Publications by authors named "Kerry Mullaney"

15 Publications

  • Page 1 of 1

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

A Performance Comparison of Commonly Used Assays to Detect RET Fusions.

Clin Cancer Res 2021 Mar 3;27(5):1316-1328. Epub 2020 Dec 3.

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

Purpose: Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced fusion-positive lung and thyroid cancer. fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort.

Experimental Design: Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a structural variant of unknown significance (SVUS) were present. Canonical DNA-level fusions and RNA-confirmed fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups.

Results: A total of 171 of 41,869 patients with DNA NGS harbored structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic fusions. The most common fusion-positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were (45%), (29.1%), and (13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for - (66.7%, 8/12). A total of 87.5% (7/8) of SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: sensitivity was highest (100%, 31/31), followed by (88.9%, 16/18) and (50%, 6/12). Specificity of RET IHC was 82% (73/89).

Conclusions: Although DNA sequencing has high sensitivity and specificity, RNA sequencing of SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for - fusions.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3208DOI Listing
March 2021

Myositis ossificans-like soft tissue aneurysmal bone cyst: a clinical, radiological, and pathological study of seven cases with COL1A1-USP6 fusion and a novel ANGPTL2-USP6 fusion.

Mod Pathol 2020 08 10;33(8):1492-1504. Epub 2020 Mar 10.

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

Herein we described the clinical, radiological, histological, and molecular characteristics of seven soft tissue aneurysmal bone cysts (STABCs) diagnosed and managed at a tertiary cancer center and to elucidate their relationship with myositis ossificans (MO). All cases had established imaging and histopathological diagnosis of STABC and were subject to fluorescence in situ hybridization (FISH) for USP6 rearrangement and Archer® FusionPlex® targeted RNA sequencing (RNASeq) analysis to identify the fusion partner. A thorough literature review of STABC and MO was conducted. The patients presented with painful masses unpreceded by trauma, occurring most commonly in the deep soft tissue of the thigh/gluteus (4/7), and also in the supraclavicular region, the axilla, and the hand. On imaging, the lesions were frequently associated with peripheral calcification on conventional radiographs and CT (6/7), cystic components on ultrasound, as well as perilesional edema (7/7) and fluid levels (3/7) on MRI. Bone scan (1/1) showed intense radiotracer uptake. Histologically, 6/7 cases demonstrated zonal arrangements reminiscent of MO. USP6 rearrangement was found in all seven cases by FISH and/or RNASeq. RNASeq further detected COL1A1-USP6 fusion in six cases and a novel ANGPTL2-USP6 fusion in one case. Four patients underwent resection of the tumors and were disease free at their last follow-up. Three patients who underwent incisional or needle biopsies had no evidence of disease progression on imaging studies. In conclusion, the clinical, radiological, and pathological overlap between STABC and MO suggests that they are closely related entities. A novel fusion ANGPTL2-USP6 is associated with distinct clinical and pathological presentation.
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http://dx.doi.org/10.1038/s41379-020-0513-4DOI Listing
August 2020

NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls.

Mod Pathol 2020 01 2;33(1):38-46. Epub 2019 Aug 2.

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

With the FDA approval of larotrectinib, NTRK fusion assessment has recently become a standard part of management for patients with locally advanced or metastatic cancers. Unlike somatic mutation assessment, the detection of NTRK fusions is not straightforward, and various assays exist at the DNA, RNA, and protein level. Here, we investigate the performance of immunohistochemistry and DNA-based next-generation sequencing to indirectly or directly detect NTRK fusions relative to an RNA-based next-generation sequencing approach in the largest cohort of NTRK fusion positive solid tumors to date. A retrospective analysis of 38,095 samples from 33,997 patients sequenced by a targeted DNA-based next-generation sequencing panel (MSK-IMPACT), 2189 of which were also examined by an RNA-based sequencing assay (MSK-Fusion), identified 87 patients with oncogenic NTRK1-3 fusions. All available institutional NTRK fusion positive cases were assessed by pan-Trk immunohistochemistry along with a cohort of control cases negative for NTRK fusions by next-generation sequencing. DNA-based sequencing showed an overall sensitivity and specificity of 81.1% and 99.9%, respectively, for the detection of NTRK fusions when compared to RNA-based sequencing. False negatives occurred when fusions involved breakpoints not covered by the assay. Immunohistochemistry showed overall sensitivity of 87.9% and specificity of 81.1%, with high sensitivity for NTRK1 (96%) and NTRK2 (100%) fusions and lower sensitivity for NTRK3 fusions (79%). Specificity was 100% for carcinomas of the colon, lung, thyroid, pancreas, and biliary tract. Decreased specificity was seen in breast and salivary gland carcinomas (82% and 52%, respectively), and positive staining was often seen in tumors with neural differentiation. Both sensitivity and specificity were poor in sarcomas. Selection of the appropriate assay for NTRK fusion detection therefore depends on tumor type and genes involved, as well as consideration of other factors such as available material, accessibility of various clinical assays, and whether comprehensive genomic testing is needed concurrently.
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http://dx.doi.org/10.1038/s41379-019-0324-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437403PMC
January 2020

High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden.

Clin Cancer Res 2019 Aug 26;25(15):4712-4722. Epub 2019 Apr 26.

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

Purpose: Targeted next-generation sequencing of DNA has become more widely used in the management of patients with lung adenocarcinoma; however, no clear mitogenic driver alteration is found in some cases. We evaluated the incremental benefit of targeted RNA sequencing (RNAseq) in the identification of gene fusions and exon 14 (ex14) alterations in DNA sequencing (DNAseq) driver-negative lung cancers.

Experimental Design: Lung cancers driver negative by MSK-IMPACT underwent further analysis using a custom RNAseq panel (MSK-Fusion). Tumor mutation burden (TMB) was assessed as a potential prioritization criterion for targeted RNAseq.

Results: As part of prospective clinical genomic testing, we profiled 2,522 lung adenocarcinomas using MSK-IMPACT, which identified 195 (7.7%) fusions and 119 (4.7%) ex14 alterations. Among 275 driver-negative cases with available tissue, 254 (92%) had sufficient material for RNAseq. A previously undetected alteration was identified in 14% (36/254) of cases, 33 of which were actionable (27 in-frame fusions, 6 ex14). Of these 33 patients, 10 then received matched targeted therapy, which achieved clinical benefit in 8 (80%). In the 32% (81/254) of DNAseq driver-negative cases with low TMB [0-5 mutations/Megabase (mut/Mb)], 25 (31%) were positive for previously undetected gene fusions on RNAseq, whereas, in 151 cases with TMB >5 mut/Mb, only 7% were positive for fusions ( < 0.0001).

Conclusions: Targeted RNAseq assays should be used in all cases that appear driver negative by DNAseq assays to ensure comprehensive detection of actionable gene rearrangements. Furthermore, we observed a significant enrichment for fusions in DNAseq driver-negative samples with low TMB, supporting the prioritization of such cases for additional RNAseq..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679790PMC
August 2019

Undifferentiated Uterine Sarcomas Represent Under-Recognized High-grade Endometrial Stromal Sarcomas.

Am J Surg Pathol 2019 05;43(5):662-669

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

Undifferentiated uterine sarcoma is a diagnosis of exclusion with limited molecular genetic data available. Recent recognition of high-grade endometrial stromal sarcomas with diverse genotypes suggests that some tumors classified as undifferentiated uterine sarcomas may represent misdiagnosed high-grade endometrial stromal sarcomas. Archival material from 10 tumors diagnosed as undifferentiated uterine sarcomas in 2009 to 2017 were collected. BCOR immunohistochemistry and fluorescence in situ hybridization (FISH) using break-apart probes flanking BCOR, ZC3H7B, CCNB3, YWHAE, NUTM2, JAZF1, and BCORL1 were performed. Tumors lacking or harboring gene rearrangement with no known fusion partner by FISH were subjected to targeted RNA sequencing. Morphology was correlated with FISH and sequencing results. BCOR expression was moderate to strong in ≥50% of cells in 8 tumors, while weak in <5% cells and negative in 2. FISH detected mutually exclusive ZC3H7B-BCOR and YWHAE-NUTM2 fusions in 3 uniform undifferentiated uterine sarcomas; 2 pleomorphic tumors harbored YWHAE rearrangement with no known partner. Targeted RNA sequencing of 5 FISH-negative uniform undifferentiated uterine sarcomas detected BRD8-PHF1 and YWHAE-NUTM2B fusions and BCOR internal tandem duplication in 4 of them. Tumors with YWHAE-NUTM2 fusions and BCOR genetic abnormalities showed morphology characteristic of high-grade endometrial stromal sarcomas. No fusions were detected by sequencing in the tumor with YWHAE rearrangement only by FISH. Most tumors classified as undifferentiated uterine sarcomas represent misdiagnosed high-grade endometrial stromal sarcomas. BCOR expression in ≥50% of cells may help triage tumors for molecular confirmation of high-grade endometrial stromal sarcoma-related genetic abnormalities. Novel YWHAE rearrangements may define a subset of true undifferentiated pleomorphic sarcomas.
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http://dx.doi.org/10.1097/PAS.0000000000001215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764763PMC
May 2019

Colorectal Carcinomas Containing Hypermethylated MLH1 Promoter and Wild-Type BRAF/KRAS Are Enriched for Targetable Kinase Fusions.

Cancer Res 2019 03 14;79(6):1047-1053. Epub 2019 Jan 14.

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

Kinase fusions are rare and poorly characterized in colorectal carcinoma, yet they present unique opportunities for targeted therapy. In this study, we characterized kinase fusions from patients with advanced colorectal carcinoma who had MSK-IMPACT testing of their tumors between January 2014 and June 2018. Patients were analyzed for the presence of fusions, microsatellite instability (MSI), and mutations. Mismatch repair (MMR), IHC, and promoter hypermethylation status of MLH1 (MLH1ph) in microsatellite instability-high (MSI-H) colorectal carcinoma with fusions were investigated. Fusion transcripts were confirmed using a targeted RNA-seq panel assay. Of 2,314 colorectal carcinomas with MSK-IMPACT testing, 21 harbored kinase fusions. Overall 57% (12/21) of colorectal carcinoma fusions were MSI-H/MMR-D. Loss of MLH1 and MLH1ph was confirmed in all 12 and all 10 cases with available material, respectively. Fusions were present in 5% of MSI-H/MMR-D colorectal carcinoma compared with 0.4% of MSS/MMR-P colorectal carcinoma ( < 0.001) and 15% of MSI-H/MMR-D colorectal carcinoma with wild-type . Of 24 total MLH1-deficient colorectal carcinomas with MLH1ph and wild-type , 10 (42%) harbored kinase fusions. Kinase fusions in MSI-H colorectal carcinoma were associated with sporadic MLH1ph rather than with Lynch syndrome, and these patients may be eligible for kinase inhibitors, particularly following resistance or toxicity in response to immunotherapy. These findings identify a molecular subset of colorectal carcinoma with kinase fusions that may be responsive to kinase inhibitors. A high frequency of targetable kinase fusions in wild-type, MSI-H colorectal carcinoma offers a rationale for routine screening to identify patients with colorectal carcinoma with kinase fusions that may be responsive to kinase inhibitors..
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420871PMC
March 2019

Diagnosis of known sarcoma fusions and novel fusion partners by targeted RNA sequencing with identification of a recurrent ACTB-FOSB fusion in pseudomyogenic hemangioendothelioma.

Mod Pathol 2019 05 21;32(5):609-620. Epub 2018 Nov 21.

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

Integration of morphological, immunohistochemical, and molecular methods is often necessary for the precise diagnosis and optimal clinical management of sarcomas. We have validated and implemented a clinical molecular diagnostic assay, MSK- Fusion Solid, for detection of gene fusions in solid tumors, including sarcomas. Starting with RNA extracted from formalin-fixed paraffin-embedded tumor material, this targeted RNA sequencing assay utilizes anchored multiplex PCR to detect oncogenic fusion transcripts involving 62 genes known to be recurrently rearranged in solid tumors including sarcomas without prior knowledge of fusion partners. From 1/2016 to 1/2018, 192 bone and soft tissue tumors were submitted for MSK- Fusion Solid analysis and 96% (184/192) successfully passed all the pre-sequencing quality control parameters and sequencing steps. These sarcomas encompass 24 major tumor types, including 175 soft tissue tumors and 9 osteosarcomas. Ewing and Ewing-like sarcomas, rhabdomyosarcoma, and sarcoma-not otherwise specified were the three most common tumor types. Diagnostic in-frame fusion transcripts were detected in 43% of cases, including 3% (6/184) with novel fusion partners, specifically TRPS1-PLAG1, VCP-TFE3, MYLK-BRAF, FUS-TFCP2, and ACTB-FOSB, the latter in two cases of pseudomyogenic hemangioendothelioma, representing a novel observation in this sarcoma. Our experience shows that this targeted RNA sequencing assay performs in a robust and sensitive fashion on RNA extracted from most routine clinical specimens of sarcomas thereby facilitating precise diagnosis and providing opportunities for novel fusion partner discovery.
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http://dx.doi.org/10.1038/s41379-018-0175-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486453PMC
May 2019

Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies.

J Clin Invest 2018 08 6;128(9):3819-3825. Epub 2018 Aug 6.

Human Oncology and Pathogenesis Program and.

Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.
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http://dx.doi.org/10.1172/JCI120787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118587PMC
August 2018

Erratum: Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.

Authors:
Ahmet Zehir Ryma Benayed Ronak H Shah Aijazuddin Syed Sumit Middha Hyunjae R Kim Preethi Srinivasan Jianjiong Gao Debyani Chakravarty Sean M Devlin Matthew D Hellmann David A Barron Alison M Schram Meera Hameed Snjezana Dogan Dara S Ross Jaclyn F Hechtman Deborah F DeLair JinJuan Yao Diana L Mandelker Donavan T Cheng Raghu Chandramohan Abhinita S Mohanty Ryan N Ptashkin Gowtham Jayakumaran Meera Prasad Mustafa H Syed Anoop Balakrishnan Rema Zhen Y Liu Khedoudja Nafa Laetitia Borsu Justyna Sadowska Jacklyn Casanova Ruben Bacares Iwona J Kiecka Anna Razumova Julie B Son Lisa Stewart Tessara Baldi Kerry A Mullaney Hikmat Al-Ahmadie Efsevia Vakiani Adam A Abeshouse Alexander V Penson Philip Jonsson Niedzica Camacho Matthew T Chang Helen H Won Benjamin E Gross Ritika Kundra Zachary J Heins Hsiao-Wei Chen Sarah Phillips Hongxin Zhang Jiaojiao Wang Angelica Ochoa Jonathan Wills Michael Eubank Stacy B Thomas Stuart M Gardos Dalicia N Reales Jesse Galle Robert Durany Roy Cambria Wassim Abida Andrea Cercek Darren R Feldman Mrinal M Gounder A Ari Hakimi James J Harding Gopa Iyer Yelena Y Janjigian Emmet J Jordan Ciara M Kelly Maeve A Lowery Luc G T Morris Antonio M Omuro Nitya Raj Pedram Razavi Alexander N Shoushtari Neerav Shukla Tara E Soumerai Anna M Varghese Rona Yaeger Jonathan Coleman Bernard Bochner Gregory J Riely Leonard B Saltz Howard I Scher Paul J Sabbatini Mark E Robson David S Klimstra Barry S Taylor Jose Baselga Nikolaus Schultz David M Hyman Maria E Arcila David B Solit Marc Ladanyi Michael F Berger

Nat Med 2017 08;23(8):1004

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http://dx.doi.org/10.1038/nm0817-1004cDOI Listing
August 2017

Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.

Authors:
Ahmet Zehir Ryma Benayed Ronak H Shah Aijazuddin Syed Sumit Middha Hyunjae R Kim Preethi Srinivasan Jianjiong Gao Debyani Chakravarty Sean M Devlin Matthew D Hellmann David A Barron Alison M Schram Meera Hameed Snjezana Dogan Dara S Ross Jaclyn F Hechtman Deborah F DeLair JinJuan Yao Diana L Mandelker Donavan T Cheng Raghu Chandramohan Abhinita S Mohanty Ryan N Ptashkin Gowtham Jayakumaran Meera Prasad Mustafa H Syed Anoop Balakrishnan Rema Zhen Y Liu Khedoudja Nafa Laetitia Borsu Justyna Sadowska Jacklyn Casanova Ruben Bacares Iwona J Kiecka Anna Razumova Julie B Son Lisa Stewart Tessara Baldi Kerry A Mullaney Hikmat Al-Ahmadie Efsevia Vakiani Adam A Abeshouse Alexander V Penson Philip Jonsson Niedzica Camacho Matthew T Chang Helen H Won Benjamin E Gross Ritika Kundra Zachary J Heins Hsiao-Wei Chen Sarah Phillips Hongxin Zhang Jiaojiao Wang Angelica Ochoa Jonathan Wills Michael Eubank Stacy B Thomas Stuart M Gardos Dalicia N Reales Jesse Galle Robert Durany Roy Cambria Wassim Abida Andrea Cercek Darren R Feldman Mrinal M Gounder A Ari Hakimi James J Harding Gopa Iyer Yelena Y Janjigian Emmet J Jordan Ciara M Kelly Maeve A Lowery Luc G T Morris Antonio M Omuro Nitya Raj Pedram Razavi Alexander N Shoushtari Neerav Shukla Tara E Soumerai Anna M Varghese Rona Yaeger Jonathan Coleman Bernard Bochner Gregory J Riely Leonard B Saltz Howard I Scher Paul J Sabbatini Mark E Robson David S Klimstra Barry S Taylor Jose Baselga Nikolaus Schultz David M Hyman Maria E Arcila David B Solit Marc Ladanyi Michael F Berger

Nat Med 2017 Jun 8;23(6):703-713. Epub 2017 May 8.

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

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.
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http://dx.doi.org/10.1038/nm.4333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461196PMC
June 2017

Identification of NTRK3 Fusions in Childhood Melanocytic Neoplasms.

J Mol Diagn 2017 05;19(3):387-396

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

Spitzoid neoplasms are a distinct group of melanocytic tumors. Genetically, they lack mutations in common melanoma-associated oncogenes. Recent studies have shown that spitzoid tumors may contain a variety of kinase fusions, including ROS1, NTRK1, ALK, BRAF, and RET fusions. We report herein the discovery of recurrent NTRK3 gene rearrangements in childhood melanocytic neoplasms with spitzoid and/or atypical features, based on genome-wide copy number analysis by single-nucleotide polymorphism array, which showed intragenic copy number changes in NTRK3. Break-apart fluorescence in situ hybridization confirmed the presence of NTRK3 rearrangement, and a novel MYO5A-NTRK3 transcript, representing an in-frame fusion of MYO5A exon 32 to NTRK3 exon 12, was identified using a rapid amplification of cDNA ends-based anchored multiplex PCR assay followed by next-generation sequencing. The predicted MYO5A-NTRK3 fusion protein consists of several N-terminal coiled-coil protein dimerization motifs encoded by MYO5A and C-terminal tyrosine kinase domain encoded by NTRK3, which is consistent with the prototypical structure of TRK oncogenic fusions. Our study also demonstrates how array-based copy number analysis can be useful in discovering gene fusions associated with unbalanced genomic aberrations flanking the fusion points. Our findings add another potentially targetable kinase fusion to the list of oncogenic fusions in melanocytic tumors.
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http://dx.doi.org/10.1016/j.jmoldx.2016.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417047PMC
May 2017

Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition.

Proc Natl Acad Sci U S A 2010 Jan 28;107(4):1630-5. Epub 2009 Dec 28.

Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.

An additional copy of the beta-amyloid precursor protein (APP) gene causes early-onset Alzheimer's disease (AD) in trisomy 21 (DS). Endosome dysfunction develops very early in DS and AD and has been implicated in the mechanism of neurodegeneration. Here, we show that morphological and functional endocytic abnormalities in fibroblasts from individuals with DS are reversed by lowering the expression of APP or beta-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs. By contrast, endosomal pathology can be induced in normal disomic (2N) fibroblasts by overexpressing APP or the C-terminal APP fragment generated by BACE-1 (betaCTF), all of which elevate the levels of betaCTFs. Expression of a mutant form of APP that cannot undergo beta-cleavage had no effect on endosomes. Pharmacological inhibition of APP gamma-secretase, which markedly reduced Abeta production but raised betaCTF levels, also induced AD-like endosome dysfunction in 2N fibroblasts and worsened this pathology in DS fibroblasts. These findings strongly implicate APP and the betaCTF of APP, and exclude Abeta and the alphaCTF, as the cause of endocytic pathway dysfunction in DS and AD, underscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics.
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http://dx.doi.org/10.1073/pnas.0908953107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824382PMC
January 2010

Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects.

Am J Pathol 2008 Aug 5;173(2):370-84. Epub 2008 Jun 5.

Laboratory for Molecular Neuropathology, Mailman Research Center, McLean Hospital, 115 Mill St., Belmont, MA 02478, USA.

Endocytic dysfunction is an early pathological change in Alzheimer's disease (AD) and Down's syndrome (DS). Using primary fibroblasts from DS individuals, we explored the interactions among endocytic compartments that are altered in AD and assessed their functional consequences in AD pathogenesis. We found that, like neurons in both AD and DS brains, DS fibroblasts exhibit increased endocytic uptake, fusion, and recycling, and trafficking of lysosomal hydrolases to rab5-positive early endosomes. Moreover, late endosomes identified using antibodies to rab7 and lysobisphosphatidic acid increased in number and appeared as enlarged, perinuclear vacuoles, resembling those in neurons of both AD and DS brains. In control fibroblasts, similar enlargement of rab5-, rab7-, and lysobisphosphatidic acid-positive endosomes was induced when endocytosis and endosomal fusion were increased by expression of either a rab5 or an active rab5 mutant, suggesting that persistent endocytic activation results in late endocytic dysfunction. Conversely, expression of a rab5 mutant that inhibits endocytic uptake reversed early and late endosomal abnormalities in DS fibroblasts. Our results indicate that DS fibroblasts recapitulate the neuronal endocytic dysfunction of AD and DS, suggesting that increased trafficking from early endosomes can account, in part, for downstream endocytic perturbations that occur in neurons in both AD and DS brains.
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http://dx.doi.org/10.2353/ajpath.2008.071053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475775PMC
August 2008