Publications by authors named "Ivanna Bihun"

7 Publications

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Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma.

Nat Genet 2020 04 23;52(4):371-377. Epub 2020 Mar 23.

Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.
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http://dx.doi.org/10.1038/s41588-020-0592-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136154PMC
April 2020

Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent Mutations in Foramen Magnum Meningiomas.

J Neurol Surg B Skull Base 2019 Dec 10;80(6):562-567. Epub 2019 Jan 10.

Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States.

 Posterior fossa meningiomas are surgically challenging tumors that are associated with high morbidity and mortality. We sought to investigate the anatomical distribution of clinically actionable mutations in posterior fossa meningioma to facilitate identifying patients amenable for systemic targeted therapy trials.  Targeted sequencing of clinically targetable , , and mutations was performed in 61 posterior fossa meningioma using Illumina NextSeq 500 to a target depth of >500 × . Samples were further interrogated for 53 cancer-relevant RNA fusions by the Archer FusionPlex panel to detect gene rearrangements.   1 ( ) mutations were detected in five cases (8.2%), four in the foramen magnum and one in the cerebellopontine angle. In contrast, none of the posterior fossa tumors harbored an ( ) or a ( ) mutation. Notably, the majority of foramen magnum meningiomas (4/7, 57%) harbored an mutation. In addition, common clinically targetable gene fusions were not detected in any of the cases.  A large subset of foramen magnum meningiomas harbor mutations and are therefore potentially amenable to targeted medical therapy. Genotyping of foramen magnum meningiomas may enable more therapeutic alternatives and guide their treatment decision process.
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http://dx.doi.org/10.1055/s-0038-1676821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864425PMC
December 2019

The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in -Mutant Breast Cancer Brain Metastases.

Clin Cancer Res 2019 06 22;25(11):3374-3383. Epub 2019 Feb 22.

Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: Previous studies have shown that the PI3K/Akt/mTOR pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models. The efficacy of GDC-0084 was evaluated in -mutant and wild-type breast cancer cell lines and the isogenic pairs of wild-type and mutant (H1047R/+) MCF10A cells . studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. , the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC.

Results: , GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in -mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in wild-type cell lines . , treatment with GDC-0084 markedly inhibited the growth of -mutant, with accompanying signaling changes, and not wild-type brain tumors.

Conclusions: The results of this study suggest that the brain-penetrant PI3K/mTOR targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685218PMC
June 2019

L265P mutation and loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas.

Blood Adv 2019 02;3(3):375-383

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified mutation in 67% (42 of 63) of patients, biallelic loss in 44% (16 of 36), and mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, ), with few areas of amplification. mutations were associated with improved progression-free and overall survival. We did not identify amplification at the / loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified mutation and loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.
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http://dx.doi.org/10.1182/bloodadvances.2018027672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373750PMC
February 2019

A Clinical Rule for Preoperative Prediction of BRAF Mutation Status in Craniopharyngiomas.

Neurosurgery 2019 08;85(2):204-210

Divisions of Neuro-Oncology and Hematology/Oncology, Departments of Medicine and Neurology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.

Background: Papillary craniopharyngiomas are characterized by BRAFV600E mutations. Targeted therapy can elicit a dramatic radiographic regression of these tumors. Therefore, prediction of BRAF mutation status before definitive surgery could enable neoadjuvant treatment strategies.

Objective: To establish preoperative prediction criteria to identify patients with a BRAF mutant craniopharyngioma.

Methods: Sixty-four patients with craniopharyngioma were included in this study. We determined BRAF mutation status by targeted sequencing. After scoring interobserver variability between presurgical clinical data and radiographic features, we established a diagnostic rule for BRAF mutation in our discovery cohort. We then validated the rule in an independent cohort.

Results: The BRAFV600E mutation was detected in 12 of 42 patients in the discovery cohort. There were no patients under age 18 with BRAF mutation. Calcification was rare in tumors with BRAF mutation (P < .001), and 92% of them were supradiaphragmatic in location. Combining these 3 features-older than 18 years, absence of calcification, and supradiaphragmatic tumor location-we established a rule for predicting BRAF mutation. In cases where all 3 criteria were fulfilled, the sensitivity and specificity for the presence of BRAF mutation were 83% and 93%, respectively. In the validation cohort (n = 22), the sensitivity was 100% and specificity was 89%.

Conclusion: We propose predictive criteria for a BRAF mutation in craniopharyngioma using preoperative clinical and radiographic data. This rule may be useful in identifying patients who could potentially benefit from neoadjuvant BRAFV600E-targeted systemic therapies.
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http://dx.doi.org/10.1093/neuros/nyy569DOI Listing
August 2019

DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome.

Acta Neuropathol 2018 11 19;136(5):779-792. Epub 2018 Aug 19.

Stephen E. and Catherine Pappas Center for Neuro-Oncology, Divisions of Hematology/Oncology and Neuro-Oncology, Departments of Medicine and Neurology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

Progressive meningiomas that have failed surgery and radiation have a poor prognosis and no standard therapy. While meningiomas are more common in females overall, progressive meningiomas are enriched in males. We performed a comprehensive molecular characterization of 169 meningiomas from 53 patients with progressive/high-grade tumors, including matched primary and recurrent samples. Exome sequencing in an initial cohort (n = 24) detected frequent alterations in genes residing on the X chromosome, with somatic intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene as the most common alteration (n = 5, 20.8%), along with alterations of other known X-linked cancer-related genes KDM6A (n =2, 8.3%), DDX3X, RBM10 and STAG2 (n = 1, 4.1% each). DMD inactivation (by genomic deletion or loss of protein expression) was ultimately detected in 17/53 progressive meningioma patients (32%). Importantly, patients with tumors harboring DMD inactivation had a shorter overall survival (OS) than their wild-type counterparts [5.1 years (95% CI 1.3-9.0) vs. median not reached (95% CI 2.9-not reached, p = 0.006)]. Given the known poor prognostic association of TERT alterations in these tumors, we also assessed for these events, and found seven patients with TERT promoter mutations and three with TERT rearrangements in this cohort (n = 10, 18.8%), including a recurrent novel RETREG1-TERT rearrangement that was present in two patients. In a multivariate model, DMD inactivation (p = 0.033, HR = 2.6, 95% CI 1.0-6.6) and TERT alterations (p = 0.005, HR = 3.8, 95% CI 1.5-9.9) were mutually independent in predicting unfavorable outcomes. Thus, DMD alterations identify a subset of progressive/high-grade meningiomas with worse outcomes.
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http://dx.doi.org/10.1007/s00401-018-1899-7DOI Listing
November 2018

Secreted factors from equine mesenchymal stromal cells diminish the effects of TGF-β1 on equine dermal fibroblasts and alter the phenotype of dermal fibroblasts isolated from cutaneous fibroproliferative wounds.

Wound Repair Regen 2017 04 27;25(2):234-247. Epub 2017 Apr 27.

Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York.

The prevalence of cutaneous fibroproliferative disorders (CFPDs) is high and almost exclusively occurs in humans (keloids and hypertrophic scars) and horses (exuberant granulation tissue), making the horse a valuable translational model for studies on prevention and treatment of human CFPDs. CFPDs arise as a result of dysregulated wound healing characterized by persistently high levels of cytokines, such as transforming growth factor beta 1 (TGF-β1), that contribute to excessive extracellular matrix deposition, and the physical disorganization of dermal fibroblasts (DF). The mesenchymal stromal cell (MSC) secretome, consisting of all factors secreted by MSC, has been shown to promote normal wound healing in both humans and horses, but its potential to treat CFPDs remains largely unexplored. Therefore, the objective of this study was to examine the effects of the equine MSC secretome on equine DF influenced by cytokines that contribute to the development of CFPDs. First, primary equine DF were treated with TGF-β1 in vitro in the presence or absence of MSC secreted products. We found that MSC secreted products could block TGF-β1-induced changes in DF morphology, proliferation rate, gene expression, and contractile-capacity. We then isolated primary DF from equine exuberant granulation tissue, to evaluate the potential of the MSC secretome to alter the phenotype of cells derived from a complex CFPD environment. These results showed that MSC secreted factors did not change proliferation or migration of these cells, but did lead to changes in expression of genes and proteins involved in extracellular matrix remodeling and did affect contractile capacity. These results warrant future studies designed to evaluate the potential of the MSC secretome to minimize the pathologies associated with CFPD in vivo.
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http://dx.doi.org/10.1111/wrr.12515DOI Listing
April 2017