E) antibody in both localization by comparison with high resolution melting analysis followed by Sanger sequencing in a parallel blinded study. A total of 230 samples distributed as primary melanoma (n = 88) and different types of metastatic samples (n = 142) were studied in 99 patients with advanced or metastatic melanoma (stage III or IV). The prevalence of each BRAF mutation was c.1799T>A, BRAF(V600E) (45.2%), c.1799_1800TG>AA, BRAF(V600E2) (3.0%), c.1798_1799GT>AA, BRAF(V600K) (3.0%), c.1801 A>G, BRAF(K601E) (1.3%), c.1789_1790CT>TC, BRAF(L597S) (0.4%), c.1780G>A, BRAF(D594N) (0.9%) respectively. IHC was positive in 109/112 samples harboring BRAF(V600E/E2) mutations and negative in other cases. The cytoplasmic staining was either strongly positive in tumor cells of BRAF(V600E) mutated cases. It appeared strong brown, different from the vesicular grey cytoplasmic pigmentation of melanophages. Concordance between the two techniques was 96.4%. Sensitivity of IHC for detecting the BRAF(V600E/E2) mutations was 97.3%, while specificity was 100%. Both our IHC and molecular study demonstrated homogeneity between primary and metastatic sites for BRAF status in melanoma. This study also provides evidence that IHC may be a cost-effective first-line method for BRAF(V600E) detection. Thereafter, molecular techniques should be used in negative, ambiguous or non-contributive cases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070826PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748080PMC
April 2014

Tetrasomy 13q31.1qter due to an inverted duplicated neocentric marker chromosome in a fetus with multiple malformations.

Am J Med Genet A 2012 Apr 14;158A(4):894-900. Epub 2012 Mar 14.

Université Paris-Sud, Service d'Histologie Embryologie et Cytogénétique, APHP, Hôpital Antoine Béclère, Clamart, France.

Small supernumerary marker chromosome (sSMC) lacking alpha satellite DNA or endogenous centromere regions are rare and contain fully functional centromeres, called neocentromeres. We report on a woman with a 14-week gestation pregnancy with a cystic hygroma and cerebellar hypoplasia at ultrasound examination. Cytogenetic studies showed a karyotype 47,XY,+mar dn. This sSMC was observed in chorionic villi, lung, and muscle tissue. Array Comparative Genomic Hybridization showed a gain from 13q31.1 to 13qter region. Fluorescent in situ hybridization with pan alpha satellite probe and probes specific for chromosome 13 showed a marker corresponding to an inversion duplication of the 13q distal chromosomal region without alpha satellite DNA sequence, suggesting the presence of a neocentromere. Examination of the fetus showed dysmorphic features, cystic cervical hygroma, postaxial polydactyly of the right hand and left foot with short fingers, malrotation of the gut, and a micropenis with hypospadias. Genotype-phenotype correlation in tetrasomy 13q is discussed according to the four 13q chromosomal breakpoints reported (13q32, 13q31, 13q21, 13q14) for chromosome 13 supernumerary markers.
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http://dx.doi.org/10.1002/ajmg.a.35258DOI Listing
April 2012

Detection and characterization of NF1 microdeletions by custom high resolution array CGH.

J Mol Diagn 2009 Nov 18;11(6):524-9. Epub 2009 Sep 18.

UMR745 INSERM, Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l'Observatoire, 75006 Paris, France.

In 5% to 10% of cases, neurofibromatosis type 1 is caused by microdeletions scattered across the entire NF1 gene and various neighboring genes. The phenotype appears to be more severe in patients with NF1 microdeletions than in patients with NF1 single point mutations. We have developed a new method for detecting and characterizing NF1 microdeletions based on a custom high-resolution oligonucleotide array comparative genomic hybridization by using the custom 8x15K Agilent array format. The array comprised a total of 14,207 oligonucleotide probes spanning the whole of chromosome 17, including 12,314 probes spanning an approximately 8 Mb interval surrounding the NF1 locus. We validated this approach by testing NF1 microdeleted DNA samples previously characterized by means of microsatellites and real-time PCR methods. Our array comparative genomic hybridization provided enough information for subsequent long-range PCR and nucleotide sequencing of the microdeletion endpoints. Unlike previously described methods, our array comparative genomic hybridization was able to unambiguously differentiate between the three types of microdeletions (type I, type II, and atypical) and to characterize atypical microdeletions. Further comparative studies of patients with well-characterized genotypes and phenotypes and different microdeletions sizes and breakpoints will help determine whether haploinsufficiency of deleted genes and/or genes rearrangements influence clinical outcomes.
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http://dx.doi.org/10.2353/jmoldx.2009.090064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765750PMC
November 2009