Brastianos, Priscilla

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Brastianos, Priscilla

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Brastianos

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Priscilla

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Brastianos, Priscilla

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Evolution of Delayed Resistance to Immunotherapy in a Melanoma Responder
(Springer Nature, 2021-05-03) Liu, David; Lin, Jia-Ren; Robitschek, Emily; Kasumova, Gyulnara; Heyde, Alexander; Shi, Alvin; Kraya, Adam; Zhang, Gao; Moll, Tabea; Frederick, Dennie; Chen, Yu-An; Schapiro, Denis; Ho, Li-Lun; Bi, Kevin; Sahu, Avinash; Mei, Shaolin; Miao, Benchun; Sharova, Tatyana; Alvarez-Breckenridge, Christopher; Stocking, Jackson; Kim, Tommy; Fadden, Riley; Lawrence, Donald; Hoang, Mai; Cahill, Daniel; Maleh Mir, Mohsen; Nowak, Martin; Brastianos, Priscilla; Lian, Christine; Ruppin, Eytan; Izar, Benjamin; Herlyn, Meenhard; Van Allen, Eliezer; Nathanson, Katherine; Flaherty, Keith; Sullivan, Ryan; Kellis, Manolis; Sorger, Peter; Boland, Genevieve
Despite initial responses, most melanoma patients develop resistance to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a metastatic melanoma patient with exceptional response followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of 7 lineages with multiple convergent, but independent resistance-associated alterations (RAAs). All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNAseq and highly-multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition amongst different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFR-High tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated 2 distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated, neural crest tumor population in melanoma immunotherapy resistance, and describes site specific differences in tumor-immune interactions via longitudinal analysis of a melanoma patient with an unusual clinical course.
Pervasive chromosomal instability and karyotype order in tumour evolution
(Springer Science and Business Media LLC, 2020-09-02) Watkins, Thomas B. K.; Lim, Emilia L.; Petkovic, Marina; Elizalde, Sergi; Birkbak, Nicolai J.; Wilson, Gareth A.; Moore, David A.; Grönroos, Eva; Rowan, Andrew; Dewhurst, Sally M.; Demeulemeester, Jonas; Dentro, Stefan C.; Horswell, Stuart; Au, Lewis; Haase, Kerstin; Escudero, Mickael; Rosenthal, Rachel; Bakir, Maise Al; Xu, Hang; Litchfield, Kevin; Lu, Wei Ting; Mourikis, Thanos P.; Dietzen, Michelle; Spain, Lavinia; Cresswell, George D.; Biswas, Dhruva; Lamy, Philippe; Nordentoft, Iver; Harbst, Katja; Castro-Giner, Francesc; Yates, Lucy R.; Caramia, Franco; Jaulin, Fanny; Vicier, Cécile; Tomlinson, Ian P. M.; Brastianos, Priscilla; Cho, Raymond J.; Bastian, Boris C.; Dyrskjøt, Lars; Jönsson, Göran B.; Savas, Peter; Loi, Sherene; Campbell, Peter J.; Andre, Fabrice; Luscombe, Nicholas M.; Steeghs, Neeltje; Tjan-Heijnen, Vivianne C. G.; Szallasi, Zoltan; Turajlic, Samra; Jamal-Hanjani, Mariam; Van Loo, Peter; Bakhoum, Samuel F.; Schwarz, Roland F.; McGranahan, Nicholas; Swanton, Charles
Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas
(Impact Journals LLC, 2017) Juratli, Tareq; Thiede, Christian; Koerner, Mara V.A.; Tummala, Shilpa; Daubner, Dirk; Shankar, Ganesh; Williams, Erik; Martinez-Lage, Maria; Soucek, Silke; Robel, Katja; Penson, Tristan; Krause, Mechthild; Appold, Steffen; Meinhardt, Matthias; Pinzer, Thomas; Miller, Julie; Krex, Dietmar; Ely, Heather A.; Silverman, Ian M.; Christiansen, Jason; Schackert, Gabriele; Wakimoto, Hiroaki; Kirsch, Matthias; Brastianos, Priscilla; Cahill, Daniel
Background: Recent studies have reported mutations in the telomerase reverse transcriptase promoter (TERTp) in meningiomas. We sought to determine the frequency, clonality and clinical significance of telomere gene alterations in a cohort of patients with progressive/higher-grade meningiomas. Methods: We characterized 64 temporally- and regionally-distinct specimens from 26 WHO grade III meningioma patients. On initial diagnoses, the meningiomas spanned all WHO grades (3 grade I, 13 grade II and 10 grade III). The tumor samples were screened for TERTp and ATRX/DAXX mutations, and TERT rearrangements. Additionally, TERTp was sequenced in a separate cohort of 19 patients with radiation-associated meningiomas. We examined the impact of mutational status on patients’ progression and overall survival. Results: Somatic TERTp mutations were detected in six patients (6/26 = 23%). Regional intratumoral heterogeneity in TERTp mutation status was noted. In 4 patients, TERTp mutations were detected in recurrent specimens but not in the available specimens of the first surgery. Additionally, a TERT gene fusion (LPCAT1-TERT) was found in one sample. In contrary, none of the investigated samples harbored an ATRX or DAXX mutation. In the cohort of radiation-induced meningiomas, TERTp mutation was detected in two patients (10.5%). Importantly, we found that patients with emergence of TERTp mutations had a substantially shorter OS than their TERTp wild-type counterparts (2.7 years, 95% CI 0.9 – 4.5 years versus 10.8 years, 95% CI 7.8 -12.8 years, p=0.003). Conclusions: In progressive/higher-grade meningiomas,TERTp mutations are associated with poor survival, supporting a model in which selection of this alteration is a harbinger of aggressive tumor development. In addition, we observe spatial intratumoral heterogeneity of TERTp mutation status, consistent with this model of late emergence in tumor evolution. Thus, early detection of TERTp mutations may define patients with more aggressive meningiomas. Stratification for TERT alterations should be adopted in future clinical trials of progressive/higher-grade meningiomas.
Clinical and radiographic response following targeting of BCAN-NTRK1 fusion in glioneuronal tumor
(Nature Publishing Group UK, 2017) Alvarez-Breckenridge, Christopher; Miller, Julie; Nayyar, Naema; Gill, Corey M.; Kaneb, Andrew; D’Andrea, Megan; Le, Long P.; Lee, Jesse; Cheng, Ju; Zheng, Zongli; Butler, William; Multani, Pratik; Chow Maneval, Edna; Ha Paek, Sun; Toyota, Brian D.; Dias-Santagata, Dora; Santagata, Sandro; Romero, Javier; Shaw, Alice; Farago, Anna; Yip, Stephen; Cahill, Daniel; Batchelor, Tracy; Iafrate, A. John; Brastianos, Priscilla
Glioneuronal tumors constitute a histologically diverse group of primary central nervous system neoplasms that are typically slow-growing and managed conservatively. Genetic alterations associated with glioneuronal tumors include BRAF mutations and oncogenic fusions. To further characterize this group of tumors, we collected a cohort of 26 glioneuronal tumors and performed in-depth genomic analysis. We identified mutations in BRAF (34%) and oncogenic fusions (30%), consistent with previously published reports. In addition, we discovered novel oncogenic fusions involving members of the NTRK gene family in a subset of our cohort. One-patient with BCAN exon 13 fused to NTRK1 exon 11 initially underwent a subtotal resection for a 4th ventricular glioneuronal tumor but ultimately required additional therapy due to progressive, symptomatic disease. Given the patient’s targetable fusion, the patient was enrolled on a clinical trial with entrectinib, a pan-Trk, ROS1, and ALK (anaplastic lymphoma kinase) inhibitor. The patient was treated for 11 months and during this time volumetric analysis of the lesion demonstrated a maximum reduction of 60% in the contrast-enhancing tumor compared to his pre-treatment magnetic resonance imaging study. The radiologic response was associated with resolution of his clinical symptoms and was maintained for 11 months on treatment. This report of a BCAN-NTRK1 fusion in glioneuronal tumors highlights its clinical importance as a novel, targetable alteration.
Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens
(Nature Publishing Group UK, 2017) Brastianos, Priscilla; Nayyar, Naema; Rosebrock, Daniel; Leshchiner, Ignaty; Gill, Corey M.; Livitz, Dimitri; Bertalan, Mia S.; D’Andrea, Megan; Hoang, Kaitlin; Aquilanti, Elisa; Chukwueke, Ugonma; Kaneb, Andrew; Chi, Andrew; Plotkin, Scott; Gerstner, Elizabeth; Frosch, Mathew P.; Suva, Mario; Cahill, Daniel; Getz, Gad; Batchelor, Tracy
Glioblastomas are malignant neoplasms composed of diverse cell populations. This intratumoral diversity has an underlying architecture, with a hierarchical relationship through clonal evolution from a common ancestor. Therapies are limited by emergence of resistant subclones from this phylogenetic reservoir. To characterize this clonal ancestral origin of recurrent tumors, we determined phylogenetic relationships using whole exome sequencing of pre-treatment IDH1/2 wild-type glioblastoma specimens, matched to post-treatment autopsy samples (n = 9) and metastatic extracranial post-treatment autopsy samples (n = 3). We identified “truncal” genetic events common to the evolutionary ancestry of the initial specimen and later recurrences, thereby inferring the identity of the precursor cell population. Mutations were identified in a subset of cases in known glioblastoma genes such as NF1(n = 3), TP53(n = 4) and EGFR(n = 5). However, by phylogenetic analysis, there were no protein-coding mutations as recurrent truncal events across the majority of cases. In contrast, whole copy-loss of chromosome 10 (12 of 12 cases), copy-loss of chromosome 9p21 (11 of 12 cases) and copy-gain in chromosome 7 (10 of 12 cases) were identified as shared events in the majority of cases. Strikingly, mutations in the TERT promoter were also identified as shared events in all evaluated pairs (9 of 9). Thus, we define four truncal non-coding genomic alterations that represent early genomic events in gliomagenesis, that identify the persistent cellular reservoir from which glioblastoma recurrences emerge. Therapies to target these key early genomic events are needed. These findings offer an evolutionary explanation for why precision therapies that target protein-coding mutations lack efficacy in GBM.
Radiation Treatment for WHO Grade II and III Meningiomas
(Frontiers Media S.A., 2013) Walcott, Brian; Nahed, Brian; Brastianos, Priscilla; Loeffler, Jay
The treatment of meningiomas is tailored to their histological grade. While World Health Organization (WHO) grade I lesions can be treated with either surgery or external beam radiation, WHO Grade II and III lesions often require a combination of the two modalities. For these high-grade lesions, conventional external beam radiation is delivered to either the residual tumor or the surgical resection margin. The optimal timing of radiation, either immediately following surgical resection or at the time of recurrence, is yet to be determined. Additionally, another method of radiation delivery, brachytherapy, can be administered locally at the time of surgery for recurrent lesions. Altogether, the complex nature of WHO grade II and III meningiomas requires careful treatment planning and delivery by a multidisciplinary team.
Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations
(2013) Brastianos, Priscilla; Horowitz, Peleg; Santagata, Sandro; Jones, Robert T.; McKenna, Aaron; Getz, Gad; Ligon, Keith; Palescandolo, Emanuele; Van Hummelen, Paul; Ducar, Matthew D.; Raza, Alina; Sunkavalli, Ashwini; MacConaill, Laura E.; Stemmer-Rachamimov, Anat; Louis, David; Hahn, William; Dunn, Ian; Beroukhim, Rameen
Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5
(Impact Journals LLC, 2014) Abedalthagafi, Malak; Merrill, Parker H.; Bi, Wenya; Jones, Robert T.; Listewnik, Marc L.; Ramkissoon, Shakti H.; Thorner, Aaron R.; Dunn, Ian; Beroukhim, Rameen; Alexander, Brian; Brastianos, Priscilla; Francis, Joshua M.; Folkerth, Rebecca D.; Ligon, Keith; Hummelen, Paul Van; Ligon, Azra; Santagata, Sandro
Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile – polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis.
Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas
(2014) Brastianos, Priscilla; Taylor-Weiner, Amaro; Manley, Peter E.; Jones, Robert T.; Dias-Santagata, Dora; Thorner, Aaron R.; Rodriguez, Fausto J.; Bernardo, Lindsay A.; Schubert, Laura; Sunkavalli, Ashwini; Shillingford, Nick; Calicchio, Monica L.; Lidov, Hart; Taha, Hala; Martinez-Lage, Maria; Santi, Mariarita; Storm, Phillip B.; Lee, John Y. K.; Palmer, James N.; Adappa, Nithin D.; Scott, R. Michael; Dunn, Ian; Laws, Edward; Stewart, Chip; Ligon, Keith; Hoang, Mai; Van Hummelen, Paul; Hahn, William; Louis, David; Resnick, Adam C.; Kieran, Mark W.; Getz, Gad; Santagata, Sandro
Rapid Intraoperative Molecular Characterization of Glioma
(American Medical Association (AMA), 2015) Shankar, Ganesh; Francis, Joshua M.; Rinne, Mikael; Ramkissoon, Shakti H.; Huang, Franklin; Venteicher, Andrew S; Akama-Garren, Elliot H.; Kang, Yun Jee; Lelic, Nina; Kim, James C.; Brown, Loreal E.; Charbonneau, Sarah K; Golby, Alexandra; Sekhar Pedamallu, Chandra; Hoang, Mai; Sullivan, Ryan; Cherniack, Andrew D.; Garraway, Levi; Stemmer-Rachamimov, Anat; Reardon, David; Wen, Patrick; Brastianos, Priscilla; Curry, William; Barker, Frederick; Hahn, William; Nahed, Brian; Ligon, Keith; Louis, David; Cahill, Daniel; Meyerson, Matthew
IMPORTANCE: Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1). OBSERVATIONS: This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%–99%) and 100% specificity (95% CI, 95%–100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe. CONCLUSIONS AND RELEVANCE: The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations.