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Clinical, genomic, and epigenomic analyses of H3K27M-mutant diffuse midline glioma long-term survivors reveal a distinct group of tumors with MAPK pathway alterations

Roberts, Holly J; Ji, Sunjong; Picca, Alberto; Sanson, Marc; Garcia, Mekka; Snuderl, Matija; Schüller, Ulrich; Picart, Thiébaud; Ducray, François; Green, Adam L; Nakano, Yoshiko; Sturm, Dominik; Abdullaev, Zied; Aldape, Kenneth; Dang, Derek; Kumar-Sinha, Chandan; Wu, Yi-Mi; Robinson, Dan; Vo, Josh N; Chinnaiyan, Arul M; Cartaxo, Rodrigo; Upadhyaya, Santhosh A; Mody, Rajen; Chiang, Jason; Baker, Suzanne; Solomon, David; Venneti, Sriram; Pratt, Drew; Waszak, Sebastian M; Koschmann, Carl
PMCID:10627895
PMID: 37851269
ISSN: 1432-0533
CID: 5590202

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma

Dolgalev, Igor; Zhou, Hua; Murrell, Nina; Le, Hortense; Sakellaropoulos, Theodore; Coudray, Nicolas; Zhu, Kelsey; Vasudevaraja, Varshini; Yeaton, Anna; Goparaju, Chandra; Li, Yonghua; Sulaiman, Imran; Tsay, Jun-Chieh J; Meyn, Peter; Mohamed, Hussein; Sydney, Iris; Shiomi, Tomoe; Ramaswami, Sitharam; Narula, Navneet; Kulicke, Ruth; Davis, Fred P; Stransky, Nicolas; Smolen, Gromoslaw A; Cheng, Wei-Yi; Cai, James; Punekar, Salman; Velcheti, Vamsidhar; Sterman, Daniel H; Poirier, J T; Neel, Ben; Wong, Kwok-Kin; Chiriboga, Luis; Heguy, Adriana; Papagiannakopoulos, Thales; Nadorp, Bettina; Snuderl, Matija; Segal, Leopoldo N; Moreira, Andre L; Pass, Harvey I; Tsirigos, Aristotelis
Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
PMCID:10632519
PMID: 37938580
ISSN: 2041-1723
CID: 5609852

Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results

McCord, Matthew; Jamshidi, Pouya; Thirunavu, Vineeth; Santana-Santos, Lucas; Vormittag-Nocito, Erica; Dittman, David; Parker, Stephanie; Baczkowski, Joseph; Jennings, Lawrence; Walshon, Jordain; McCortney, Kathleen; Galbraith, Kristyn; Zhang, Hui; Lukas, Rimas V; Stupp, Roger; Dixit, Karan; Kumthekar, Priya; Heimberger, Amy B; Snuderl, Matija; Horbinski, Craig
MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but histologic estimates of cellularity are subjective. We sought to determine whether driver mutation variant allelic frequency (VAF) could serve as a more objective metric for cellularity and identify possible false-negative MGMT samples. Among 691 adult-type diffuse gliomas, MGMT promoter methylation was assessed by pyrosequencing (N = 445) or DNA methylation array (N = 246); VAFs of TERT and IDH driver mutations were assessed by next generation sequencing. MGMT results were analyzed in relation to VAF. By pyrosequencing, 56% of all gliomas with driver mutation VAF ≥ 0.325 had MGMT promoter methylation, versus only 37% with VAF < 0.325 (p < 0.0001). The mean MGMT promoter pyrosequencing score was 19.3% for samples with VAF VAF ≥ 0.325, versus 12.7% for samples with VAF < 0.325 (p < 0.0001). Optimal VAF cutoffs differed among glioma subtypes (IDH wildtype glioblastoma: 0.12-0.18, IDH mutant astrocytoma: ~0.33, IDH mutant and 1p/19q co-deleted oligodendroglioma: 0.3-0.4). Methylation array was more sensitive for MGMT promoter methylation at lower VAFs than pyrosequencing. Microscopic examination tended to overestimate tumor cellularity when VAF was low. Re-testing low-VAF cases with methylation array and droplet digital PCR (ddPCR) confirmed that a subset of them had originally been false-negative. We conclude that driver mutation VAF is a useful quality assurance metric when evaluating MGMT promoter methylation tests, as it can help identify possible false-negative cases.
PMCID:10623846
PMID: 37919784
ISSN: 2051-5960
CID: 5590322

Endometrial/Endometrioid Stromal Tumors With Extensive Whorling and CTNNB1 Translocation : A Report of 3 Cases [Case Report]

Boyraz, Baris; da Cruz Paula, Arnaud; Deveraux, Kelly A; Tran, Ivy; da Silva, Edaise M; Young, Robert H; Snuderl, Matija; Weigelt, Britta; Oliva, Esther
Endometrial/endometrioid stromal tumors are rare and morphologically heterogenous, and their diagnosis may be challenging. We identified 3 endometrial/endometrioid stromal tumors with identical and previously undescribed histologic features and herein report their morphologic, immunohistochemical, and molecular profiles. Patients were 53, 62, and 79 years. Tumors were well-circumscribed, tan-yellow solid masses measuring 10.0, 11.0, and 18.7 cm, and were intramyometrial (n=2) or in the broad ligament (n=1). All showed small, tight whorls of epithelioid to slightly spindled tumor cells with minimal cytoplasm and negligible mitoses, multifocally associated with hyalinization and myxoid change set in a loose fibroblastic background with small, delicate vessels. This morphology was seen throughout in 1 tumor and in ∼20% and 70% of the 2 others with the remaining areas showing sex cord-like differentiation. Tumor cells expressed CD10 (3/3, 1 focal), calretinin (3/3 diffuse), WT1 (3/3 diffuse), estrogen receptor (1/1, diffuse). RNA-sequencing was successful in 1 tumor and revealed a GREB1-CTNNB1 in-frame fusion. All 3 tumors harbored a CTNNB1 translocation by fluorescence in situ hybridization correlating with nuclear β-catenin expression. Whole-genome DNA methylation analysis classified all 3 tumors within the low-grade endometrial stromal sarcoma reference class with flat copy number profiles. One patient (79-y-old) died of unrelated causes 2 months after surgery and the other 2 were alive without disease after 13 and 75 months. We have described a rare subset of endometrial/endometrioid stromal tumors with extensive whorling and a CTNNB1 translocation, expanding the morphologic and molecular spectrum of these neoplasms.
PMID: 37584555
ISSN: 1532-0979
CID: 5610032

DNA Methylation Signature of Synchronous Endometrioid Endometrial and Ovarian Carcinomas

Hsu Lin, Lawrence; Allison, Douglas H R; Turashvili, Gulisa; Vasudevaraja, Varshini; Tran, Ivy; Serrano, Jonathan; Weigelt, Britta; Ladanyi, Marc; Abu-Rustum, Nadeem R; Snuderl, Matija; Chiang, Sarah
Next-generation sequencing (NGS) studies have demonstrated that co-occurring sporadic endometrioid endometrial carcinoma (EEC) and endometrioid ovarian carcinoma (EOC) are clonally related, suggesting that they originate from a single primary tumor. Despite clonality, synchronous EEC and EOC when diagnosed at early stage behave indolently, similar to isolated primary EEC or isolated primary EOC. In the present study, we compared the DNA methylation signatures of co-occurring EEC and EOC with those of isolated primary EEC and isolated primary EOC. We also performed targeted NGS to assess the clonal relatedness of 7 co-occurring EEC and EOC (4 synchronous EEC and EOC and 3 metastatic EEC based on pathologic criteria). NGS confirmed a clonal relationship in all co-occurring EEC and EOC. DNA methylation profiling showed distinct epigenetic signatures of isolated primary EEC and isolated primary EOC. Endometrial tumors from co-occurring EEC and EOC clustered with isolated primary EEC while their ovarian counterparts clustered with isolated primary EOC. Three co-occurring EEC and EOC cases with peritoneal lesions showed a closer epigenetic signature and copy number variation profile between the peritoneal lesion and EOC than EEC. In conclusion, synchronous sporadic EEC and EOC are clonally related but demonstrate a shift in DNA methylation signatures between ovarian and endometrial tumors as well as epigenetic overlap between ovarian and peritoneal tumors. Our results suggest that tumor microenvironment in the ovary may play a role in epigenetic modulation of metastatic EEC.
PMID: 37652400
ISSN: 1530-0285
CID: 5611432

DNA Methylation Identifies Epigenetic Subtypes of Triple-Negative Breast Cancers With Distinct Clinicopathologic and Molecular Features

Lin, Lawrence Hsu; Tran, Ivy; Yang, Yiying; Shen, Guomiao; Miah, Pabel; Cotzia, Paolo; Roses, Daniel; Schnabel, Freya; Darvishian, Farbod; Snuderl, Matija
Triple-negative breast cancers (TNBC) include diverse carcinomas with heterogeneous clinical behavior. DNA methylation is a useful tool in classifying a variety of cancers. In this study, we analyzed TNBC using DNA methylation profiling and compared the results to those of mutational analysis. DNA methylation profiling (Infinium MethylationEPIC array, Illumina) and 50-gene panel-targeted DNA sequencing were performed in 44 treatment-naïve TNBC. We identified 3 distinct DNA methylation clusters with specific clinicopathologic and molecular features. Cluster 1 (phosphoinositide 3-kinase/protein kinase B-enriched cluster; n = 9) patients were significantly older (mean age, 71 years; P = .008) with tumors that were more likely to exhibit apocrine differentiation (78%; P < .001), a lower grade (44% were grade 2), a lower proliferation index (median Ki-67, 15%; P = .002), and lower tumor-infiltrating lymphocyte fractions (median, 15%; P = .0142). Tumors carried recurrent PIK3CA and AKT1 mutations and a higher percentage of low HER-2 expression (89%; P = .033). Cluster 3 (chromosomal instability cluster; n = 28) patients were significantly younger (median age, 57 years). Tumors were of higher grade (grade 3, 93%), had a higher proliferation index (median Ki-67, 75%), and were with a high fraction of tumor-infiltrating lymphocytes (median, 30%). Ninety-one percent of the germline BRCA1/2 mutation carriers were in cluster 3, and these tumors showed the highest level of copy number alterations. Cluster 2 represented cases with intermediate clinicopathologic characteristics and no specific molecular profile (no specific molecular profile cluster; n = 7). There were no differences in relation to stage, recurrence, and survival. In conclusion, DNA methylation profiling is a promising tool to classify patients with TNBC into biologically relevant groups, which may result in better disease characterization and reveal potential targets for emerging therapies.
PMID: 37595637
ISSN: 1530-0285
CID: 5607792

Recurrent TRAK1::RAF1 Fusions in pediatric low-grade gliomas

Benhamida, Jamal K; Harmsen, Hannah J; Ma, Deqin; William, Christopher M; Li, Bryan K; Villafania, Liliana; Sukhadia, Purvil; Mullaney, Kerry A; Dewan, Michael C; Vakiani, Efsevia; Karajannis, Matthias A; Snuderl, Matija; Zagzag, David; Ladanyi, Marc; Rosenblum, Marc K; Bale, Tejus A
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
PMID: 37399073
ISSN: 1750-3639
CID: 5539042

Clinical Validation of Stimulated Raman Histology for Rapid Intraoperative Diagnosis of Central Nervous System Tumors

Movahed-Ezazi, Misha; Nasir-Moin, Mustafa; Fang, Camila; Pizzillo, Isabella; Galbraith, Kristyn; Drexler, Steven; Krasnozhen-Ratush, Olga A; Shroff, Seema; Zagzag, David; William, Christopher; Orringer, Daniel; Snuderl, Matija
Stimulated Raman histology (SRH) is an ex vivo optical imaging method that enables microscopic examination of fresh tissue intraoperatively. The conventional intraoperative method uses frozen section analysis, which is labor and time intensive, introduces artifacts that limit diagnostic accuracy, and consumes tissue. SRH imaging allows rapid microscopic imaging of fresh tissue, avoids tissue loss, and enables remote telepathology review. This improves access to expert neuropathology consultation in both low- and high-resource practices. We clinically validated SRH by performing a blinded, retrospective two-arm telepathology study to clinically validate SRH for telepathology at our institution. Using surgical specimens from 47 subjects, we generated a data set composed of 47 SRH images and 47 matched whole slide images (WSIs) of formalin-fixed, paraffin-embedded tissue stained with hematoxylin and eosin, with associated intraoperative clinicoradiologic information and structured diagnostic questions. We compared diagnostic concordance between WSI and SRH-rendered diagnoses. Also, we compared the 1-year median turnaround time (TAT) of intraoperative conventional neuropathology frozen sections with prospectively rendered SRH-telepathology TAT. All SRH images were of sufficient quality for diagnostic review. A review of SRH images showed high accuracy in distinguishing glial from nonglial tumors (96.5% SRH vs 98% WSIs) and predicting final diagnosis (85.9% SRH vs 93.1% WSIs). SRH-based diagnosis and WSI-permanent section diagnosis had high concordance (κ = 0.76). The median TAT for prospectively SRH-rendered diagnosis was 3.7 minutes, approximately 10-fold shorter than the median frozen section TAT (31 minutes). The SRH-imaging procedure did not affect ancillary studies. SRH generates diagnostic virtual histologic images with accuracy comparable to conventional hematoxylin and eosin-based methods in a rapid manner. Our study represents the largest and most rigorous clinical validation of SRH to date. It supports the feasibility of implementing SRH as a rapid method for intraoperative diagnosis complementary to conventional pathology laboratory methods.
PMID: 37201685
ISSN: 1530-0285
CID: 5508102

Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions

Bogumil, Henri; Sill, Martin; Schrimpf, Daniel; Ismer, Britta; Blume, Christina; Rahmanzade, Ramin; Hinz, Felix; Cherkezov, Asan; Banan, Rouzbeh; Friedel, Dennis; Reuss, David E; Selt, Florian; Ecker, Jonas; Milde, Till; Pajtler, Kristian W; Schittenhelm, Jens; Hench, Jürgen; Frank, Stephan; Boldt, Henning B; Kristensen, Bjarne Winther; Scheie, David; Melchior, Linea C; Olesen, Viola; Sehested, Astrid; Boué, Daniel R; Abdullaev, Zied; Satgunaseelan, Laveniya; Kurth, Ina; Seidlitz, Annekatrin; White, Christine L; Ng, Ho-Keung; Shi, Zhi-Feng; Haberler, Christine; Deckert, Martina; Timmer, Marco; Goldbrunner, Roland; Tauziède-Espariat, Arnault; Varlet, Pascale; Brandner, Sebastian; Alexandrescu, Sanda; Snuderl, Matija; Aldape, Kenneth; Korshunov, Andrey; Witt, Olaf; Herold-Mende, Christel; Unterberg, Andreas; Wick, Wolfgang; Pfister, Stefan M; von Deimling, Andreas; Jones, David T W; Sahm, Felix; Sievers, Philipp
Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.
PMCID:10119244
PMID: 36933012
ISSN: 1432-0533
CID: 5464782

3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma

Okonechnikov, Konstantin; Camgöz, Aylin; Chapman, Owen; Wani, Sameena; Park, Donglim Esther; Hübner, Jens-Martin; Chakraborty, Abhijit; Pagadala, Meghana; Bump, Rosalind; Chandran, Sahaana; Kraft, Katerina; Acuna-Hidalgo, Rocio; Reid, Derek; Sikkink, Kristin; Mauermann, Monika; Juarez, Edwin F; Jenseit, Anne; Robinson, James T; Pajtler, Kristian W; Milde, Till; Jäger, Natalie; Fiesel, Petra; Morgan, Ling; Sridhar, Sunita; Coufal, Nicole G; Levy, Michael; Malicki, Denise; Hobbs, Charlotte; Kingsmore, Stephen; Nahas, Shareef; Snuderl, Matija; Crawford, John; Wechsler-Reya, Robert J; Davidson, Tom Belle; Cotter, Jennifer; Michaiel, George; Fleischhack, Gudrun; Mundlos, Stefan; Schmitt, Anthony; Carter, Hannah; Michealraj, Kulandaimanuvel Antony; Kumar, Sachin A; Taylor, Michael D; Rich, Jeremy; Buchholz, Frank; Mesirov, Jill P; Pfister, Stefan M; Ay, Ferhat; Dixon, Jesse R; Kool, Marcel; Chavez, Lukas
Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.
PMCID:10121654
PMID: 37085539
ISSN: 2041-1723
CID: 5464632