Publications by authors named "Jamal K Benhamida"

7 Publications

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Sarcoma classification by DNA methylation profiling.

Authors:
Christian Koelsche Daniel Schrimpf Damian Stichel Martin Sill Felix Sahm David E Reuss Mirjam Blattner Barbara Worst Christoph E Heilig Katja Beck Peter Horak Simon Kreutzfeldt Elke Paff Sebastian Stark Pascal Johann Florian Selt Jonas Ecker Dominik Sturm Kristian W Pajtler Annekathrin Reinhardt Annika K Wefers Philipp Sievers Azadeh Ebrahimi Abigail Suwala Francisco Fernández-Klett Belén Casalini Andrey Korshunov Volker Hovestadt Felix K F Kommoss Mark Kriegsmann Matthias Schick Melanie Bewerunge-Hudler Till Milde Olaf Witt Andreas E Kulozik Marcel Kool Laura Romero-Pérez Thomas G P Grünewald Thomas Kirchner Wolfgang Wick Michael Platten Andreas Unterberg Matthias Uhl Amir Abdollahi Jürgen Debus Burkhard Lehner Christian Thomas Martin Hasselblatt Werner Paulus Christian Hartmann Ori Staszewski Marco Prinz Jürgen Hench Stephan Frank Yvonne M H Versleijen-Jonkers Marije E Weidema Thomas Mentzel Klaus Griewank Enrique de Álava Juan Díaz Martín Miguel A Idoate Gastearena Kenneth Tou-En Chang Sharon Yin Yee Low Adrian Cuevas-Bourdier Michel Mittelbronn Martin Mynarek Stefan Rutkowski Ulrich Schüller Viktor F Mautner Jens Schittenhelm Jonathan Serrano Matija Snuderl Reinhard Büttner Thomas Klingebiel Rolf Buslei Manfred Gessler Pieter Wesseling Winand N M Dinjens Sebastian Brandner Zane Jaunmuktane Iben Lyskjær Peter Schirmacher Albrecht Stenzinger Benedikt Brors Hanno Glimm Christoph Heining Oscar M Tirado Miguel Sáinz-Jaspeado Jaume Mora Javier Alonso Xavier Garcia Del Muro Sebastian Moran Manel Esteller Jamal K Benhamida Marc Ladanyi Eva Wardelmann Cristina Antonescu Adrienne Flanagan Uta Dirksen Peter Hohenberger Daniel Baumhoer Wolfgang Hartmann Christian Vokuhl Uta Flucke Iver Petersen Gunhild Mechtersheimer David Capper David T W Jones Stefan Fröhling Stefan M Pfister Andreas von Deimling

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

A Pan-Cancer Study of Somatic TERT Promoter Mutations and Amplification in 30,773 Tumors Profiled by Clinical Genomic Sequencing.

J Mol Diagn 2021 Feb 5;23(2):253-263. Epub 2020 Dec 5.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

TERT gene promoter mutations are known in multiple cancer types. Other TERT alterations remain poorly characterized. Sequencing data from 30,773 tumors analyzed by a hybridization capture next-generation sequencing assay (Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets) were analyzed for the presence of TERT alterations. Promoter rearrangements (500 bases upstream of the transcriptional start site), hypermethylation (n = 57), and gene expression (n = 155) were evaluated for a subset of cases. Mutually exclusive and recurrent promoter mutations were identified at three hot spots upstream of the transcriptional start site in 11.3% of cases (-124: 74%; -146: 24%; and -138: <2%). Mutually exclusive amplification events were identified in another 2.3% of cases, whereas mutually exclusive rearrangements proximal to the TERT gene were seen in 24 cases. The highest incidence of TERT promoter mutations was seen in cutaneous melanoma (82%), whereas amplification events significantly outnumbered promoter mutations in well-differentiated/dedifferentiated liposarcoma (14.1% versus 2.4%) and adrenocortical carcinoma (13.6% versus 4.5%). Gene expression analysis suggests that the highest levels of gene expression are seen in cases with amplifications and rearrangements. Hypermethylation events upstream of the TERT coding sequence were not mutually exclusive with known pathogenic alterations. Studies aimed at defining the prevalence and prognostic impact of TERT alterations should incorporate other pathogenic TERT alterations as these may impact telomerase function.
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http://dx.doi.org/10.1016/j.jmoldx.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874333PMC
February 2021

Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions.

Acta Neuropathol Commun 2020 11 9;8(1):186. Epub 2020 Nov 9.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

A subset of glioblastomas (GBMs) harbors potentially druggable oncogenic FGFR3-TACC3 (F3T3) fusions. However, their associated molecular and clinical features are poorly understood. Here we analyze the frequency of F3T3-fusion positivity, its associated genetic and methylation profiles, and its impact on survival in 906 IDH-wildtype GBM patients. We establish an F3T3 prevalence of 4.1% and delineate its associations with cancer signaling pathway alterations. F3T3-positive GBMs had lower tumor mutational and copy-number alteration burdens than F3T3-wildtype GBMs. Although F3T3 fusions were predominantly mutually exclusive with other oncogenic RTK pathway alterations, they did rarely co-occur with EGFR amplification. They were less likely to harbor TP53 alterations. By methylation profiling, they were more likely to be assigned the mesenchymal or RTK II subclass. Despite being older at diagnosis and having similar frequencies of MGMT promoter hypermethylation, patients with F3T3-positive GBMs lived about 8 months longer than those with F3T3-wildtype tumors. While consistent with IDH-wildtype GBM, F3T3-positive GBMs exhibit distinct biological features, underscoring the importance of pursuing molecular studies prior to clinical trial enrollment and targeted treatment.
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http://dx.doi.org/10.1186/s40478-020-01058-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653727PMC
November 2020

Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies.

Fam Cancer 2020 Oct 9. Epub 2020 Oct 9.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The widespread use of tumor DNA mismatch repair (MMR) protein immunohistochemistry in gastrointestinal tract (GIT) carcinomas has unveiled cases where the MMR protein status differs between synchronous/metachronous tumors from the same patients. This study aims at examining the frequency, patterns and molecular etiologies of such inter-tumoral MMR discordances. We analyzed a cohort of 2159 colorectal cancer (CRC) patients collected over a 5-year period and found that 1.3% of the patients (27/2159) had ≥ 2 primary CRCs, and 25.9% of the patients with ≥ 2 primary CRCs (7/27) exhibited inter-tumoral MMR discordance. We then combined the seven MMR-discordant CRC patients with three additional MMR-discordant GIT carcinoma patients and evaluated their discordant patterns and associated molecular abnormalities. The 10 patients consisted of 3 patients with Lynch syndrome (LS), 1 with polymerase proofreading-associated polyposis (PAPP), 1 with familial adenomatous polyposis (FAP), and 5 deemed to have no cancer disposing hereditary syndromes. Their MMR discordances were associated with the following etiologies: (1) PMS2-LS manifesting PMS2-deficient cancer at an old age when a co-incidental sporadic MMR-proficient cancer also occurred; (2) microsatellite instability-driven secondary somatic MSH6-inactivation occurring in only one-and not all-PMS2-LS associated MMR-deficient carcinomas; (3) "compound LS" with germline mutations in two MMR genes manifesting different tumors with deficiencies in different MMR proteins; (4) PAPP or FAP syndrome-associated MMR-proficient cancer co-occurring metachronously with a somatic MMR-deficient cancer; and (5) non-syndromic patients with sporadic MMR-proficient cancers co-occurring synchronously/metachronously with sporadic MMR-deficient cancers. Our study thus suggests that inter-tumoral MMR discordance is not uncommon among patients with multiple primary GIT carcinomas (25.9% in patients with ≥ 2 CRCs), and may be associated with widely varied molecular etiologies. Awareness of these patterns is essential in ensuring the most effective strategies in both LS detection and treatment decision-making. When selecting patients for immunotherapy, MMR testing should be performed on the tumor or tumors that are being treated.
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http://dx.doi.org/10.1007/s10689-020-00210-4DOI Listing
October 2020

RAS/MAPK Pathway Driver Alterations Are Significantly Associated With Oncogenic KIT Mutations in Germ-cell Tumors.

Urology 2020 Oct 25;144:111-116. Epub 2020 Jul 25.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: To report the mutational profile and clinical outcomes of a cohort of patients with KIT-mutant seminomas and nonseminomatous germ-cell tumors (SGCT/NSGCTs).

Patients And Methods: Retrospective cohort study of all patients with KIT-mutant GCTs sequenced at Memorial Sloan Kettering between March 2014 and March 2020. Tumors were assessed with MSK-IMPACT, a DNA next-generation sequencing assay for targeted sequencing of up to 468 key cancer genes.

Results: Among 568 patients with GCTs, 8.1% had somatic KIT mutations, including 28 seminomas and 18 mixed/NSGCTs. Exons 17 (67.3%), 11 (22.4%), and 13 (6.1%) were most commonly affected. KIT-mutant cases were enriched for oncogenic RAS/MAPK pathway alterations compared to KIT-wildtype cases (34.8% vs 19.2%, P = .02). Among KIT-mutant cases, concurrent mutations were noted in KRAS (21.7%), RRAS2 (11.8%), CBL (6.5%), NRAS (4.3%), MAP2K1 (2.2%), and RAC1 (2.2%). Mutations in KRAS, RRAS2, and NRAS were mutually exclusive. In all, 73.9% of patients developed metastases and 95.7% received chemotherapy. No patients received KIT-directed tyrosine kinase inhibitors (TKIs). Classification as a NSGCT rather than a SGCT was associated with an increased risk of death (hazard ratio 9.1, 95% confidence interval 1.1-78.4, P = .04) while the presence of a concurrent RAS/MAPK pathway alteration was not (hazard ratio 0.8, 95% confidence interval 0.1-4.3, P = .76).

Conclusion: Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of KIT-directed TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy.
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http://dx.doi.org/10.1016/j.urology.2020.07.027DOI Listing
October 2020

Reliable Clinical MLH1 Promoter Hypermethylation Assessment Using a High-Throughput Genome-Wide Methylation Array Platform.

J Mol Diagn 2020 03 24;22(3):368-375. Epub 2019 Dec 24.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.

Clinical testing for MLH1 promoter hypermethylation status is important in the workup of patients with MLH1-deficient colorectal and uterine carcinomas when evaluating patients for Lynch syndrome. Current assays use single gene-based methods to assess promoter hypermethylation. Herein, we describe the development and report the performance of a clinical assay for MLH1 promoter hypermethylation using the Infinium methylationEPIC (850k) bead-array platform. Using four cytosine-guanine dinucleotide (CpG) sites within the MLH1 gene promoter, a qualitative MLH1 promoter hypermethylation assay was developed and validated using 63 gastrointestinal and uterine carcinoma samples of known hypermethylation status based on a pyrosequencing reference test. The array-based method achieves clinically robust and reproducible results at an analytical sensitivity level of 8%. Of importance, the 850k array contains probes targeting >850,000 additional CpG sites across the genome, covering sites in most known genes as well as important enhancer regions provided by the Encyclopedia of DNA Elements and Functional Annotation of The Mammalian Genome projects. Thus, the testing modality presented may also be applied to determine the methylation status of other clinically relevant genes or regulatory regions, potentially providing a single laboratory testing workflow for all clinical methylation assays. Furthermore, the concomitant acquisition of genome-wide methylation information provides a workflow that seamlessly enables wider translational epigenetic research.
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http://dx.doi.org/10.1016/j.jmoldx.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103764PMC
March 2020

Sclerosing epithelioid mesenchymal neoplasm of the pancreas - a proposed new entity.

Mod Pathol 2020 03 5;33(3):456-467. Epub 2019 Aug 5.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

We have encountered pancreatic tumors with unique histologic features, which do not conform to any of the known tumors of the pancreas or other anatomical sites. We aimed to define their clinicopathologic features and whether they are characterized by recurrent molecular signatures. Eight cases were identified; studied histologically and by immunohistochemistry. Selected cases were also subjected to whole-exome sequencing (WES; n = 4), RNA-sequencing (n = 6), Archer FusionPlex assay (n = 5), methylation profiling using the Illumina MethylationEPIC (850k) array platform (n = 6), and TERT promoter sequencing (n = 5). Six neoplasms occurred in females. The mean age was 43 years (range: 26-75). Five occurred in the head/neck of the pancreas. All patients were treated surgically; none received neoadjuvant/adjuvant therapy. All patients are free of disease after 53 months of median follow-up (range: 8-94). The tumors were well-circumscribed, and the median size was 1.8 cm (range: 1.3-5.8). Microscopically, the unencapsulated tumors had a geographic pattern of epithelioid cell nests alternating with spindle cell fascicles. Some areas showed dense fibrosis, in which enmeshed tumor cells imparted a slit-like pattern. The predominant epithelioid cells had scant cytoplasm and round-oval nuclei with open chromatin. The spindle cells displayed irregular, hyperchromatic nuclei. Mitoses were rare. No lymph node metastases were identified. All tumors were positive for vimentin, CD99 and cytokeratin (patchy), while negative for markers of solid pseudopapillary neoplasm, neuroendocrine, acinar, myogenic/rhabdoid, vascular, melanocytic, or lymphoid differentiation, gastrointestinal stromal tumor as well as MUC4. Whole-exome sequencing revealed no recurrent somatic mutations or amplifications/homozygous deletions in any known oncogenes or tumor suppressor genes. RNA-sequencing and the Archer FusionPlex assay did not detect any recurrent likely pathogenic gene fusions. Single sample gene set enrichment analysis revealed that these tumors display a likely mesenchymal transcriptomic program. Unsupervised analysis (t-SNE) of their methylation profiles against a set of different mesenchymal neoplasms demonstrated a distinct methylation pattern. Here, we describe pancreatic neoplasms with unique morphologic/immunophenotypic features and a distinct methylation pattern, along with a lack of abnormalities in any of key genetic drivers, supporting that these neoplasms represent a novel entity with an indolent clinical course. Given their mesenchymal transcriptomic features, we propose the designation of "sclerosing epithelioid mesenchymal neoplasm" of the pancreas.
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http://dx.doi.org/10.1038/s41379-019-0334-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000300PMC
March 2020