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

Shih DJH, Nayyar N, Bihun I, Dagogo-Jack I, Gill CM, Aquilanti E, Bertalan M, Kaplan A, D’Andrea MR, Chukwueke U, Ippen FM, Alvarez-Breckenridge C, Camarda ND, Lastrapes M, McCabe D, Kuter B, Kaufman B, Strickland MR, Martinez-Gutierrez JC, Nagabhushan D, De Sauvage M, White MD, Castro BA, Hoang K, Kaneb A, Batchelor ED, Paek SH, Park SH, Martinez-Lage M, Berghoff AS, Merrill P, Gerstner ER, Batchelor TT, Frosch MP, Frazier RP, Borger DR, Iafrate AJ, Johnson BE, Santagata S, Preusser M, Cahill DP, Carter SL, Brastianos PK .Nat Genet. 2020 Apr;52(4):371-377. doi: 10.1038/s41588-020-0592-7

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Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis.

Brastianos PK, Lee EQ, Cohen JV, Tolaney SM, Lin NU, Wang N, Chukwueke U, White MD, Nayyar N, Kim A, Alvarez-Breckenridge C, Krop I, Mahar MK, Bertalan MS, Shaw B, Mora JL, Goss N, Subramanian M, Nayak L, Dietrich J, Forst DA, Nahed BV, Batchelor TT, Shih HA, Gerstner ER, Moy B, Lawrence D, Giobbie-Hurder A, Carter SL, Oh K, Cahill DP, Sullivan RJ. Nat Med. 2020 Aug;26(8):1280-1284. doi: 10.1038/s41591-020-0918-0.

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Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas.

Brastianos PK, Taylor-Weiner A, Manley PE, Jones RT, Dias-Santagata D, Thorner AR, Lawrence MS, Rodriguez FJ, Bernardo LA, Schubert L, Sunkavalli A, Shillingford N, Calicchio ML, Lidov HG, Taha H, Martinez-Lage M, Santi M, Storm PB, Lee JY, Palmer JN, Adappa ND, Scott RM, Dunn IF, Laws ER Jr, Stewart C, Ligon KL, Hoang MP, Van Hummelen P, Hahn WC, Louis DN, Resnick AC, Kieran MW, Getz G, Santagata S.

Sporadic hemangioblastomas are characterized by cryptic VHL inactivation.

Hemangioblastomas consist of 10-20% neoplastic “stromal” cells within a vascular tumor cell mass of reactive pericytes, endothelium and lymphocytes. Familial cases of central nervous system hemangioblastoma uniformly result from mutations in the Von Hippel-Lindau (VHL) gene. In contrast, inactivation of VHL has been previously observed in only a minority of sporadic hemangioblastomas, suggesting an alternative genetic etiology. We performed deep-coverage DNA sequencing on 32 sporadic hemangioblastomas (whole exome discovery cohort n = 10, validation n = 22), followed by analysis of clonality, copy number alteration, and somatic mutation. We identified somatic mutation, loss of heterozygosity and/or deletion of VHL in 8 of 10 discovery cohort tumors. VHL inactivating events were ultimately detected in 78% (25/32) of cases. No other gene was significantly mutated. Overall, deep-coverage sequence analysis techniques uncovered VHL alterations within the neoplastic fraction of these tumors at higher frequencies than previously reported. Our findings support the central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas.

Shankar GM, Taylor-Weiner A, Lelic N, Jones RT, Kim JC, Francis JM, Abedalthagafi M, Borges LF, Coumans JV, Curry WT, Nahed BV, Shin JH, Paek SH, Park SH, Stewart C, Lawrence MS, Cibulskis K, Thorner AR, Van Hummelen P, Stemmer-Rachamimov AO, Batchelor TT, Carter SL, Hoang MP, Santagata S, Louis DN, Barker FG, Meyerson M, Getz G, Brastianos PK, Cahill DP.

Acta Neuropathol Commun. 2014 Dec 24;2:167. doi: 10.1186/s40478-014-0167-x.

Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.

Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases

Brastianos PK#1,2,3,4,5, Carter SL#6,5, Santagata S7,8, Cahill DP9, Taylor-Weiner A5, Jones RT4,10, Van Allen EM4,5, Lawrence MS5, Horowitz PM11, Cibulskis K5, Ligon KL4,8, Tabernero J12, Seoane J12, Martinez-Saez E13, Curry WT9, Dunn IF11, Paek SH14, Park SH14, McKenna A5, Chevalier A5, Rosenberg M5, Barker FG 2nd9, Gill CM3, Van Hummelen P4,10, Thorner AR4,10, Johnson BE4, Hoang MP15, Choueiri TK4, Signoretti S8, Sougnez C5, Rabin MS4, Lin NU4, Winer EP4, Stemmer-Rachamimov A15, Meyerson M4,10,5,8, Garraway L4,6,5, Gabriel S5, Lander ES5, Beroukhim R4,7,5, Batchelor TT2, Baselga J16, Louis DN15, Getz G#15,3,5, Hahn WC#4,10,5.

Cancer Discov. 2015 Nov;5(11):1164-1177. doi: 10.1158/2159-8290.CD-15-0369. Epub 2015 Sep 26.

Dramatic Response of BRAF V600E Mutant Papillary Craniopharyngioma to Targeted Therapy.

We recently reported that BRAF V600E is the principal oncogenic driver of papillary craniopharyngioma, a highly morbid intracranial tumor commonly refractory to treatment. Here, we describe our treatment of a man age 39 years with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg, orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of treatment, tumor volume was reduced by 85%. Mutations that commonly mediate resistance to MAPK pathway inhibition were not detected in a post-treatment sample by whole exome sequencing. A blood-based BRAF V600E assay detected circulating BRAF V600E in the patient’s blood. Re-evaluation of the existing management paradigms for craniopharyngioma is warranted, as patient morbidity might be reduced by noninvasive mutation testing and neoadjuvant-targeted treatment.

Brastianos PK1, Shankar GM1, Gill CM1, Taylor-Weiner A1, Nayyar N1, Panka DJ1, Sullivan RJ1, Frederick DT1, Abedalthagafi M1, Jones PS1, Dunn IF1, Nahed BV1, Romero JM1, Louis DN1, Getz G1, Cahill DP1, Santagata S1, Curry WT Jr1, Barker FG 2nd1.

J Natl Cancer Inst. 2015 Oct 23;108(2). pii: djv310. doi: 10.1093/jnci/djv310. Print 2016 Feb.

Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas.

BACKGROUND:

Patients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making.

METHODS:

To define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas.

RESULTS:

The tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome.

CONCLUSION:

We define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.

Shankar GM1,2,3,4,5, Abedalthagafi M3,6,7,8, Vaubel RA9, Merrill PH6, Nayyar N4,5, Gill CM4,5, Brewster R6, Bi WL10, Agarwalla PK11, Thorner AR12,13, Reardon DA3,12,14, Al-Mefty O3,10, Wen PY3,12,14, Alexander BM3,15, van Hummelen P12,13, Batchelor TT3,4,5, Ligon KL3,5,12, Ligon AH3,6,16, Meyerson M2,3,12,13, Dunn IF3,10,14, Beroukhim R3,6,12,14, Louis DN3,5,17, Perry A18, Carter SL3,19,20, Giannini C9, Curry WT Jr3,5,11, Cahill DP3,5,11, Barker FG 2nd3,5,11, Brastianos PK1,2,3,4,5, Santagata S3,6,21,22.

Neuro Oncol. 2017 Apr 1;19(4):535-545. doi: 10.1093/neuonc/now235.

Clinical and radiographic response following targeting of BCAN-NTRK1 fusion in glioneuronal tumor.

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.

Alvarez-Breckenridge C, Miller JJ, Nayyar N, Gill CM, Kaneb A, D’Andrea M, Le LP, Lee J, Cheng J, Zheng Z, Butler WE, Multani P, Chow Maneval E, Ha Paek S, Toyota BD, Dias-Santagata D, Santagata S, Romero J, Shaw AT, Farago AF, Yip S, Cahill DP, Batchelor TT, Iafrate AJ, BrastianosPK.
NPJ Precis Oncol. 2017 Mar 20;1(1):5. doi: 10.1038/s41698-017-0009-y. eCollection 2017.

Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas.

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.

Juratli TA1,2, Thiede C3, Koerner MVA1, Tummala SS1, Daubner D4, Shankar GM1, Williams EA5, Martinez-Lage M5, Soucek S2, Robel K2, Penson T1, Krause M6,7,8, Appold S6,7,8, Meinhardt M9, Pinzer T2, Miller JJ10, Krex D2,7, Ely HA11, Silverman IM11, Christiansen J11, Schackert G2,7, Wakimoto H1, Kirsch M2,7, Brastianos PK12, Cahill DP1.

Oncotarget. 2017 Nov 24;8(65):109228-109237. doi: 10.18632/oncotarget.22650. eCollection 2017 Dec 12.