Publications by authors named "Lea F Surrey"

51 Publications

NTRK-Rearranged soft tissue neoplasms: A review of evolving diagnostic entities and algorithmic detection methods.

Cancer Genet 2021 Nov 3;260-261:6-13. Epub 2021 Nov 3.

Department of Pathology, Oregon Health & Science University, Portland, OR, USA.

The spectrum of tumors with NTRK1/2/3 rearrangements has expanded with widespread use of next generation sequencing (NGS) technology. For many years it was known that a majority of infantile fibrosarcomas (IFS), and their counterpart in the kidney, cellular congenital mesoblastic nephroma, contain the recurrent ETV6-NTRK3 fusion. Sequencing RNA transcripts from IFS and their morphologically similar counterparts in older children and adults has shown rearrangements with other 5' partners combined with NTRK1, NTRK2, and NTRK3 can also occur. For those tumors occurring outside of the infant age group, this has resulted in a proposed new diagnostic entity of "NTRK-rearranged spindle cell neoplasm." The clinical behavior of NTRK rearranged soft tissue tumors varies, though most show localized disease with rare metastases. The pathology of NTRK rearranged tumors exists on a spectrum, with overlapping features of classic infantile fibrosarcoma, lipofibromatosis, and malignant peripheral nerve sheath tumor. In this tumor spectrum, clinical and pathologic predictive factors are largely still to be determined, with no clear association between histologic grade and severity of disease. Of critical importance is detection of the NTRK rearrangement in order to guide treatment in patients with unresectable and metastatic disease. While resection is the definitive treatment, these tumors do show response to targeted TRK kinase inhibitors. Multiple detection methods are available, including immunohistochemistry, FISH, and next generation sequencing, which each have their merits and potential pitfalls. We aim to review the clinical characteristics and histomorphology of mesenchymal tumors with NTRK rearrangements as well as discuss molecular detection methods and diagnostic algorithms specific for soft tissue tumors.
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http://dx.doi.org/10.1016/j.cancergen.2021.10.007DOI Listing
November 2021

Thyroid Lobectomy for T1 Papillary Thyroid Carcinoma in Pediatric Patients.

JAMA Otolaryngol Head Neck Surg 2021 Nov;147(11):943-950

Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia.

Importance: The current recommendation for pediatric patients with papillary thyroid cancer (PTC) is a total thyroidectomy. This recommendation applies to all stages of PTC, including papillary thyroid microcarcinoma (≤1 cm, T1a) tumors.

Objective: To evaluate the characteristics of American Joint Committee on Cancer T1 PTC tumors in a large pediatric population and to identify a subgroup of patients who may benefit from a thyroid lobectomy instead of a total thyroidectomy.

Design, Setting, And Participants: This retrospective cohort study was conducted from January 1, 2009, to May 31, 2020. The study took place at a tertiary care medical center and included 102 patients who were surgically treated for T1 PTC: 52 with stage T1a (≤1 cm) tumors and 50 with stage T1b (>1 cm but ≤2 cm) tumors.

Main Outcomes And Measures: Primary outcomes included the presence of bilateral disease and lymph node metastasis.

Results: A total of 102 patients (mean age, 15.3 years [range, 9.7-18.9 years]; 84 girls [82.4%]) were included in the analysis. Among 52 patients with T1a tumors, 10 (19.2%) had bilateral disease, and 15 (28.8%) had central neck lymph node (N1a) metastasis. Among 50 patients with T1b tumors, 10 (20%) had bilateral and 13 (26%) had N1a disease. Of those with T1a, unilateral multifocality was associated with bilateral disease (odds ratio [OR], 2.1; 95% CI, 1.3-3.4) and N1a disease (OR, 5.1; 95% CI, 1.5-17.6). Both N1a disease (OR, 20.0; 95% CI, 3.5-115.0) and ≥4 positive lymph nodes (OR, 8.6; 95% CI, 1.2-60.9) were associated with bilateral disease. In patients with no pathologic evidence of lymph node metastasis (N0), there was a 95% rate of unilateral PTC. In patients with T1b tumors, unilateral multifocality was also associated with bilateral disease (OR, 1.8; 95% CI, 1.3-2.7). Patients with T1b tumors had an increased risk of lateral (N1b) neck lymph node metastasis when compared with those with T1a tumors (OR, 3.7; 95% CI, 1.0-14.5).

Conclusions And Relevance: The findings of this cohort study suggest that, in patients with unifocal T1a PTC without clinically evident nodal disease on preoperative ultrasonography, a thyroid lobectomy and central neck dissection may be considered. If there is no evidence of unilateral multifocality or if there are fewer than 4 positive lymph nodes on postoperative pathology, then close observation may be considered. These findings have substantial clinical implications and may result in practice changes regarding the extent of thyroid surgery on low-stage pediatric PTC.
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http://dx.doi.org/10.1001/jamaoto.2021.2359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461547PMC
November 2021

Mesenchymal PLAG1 Tumor With PCMTD1-PLAG1 Fusion in an Infant: A New Type of "Plagoma".

Am J Dermatopathol 2021 Jul 20. Epub 2021 Jul 20.

Department of Dermatology, University Clinic of Navarra, School of Medicine, University of Navarra, Pamplona, Spain; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Roma, Italy; Department of Pathology, Ospedale Bambino Gesù, Roma, Italy; Orthopedic Division, University of Pittsburgh Medical Center, Pittsburgh, PA; and Department of Pathology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.

Abstract: In the past decade, there have been major advances in knowledge related to mesenchymal tumors, and new genetic alterations are being delineated. We report a mesenchymal spindle cell neoplasm harboring a novel gene fusion in an infant. Histopathologically, the neoplasm shared some features with sclerosing perineurioma, but immunohistochemically, EMA was negative, whereas GLUT1, NK1-C3, and BCOR were positive. Next-generation sequencing revealed a PCMTD1-pleomorphic adenoma gene 1 (PLAG1) fusion. PLAG1 contributes to the expression of a variety of genes implicated in regulating cell proliferation, and PCMTD1 has been related to the development of certain carcinomas. Recently, other soft tissue tumors in young children associated with PLAG1 fusion variants have been reported. Perhaps, mesenchymal neoplasms presenting PLAG1 fusions with different genes would confirm a specific group (PLAG mesenchymal tumours or "plagomas") in the near future.
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http://dx.doi.org/10.1097/DAD.0000000000001978DOI Listing
July 2021

Clinical case conundrum: Hyperlactataemia in a case of type 1 diabetes with chronic hyperglycaemia.

Diabet Med 2021 Oct 12;38(10):e14629. Epub 2021 Jul 12.

Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

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http://dx.doi.org/10.1111/dme.14629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429068PMC
October 2021

NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome.

JCO Precis Oncol 2021 14;1. Epub 2021 Jan 14.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Purpose: Neurotrophic tyrosine receptor kinase (NTRK) fusions have been described as oncogenic drivers in a variety of tumors. However, little is known about the overall frequency of NTRK fusion in unselected pediatric tumors. Here, we assessed the frequency, fusion partners, and clinical course in pediatric patients with NTRK fusion-positive tumors.

Patients And Methods: We studied 1,347 consecutive pediatric tumors from 1,217 patients who underwent tumor genomic profiling using custom-designed DNA and RNA next-generation sequencing panels. NTRK fusions identified were orthogonally confirmed.

Results And Discussion: NTRK fusions were identified in 29 tumors from 27 patients with a positive yield of 2.22% for all patients and 3.08% for solid tumors. Although fusions were found exclusively in CNS tumors and fusions were highly enriched in papillary thyroid carcinomas, fusions were identified in all tumor categories. The most canonical fusion was observed in 10 patients with diverse types of tumors. Several novel NTRK fusions were observed in rare tumor types, including in ganglioglioma and in papillary thyroid carcinomas. The detection of an NTRK fusion confirmed the morphologic diagnosis including five cases where the final tumor diagnosis was largely based on the discovery of an NTRK fusion. In one patient, the diagnosis was changed because of the identification of an fusion. One patient with infantile fibrosarcoma was treated with larotrectinib and achieved complete pathologic remission.

Conclusion: NTRK fusions are more frequently seen in pediatric tumors than in adult tumors and involve a broader panel of fusion partners and a wider range of tumors than previously recognized. These results highlight the importance of screening for NTRK fusions as part of the tumor genomic profiling for patients with pediatric cancer.
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http://dx.doi.org/10.1200/PO.20.00250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140782PMC
January 2021

Novel MEAF6-SUZ12 fusion in ossifying fibromyxoid tumor with unusual features.

Genes Chromosomes Cancer 2021 Sep 21;60(9):631-634. Epub 2021 Apr 21.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain differentiation that has the capacity for local recurrence and metastasis. Many OFMTs, including typical, atypical, and malignant tumors, have demonstrated recurrent gene fusions. The fusion partners reported to date share a common core function in that they play either a direct or indirect role in processes influencing histone modification. Herein, we report an OFMT with unusual morphology and non-specific immunoprofile harboring a novel MEAF6-SUZ12 fusion. A 34-year-old male presented with a slowly growing mass in the right antecubital fossa. Excision demonstrated a 6.9 cm partially encapsulated, tan-white, lobulated, and calcified lesion. Microscopic evaluation demonstrated cytologically bland spindle to ovoid cells arranged in a haphazard manner within a fibromyxoid background containing dense collagen, often with sclerotic nodules, and randomly distributed ossification. The tumor cells were diffusely positive for CD34 while essentially negative for S100, desmin, MUC4, SOX10, AE1/3, SMA, and EMA. Next-generation sequencing studies (sarcoma gene fusion next-generation sequencing panel with subsequent Sanger confirmation) performed on formalin-fixed paraffin-embedded tissue detected a fusion product between MEAF6 exon 4 (NM_001270875) and SUZ12 exon 2 (NM_001321207.1). The proposed mechanism of pathogenesis in OFMT, namely epigenetic dysregulation, is reinforced by the fact that both of these partner genes are involved in histone modification.
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http://dx.doi.org/10.1002/gcc.22951DOI Listing
September 2021

Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies.

Cold Spring Harb Mol Case Stud 2021 04 8;7(2). Epub 2021 Apr 8.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia but is approximately 500 times more likely to develop in children with Down syndrome (DS) through transformation of transient abnormal myelopoiesis (TAM). This study investigates the clinical significance of genomic heterogeneity of AMKL in children with and without DS and in children with TAM. Genomic evaluation of nine patients with DS-related TAM or AMKL, and six patients with non-DS AMKL, included conventional cytogenetics and a comprehensive next-generation sequencing panel for single-nucleotide variants/indels and copy-number variants in 118 genes and fusions involving 110 genes. Recurrent gene fusions were found in all patients with non-DS, including two individuals with complex genomes and either a or a - fusion, and the remaining harbored a fusion, which arose from both typical and atypical cytogenetic mechanisms. These fusions guided treatment protocols and resulted in a change in diagnosis in two patients. The nine patients with DS had constitutional trisomy 21 and somatic mutations, and those with DS-AMKL had two to four additional clinically significant somatic mutations. Comprehensive genomic characterization provides critical information for diagnosis, risk stratification, and treatment decisions for patients with AMKL. Continued genetic and clinical characterization of these rare cancers will aid in improving patient management.
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http://dx.doi.org/10.1101/mcs.a005975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040732PMC
April 2021

OncoTree: A Cancer Classification System for Precision Oncology.

JCO Clin Cancer Inform 2021 02;5:221-230

Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Cancer classification is foundational for patient care and oncology research. Systems such as International Classification of Diseases for Oncology (ICD-O), Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT), and National Cancer Institute Thesaurus (NCIt) provide large sets of cancer classification terminologies but they lack a dynamic modernized cancer classification platform that addresses the fast-evolving needs in clinical reporting of genomic sequencing results and associated oncology research.

Methods: To meet these needs, we have developed OncoTree, an open-source cancer classification system. It is maintained by a cross-institutional committee of oncologists, pathologists, scientists, and engineers, accessible via an open-source Web user interface and an application programming interface.

Results: OncoTree currently includes 868 tumor types across 32 organ sites. OncoTree has been adopted as the tumor classification system for American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE), a large genomic and clinical data-sharing consortium, and for clinical molecular testing efforts at Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute. It is also used by precision oncology tools such as OncoKB and cBioPortal for Cancer Genomics.

Conclusion: OncoTree is a dynamic and flexible community-driven cancer classification platform encompassing rare and common cancers that provides clinically relevant and appropriately granular cancer classification for clinical decision support systems and oncology research.
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http://dx.doi.org/10.1200/CCI.20.00108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240791PMC
February 2021

Dorsal Medial Cuneiform Bony Outgrowth-Apophysis or Exostosis: A Case Report.

JBJS Case Connect 2021 Feb 11;11(1):e20.00194. Epub 2021 Feb 11.

Department of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Case: Three female children (11-15 years) presented with painful dorsomedial medial cuneiform masses that did not improve after conservative treatment. Findings were consistent with a diagnosis of medial cuneiform apophysis. After surgical resection, no patients had recurrence, although one continued to have pain from a deep peroneal nerve sensory branch that was resected. One patient had an intramass physis identified.

Conclusion: When surgically removing dorsomedial cuneiform masses, surgeons should decompress overlying sensory nerve branches, detach and subsequently repair muscular attachments, and remove the entire stump to prevent regrowth because some of these masses may be apophyses and not exostoses.
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http://dx.doi.org/10.2106/JBJS.CC.20.00194DOI Listing
February 2021

Melanotic Neuroectodermal Tumor of Infancy (MNTI) and Pineal Anlage Tumor (PAT) Harbor A Medulloblastoma Signature by DNA Methylation Profiling.

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Department of Pediatric Onco-Hematology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI ( = 7) and PAT ( = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients' mean age was 8 months (range: 4-48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.
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http://dx.doi.org/10.3390/cancers13040706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916108PMC
February 2021

BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers.

Pediatr Blood Cancer 2021 06 9;68(6):e28933. Epub 2021 Feb 9.

Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here, we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.
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http://dx.doi.org/10.1002/pbc.28933DOI Listing
June 2021

The spectrum of rare central nervous system (CNS) tumors with EWSR1-non-ETS fusions: experience from three pediatric institutions with review of the literature.

Brain Pathol 2021 01 6;31(1):70-83. Epub 2020 Nov 6.

General Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.

The group of CNS mesenchymal (non-meningothelial) and primary glial/neuronal tumors in association with EWSR1-non-ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1-rearranged tumors confirmed by at least one molecular technique. Extra-axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1-ETS family fusions) were excluded. Additional studies, including anchored multiplex-PCR with next-generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1-WT1; n = 1) and tumors of uncertain histogenesis (EWSR1-CREM, n = 1; EWSR1-CREB1, n = 1; EWSR1-PLAGL1, n = 1; and EWSR1-PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1-CREM, EWSR1-PLAGL1 and EWSR1-PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow-up of 30 months. In conclusion, we describe five primary EWSR1-non-ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors.
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http://dx.doi.org/10.1111/bpa.12900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018079PMC
January 2021

Novel APOD-GLI1 rearrangement in a sarcoma of unknown lineage.

Histopathology 2021 01 25;78(2):338-340. Epub 2020 Oct 25.

Department of Pathology and Laboratory Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

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http://dx.doi.org/10.1111/his.14235DOI Listing
January 2021

A dual-genotype oligoastrocytoma with histologic, molecular, radiological and time-course features.

Acta Neuropathol Commun 2020 07 20;8(1):115. Epub 2020 Jul 20.

Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.

A case of a true dual-genotype IDH-mutant oligoastrocytoma with two different cell types within a single mass in a young woman is presented. Imaging findings of the left frontal infiltrating glioma predicted the two neoplastic components that were identified upon resection. Tissue examination demonstrated areas of tumor with contrasting histologic and molecular features, including specific IDH1, ATRX, TP53, TERT and CIC mutational profiles, consistent with oligodendroglioma and astrocytoma, respectively. The clinical and radiological course over 17 months from first diagnosis included three surgical resections with slow progression of the astrocytic component, and ultimately chemotherapy and radiation treatments were commenced. Reports of the clinical courses for these rare cases of dual-genotype oligoastrocytomas will inform therapy choices, to optimize benefit while minimizing side effects. The steadily increasing number of cases suggests that the neoplasm might be reconsidered as an official entity by the WHO.
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http://dx.doi.org/10.1186/s40478-020-00998-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372861PMC
July 2020

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.

Cancer Cell 2020 04;37(4):569-583.e5

Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.
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http://dx.doi.org/10.1016/j.ccell.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169997PMC
April 2020

Novel PPP1CB-ALK fusion in spindle cell tumor defined by S100 and CD34 coexpression and distinctive stromal and perivascular hyalinization.

Genes Chromosomes Cancer 2020 08 4;59(8):495-499. Epub 2020 Apr 4.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

A novel group of S100- and CD34-positive spindle cell tumors with distinctive stromal and perivascular hyalinization harboring recurrent gene fusions involving kinases including RAF1, BRAF, NTRK1/2/3, and RET have been recently reported. To our knowledge, no such cases harboring ALK rearrangements have been identified. We report a previously healthy 41-year-old male with a 12-cm intramuscular shoulder mass. The tumor was composed of bland-appearing spindled to epithelioid cells, arranged in a patternless pattern in a background of loose myxoid stroma containing striking amianthoid-like stromal collagen and perivascular rings. In accordance with the previously reported tumors, the tumor cells showed diffuse immunopositivity with S100 and CD34, while lacking SOX10 expression. Targeted RNA-based next-generation sequencing identified a novel serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB)-ALK fusion gene. Although ALK break-apart was not detected by FISH, likely due to a paracentric inversion of chromosome 2, the presence of the fusion was confirmed by Sanger sequencing showing a 10-bp linker between exon 6 of PPP1CB and intron 19 of ALK while maintaining reading frame. Subsequent ALK-1 immunostain exhibited diffuse cytoplasmic staining in the tumor cells. Our case expands the molecular genetic spectrum of the distinctive group of spindle cell tumors with CD34/S100+ immunophenotype, supporting the important role of various kinases as drivers of oncogenesis. Awareness of this entity including its unique morphologic and immunophenotypic features as well as its interchangeable kinase gene fusions is crucial for correct classification and potential targeted therapy, particularly in aggressive subsets.
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http://dx.doi.org/10.1002/gcc.22844DOI Listing
August 2020

miRNA expression can classify pediatric thyroid lesions and increases the diagnostic yield of mutation testing.

Pediatr Blood Cancer 2020 06 20;67(6):e28276. Epub 2020 Mar 20.

Division of Endocrinology and Diabetes, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Genetic alterations in multiple cell signaling pathways are involved in the molecular pathogenesis of thyroid cancer. Oncogene mutation testing and gene-expression profiling are routinely used for the preoperative risk management of adult thyroid nodules. In this study, we evaluated the potential value of miRNA biomarkers for the classification of pediatric thyroid lesions.

Procedure: Double-blind case-control study with 113 resected pediatric lesions: 66 malignant and 47 benign. Quantitative and qualitative molecular data generated with a 10-miRNA expression panel (ThyraMIR) and a next-generation sequencing oncogene panel (ThyGeNEXT) were compared with clinicopathological parameters.

Results: miRNAs were differentially expressed in benign versus malignant tumors with distinct expression patterns in different histopathology categories. The 10-miRNA classifier identified 39 (59%) malignant lesions with 100% specificity. A positive classifier score was associated with lymph node metastasis, extrathyroidal extension and intrathyroidal spread. Genetic alterations associated with increased risk for malignancy were detected in 35 (53%) malignant cases, 20 positive for point mutations in BRAF, HRAS, KRAS, NRAS, PIK3CA, or TERT and 15 positive for gene rearrangements involving ALK, NTRK3, PPARG, or RET. The 10-miRNA classifier correctly identified 11 mutation-negative malignant cases. The performance of the combined molecular test was 70% sensitivity and 96% specificity with an area under the curve of 0.924.

Conclusions: These data suggest that the regulatory miRNA pathways underlying thyroid tumorigenesis are similar in adults and children. miRNA expression can identify malignant lesions with high specificity, augment the diagnostic yield of mutation testing, and improve the molecular classification of pediatric thyroid nodules.
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http://dx.doi.org/10.1002/pbc.28276DOI Listing
June 2020

Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms.

Histopathology 2020 Jun 15;76(7):1032-1041. Epub 2020 May 15.

Department of Pathology, Boston Children's Hospital, Boston, MA, USA.

Aims: The classification of paediatric spindle mesenchymal tumours is evolving, and the spectrum of so-called 'infantile fibrosarcoma' has expanded to include tumours with NTRK, BRAF and MET gene fusions. RET-rearranged paediatric spindle cell neoplasms are an emerging group; there is sparse literature on their clinical, pathological and genetic features, and their nosological place in the canon of soft tissue tumours is uncertain. In this study, we report five RET-rearranged paediatric spindle cell tumours with fusion partners MYH10, KIAA1217 and CLIP2.

Methods And Results: The tumours occurred in the pelvic region, paraspinal region, kidney and subcutaneous tissue of hand and abdomen. The patients' ages ranged from 6 months to 13 years (median 1 year). The tumours were composed of monomorphic spindle cells arranged in a fascicular pattern. Lesional cells had minimally atypical ovoid or tapered nuclei and pale cytoplasm with indistinct borders. Necrosis was not identified. Mitoses numbered three to 12 per 10 high-power field. Cases showed inconsistent and variable expression of S100, CD34 and SMA. Clinical behaviour ranged from small lesions potentially cured by simple resection to large lesions exhibiting metastasis, but responsive to kinase inhibitor therapy.

Conclusions: Our findings help to define RET-rearranged spindle cell tumours. Although it is likely that these tumours comprise part of the morphological and clinical spectrum of infantile fibrosarcoma (IFS), identification of RET gene alteration is important for its unique therapeutic implications.
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http://dx.doi.org/10.1111/his.14082DOI Listing
June 2020

Tatton-Brown-Rahman syndrome: Six individuals with novel features.

Am J Med Genet A 2020 04 21;182(4):673-680. Epub 2020 Jan 21.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

Tatton-Brown Rahman syndrome (TBRS) is an overgrowth-intellectual disability syndrome caused by heterozygous variants in DNMT3A. Seventy-eight individuals have been reported with a consistent phenotype of somatic overgrowth, mild to moderate intellectual disability, and similar dysmorphisms. We present six individuals with TBRS, including the youngest individual thus far reported, first individual to be diagnosed with tumor testing and two individuals with variants at the Arg882 domain, bringing the total number of reported cases to 82. Patients reported herein have additional clinical features not previously reported in TBRS. One patient had congenital diaphragmatic hernia. One patient carrying the recurrent p.Arg882His DNMT3A variant, who was previously reported as having a phenotype due to a truncating variant in the CLTC gene, developed a ganglioneuroblastoma at 18 months and T-cell lymphoblastic lymphoma at 6 years of age. Four patients manifested symptoms suggestive of autonomic dysfunction, including central sleep apnea, postural orthostatic hypotension, and episodic vasomotor instability in the extremities. We discuss the molecular and clinical findings in our patients with TBRS in context of existing literature.
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http://dx.doi.org/10.1002/ajmg.a.61475DOI Listing
April 2020

Cardiac Magnetic Resonance-Derived Metrics Are Predictive of Liver Fibrosis in Fontan Patients.

Ann Thorac Surg 2020 06 14;109(6):1904-1911. Epub 2019 Nov 14.

Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Liver fibrosis is a serious complication of single ventricle Fontan survivors. Its causes are of great interest, and potential solutions to halt or delay progression are needed. The purpose of this study is to investigate if prior hemodynamics and anatomy can predict liver fibrosis severity in these patients.

Methods: Twenty-one Fontan patients with cardiac magnetic resonance (CMR) data obtained greater than 1 year before liver biopsy data were included. Computational fluid dynamic simulations were performed to quantify total cavopulmonary connection (TCPC) flow dynamics using patient-specific anatomies and blood flow waveforms reconstructed from CMR data. Collagen deposition (a measure of liver fibrosis) was quantified by digital image analysis of Sirius red-stained slides. Statistical analyses were performed to investigate potential relationships between Fontan hemodynamics and liver fibrosis.

Results: With an average time of 6.7 ± 2.9 years (range, 2-11 years) between CMR and biopsy, TCPC resistance and left pulmonary artery stenosis showed significant, positive correlations with magnitude of liver fibrosis (r = 0.54, P = .026; and r = 0.55, P = .028, respectively). The change in inferior vena cava flow rate over time also showed a significant positive correlation with magnitude of liver fibrosis (r = 0.91, P = .001).

Conclusions: TCPC resistance, left pulmonary artery stenosis, and increased inferior vena cava flow are positively associated with liver fibrosis after Fontan operation and hold promise as important predictors of hepatic decline. These findings encourage preprocedural planning and interventional strategies to improve TCPC performance and reduce vessel stenosis. Further investigation is warranted to design the ideal Fontan circulation and optimize flow dynamics to reduce the risk of liver fibrosis.
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http://dx.doi.org/10.1016/j.athoracsur.2019.09.070DOI Listing
June 2020

Infantile inflammatory myofibroblastic tumors: clinicopathological and molecular characterization of 12 cases.

Mod Pathol 2020 04 5;33(4):576-590. Epub 2019 Nov 5.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Inflammatory myofibroblastic tumors arising in infants are rare, poorly investigated and mostly reported as isolated cases or as a part of larger series thus, their clinicopathological and molecular features are essentially unknown. Archival files from two large pediatric institutions and a tumor registry were queried for pediatric inflammatory myofibroblastic tumors. Available material from patients ≤12 months of age was reviewed. Additional immunostains (ALK-1, D240, WT1) and ALK-FISH studies were performed as needed. Targeted anchored multiplex PCR with next-generation sequencing was done in all cases. A total of 12 of 131 infantile cases (mean 5.5 months) were identified (M:F of 2:1). Anatomic locations included intestinal/mesenteric (n = 6), head/neck (n = 3), and viscera (n = 3). Half of tumors showed a hypocellular myxoid pattern, perivascular condensation, and prominent vasculature with vague glomeruloid structures present in four of them. The remaining cases exhibited a more cellular pattern with minimal myxoid component. ALK-1 immunohistochemistry was positive in most cases (11/12) with cytoplasmic-diffuse (n = 6), cytoplasmic-granular (n = 2), and dot-like (n = 3) staining patterns. ALK fusion partners identified in five cases included EML4, TPM4, RANBP2, and a novel KLC1. Three inflammatory myofibroblastic tumors showed fusions with other kinases including TFG-ROS1 and novel FN1-ROS1 and RBPMS-NTRK3 rearrangements. Favorable outcome was documented in most cases (10/11) with available follow-up (median 17 months) while three patients were successfully treated with crizotinib. In summary, infantile inflammatory myofibroblastic tumors are rare and can exhibit paucicellular, extensively myxoid/vascular morphology with peculiar immunophenotype mimicking other mesenchymal or vascular lesions. All tumors harbored kinase fusions involving ALK, ROS1, and NTRK3 including three novel fusion partners (KLC1, FN1, and RBPMS, respectively). A favorable response to crizotinib seen in three cases supports its potential use in infants as seen in older patients. Awareness of these unusual morphologic, immunophenotypic, and molecular features is critical for appropriate diagnosis and optimized targeted therapy.
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http://dx.doi.org/10.1038/s41379-019-0406-6DOI Listing
April 2020

Association of rare non-coding SNVs in the lung-specific FOXF1 enhancer with a mitigation of the lethal ACDMPV phenotype.

Hum Genet 2019 Dec 4;138(11-12):1301-1311. Epub 2019 Nov 4.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Haploinsufficiency of FOXF1 causes alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe two similar heterozygous CNV deletions involving the FOXF1 enhancer and re-analyze FOXF1 missense mutation, all associated with an unexpectedly mitigated disease phenotype. In one case, the deletion of the maternal allele of the FOXF1 enhancer caused pulmonary hypertension and histopathologically diagnosed MPV without the typical ACD features. In the second case, the deletion of the paternal enhancer resulted in ACDMPV rather than the expected neonatal lethality. In both cases, FOXF1 expression in lung tissue was higher than usually seen or expected in patients with similar deletions, suggesting an increased activity of the remaining allele of the enhancer. Sequencing of these alleles revealed two rare SNVs, rs150502618-A and rs79301423-T, mapping to the partially overlapping binding sites for TFAP2s and CTCF in the core region of the enhancer. Moreover, in a family with three histopathologically-diagnosed ACDMPV siblings whose missense FOXF1 mutation was inherited from the healthy non-mosaic carrier mother, we have identified a rare SNV rs28571077-A within 2-kb of the above-mentioned non-coding SNVs in the FOXF1 enhancer in the mother, that was absent in the affected newborns and 13 unrelated ACDMPV patients with CNV deletions of this genomic region. Based on the low population frequencies of these three variants, their absence in ACDMPV patients, the results of reporter assay, RNAi and EMSA experiments, and in silico predictions, we propose that the described SNVs might have acted on FOXF1 enhancer as hypermorphs.
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http://dx.doi.org/10.1007/s00439-019-02073-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874894PMC
December 2019

Genomic Analysis of Dysembryoplastic Neuroepithelial Tumor Spectrum Reveals a Diversity of Molecular Alterations Dysregulating the MAPK and PI3K/mTOR Pathways.

J Neuropathol Exp Neurol 2019 12;78(12):1100-1111

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia.

Dysembryoplastic neuroepithelial tumors (DNT) lacking key diagnostic criteria are challenging to diagnose and sometimes fall into the broader category of mixed neuronal-glial tumors (MNGT) or the recently described polymorphous low-grade neuroepithelial tumor of the young (PLNTY). We examined 41 patients with DNT, MNGT, or PLNTY for histologic features, genomic findings, and progression-free survival (PFS). Genomic analysis included sequence and copy number variants and RNA-sequencing. Classic DNT (n = 26) was compared with those with diffuse growth without cortical nodules (n = 15), 6 of which exhibited impressive CD34 staining classifying them as PLNTY. Genomic analysis was complete in 33, with sequence alterations recurrently identified in BRAF, FGFR1, NF1, and PDGFRA, as well as 7 fusion genes involving FGFR2, FGFR1, NTRK2, and BRAF. Genetic alterations did not distinguish between MNGTs, DNTs, or PLNTYs; however, FGFR1 alterations were confined to DNT, and PLNTYs contained BRAF V600E or FGFR2 fusion genes. Analysis of PFS showed no significant difference by histology or genetic alteration; however, numbers were small and follow-up time short. Further molecular characterization of a PLNTY-related gene fusion, FGFR2-CTNNA3, demonstrated oncogenic potential via MAPK/PI3K/mTOR pathway activation. Overall, DNT-MNGT spectrum tumors exhibit diverse genomic alterations, with more than half (19/33) leading to MAPK/PI3K pathway alterations.
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http://dx.doi.org/10.1093/jnen/nlz101DOI Listing
December 2019

Extrathyroidal Extension is an Important Predictor of Regional Lymph Node Metastasis in Pediatric Differentiated Thyroid Cancer.

Thyroid 2020 07 1;30(7):1037-1043. Epub 2019 Oct 1.

Division of Endocrinology and Diabetes; The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

The American Joint Committee Cancer (AJCC) TNM system predicts survival in patients with differentiated thyroid cancer (DTC). In the eighth edition of the AJCC TNM, microscopic extrathyroidal extension (microETE) was removed and tumor size >4 cm was maintained in the definition of T3 disease to reduce unnecessarily aggressive therapy for adults at low risk of death from DTC. In pediatric patients where DTC survival rates are high, the AJCC TNM is used to identify patients at increased risk of persistent, postsurgical disease, to identify patients who benefit from radioactive iodine therapy. The aim of this study was to assess the correlation of microETE with cervical lymph node (LN) metastasis in pediatric patients and to determine if tumor size or microETE is more informative in predicting regional LN disease. Patients with DTC <19 years of age at the time of thyroidectomy with AJCC T3 tumors (seventh edition) and the presence of LNs on the surgical specimen were included in this retrospective chart review. Pathological findings were confirmed by pathologist review. Forty-five patients with AJCC T3 designation were included, 34 with microETE and 11 without microETE. Of those with microETE, 32 (94.1%) demonstrated regional LN metastasis compared with 5/11 patients (45.5%) without microETE ( = 0.001). In addition, microETE was associated with lateral neck LN metastasis ( = 0.004), bilateral disease ( = 0.001), and tumor multifocality ( = 0.003). Patients with microETE had smaller tumors (median = 2.5 cm, interquartile range [IQR]: 1.6-4.5) compared with patients without microETE (median = 5 cm, IQR: 4.2-5.4;  = 0.02). No increased association was found between microETE and vascular invasion, distant metastasis, or persistent/recurrent disease. In pediatric patients with DTC, microETE is a strong predictor of LN metastasis when compared with tumor size. For patients who do not undergo prophylactic central neck LN dissection, the presence of microETE predicts an increased risk of postsurgical disease and should be included in future revisions of the American Thyroid Association pediatric risk stratification categories.
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http://dx.doi.org/10.1089/thy.2019.0229DOI Listing
July 2020

Development and Clinical Validation of a Large Fusion Gene Panel for Pediatric Cancers.

J Mol Diagn 2019 09 27;21(5):873-883. Epub 2019 Jun 27.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Electronic address:

Gene fusions are one of the most common genomic alterations in pediatric cancer. Many fusions encode oncogenic drivers and play important roles in cancer diagnosis, risk stratification, and treatment selection. We report the development and clinical validation of a large custom-designed RNA sequencing panel, CHOP Fusion panel, using anchored multiplex PCR technology. The panel interrogates 106 cancer genes known to be involved in nearly 600 different fusions reported in hematological malignancies and solid tumors. The panel works well with different types of samples, including formalin-fixed, paraffin-embedded samples. The panel demonstrated excellent analytic accuracy, with 100% sensitivity and specificity on 60 pediatric tumor validation samples. In addition to identifying all known fusions in the validation samples, three unrecognized, yet clinically significant, fusions were also detected. A total of 276 clinical cases were analyzed after the validation, and 51 different fusions were identified in 104 cases. Of these fusions, 16 were not previously reported at the time of discovery. These fusions provided genomic information useful for clinical management. Our experience demonstrates that CHOP Fusion panel can detect the vast majority of known and certain novel clinically relevant fusion genes in pediatric cancers accurately, efficiently, and cost-effectively; and the panel provides an excellent tool for new fusion gene discovery.
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http://dx.doi.org/10.1016/j.jmoldx.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734859PMC
September 2019

Clinical utility of custom-designed NGS panel testing in pediatric tumors.

Genome Med 2019 05 28;11(1):32. Epub 2019 May 28.

Department of Pathology and Laboratory Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.

Background: Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved towards broad-based next-generation sequencing (NGS) panels. Here, we report the laboratory validation and clinical utility of a large cohort of clinical NGS somatic sequencing results in diagnosis, prognosis, and treatment of a wide range of pediatric cancers.

Methods: Subjects were accrued retrospectively at a single pediatric quaternary-care hospital. Sequence analyses were performed on 367 pediatric cancer samples using custom-designed NGS panels over a 15-month period. Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed.

Results: NGS panel testing was incorporated meaningfully into clinical care in 88.7% of leukemia/lymphomas, 90.6% of central nervous system (CNS) tumors, and 62.6% of non-CNS solid tumors included in this cohort. A change in diagnosis as a result of testing occurred in 3.3% of cases. Additionally, 19.4% of all patients had variants requiring further evaluation for potential germline alteration.

Conclusions: Use of somatic NGS panel testing resulted in a significant impact on clinical care, including diagnosis, prognosis, and treatment planning in 78.7% of pediatric patients tested in our institution. Somatic NGS tumor testing should be implemented as part of the routine diagnostic workup of newly diagnosed and relapsed pediatric cancer patients.
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http://dx.doi.org/10.1186/s13073-019-0644-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537185PMC
May 2019

Next-Generation Sequencing (NGS) Methods Show Superior or Equivalent Performance to Non-NGS Methods on , , and Proficiency Testing Samples.

Arch Pathol Lab Med 2019 08 13;143(8):980-984. Epub 2019 Mar 13.

From the Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia (Dr Surrey) Peoria Tazewell Pathology Group, Peoria, Illinois (Dr Oakley); the Department of Pathology, University of North Carolina, Chapel Hill (Dr Merker); Biostatistics (Mr Long) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur); and the Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Dr Kim).

Context.—: There has been a rapid expansion of next-generation sequencing (NGS)-based assays for the detection of somatic variants in solid tumors. However, limited data are available regarding the comparative performance of NGS and non-NGS assays using standardized samples across a large number of laboratories.

Objective.—: To compare the performance of NGS and non-NGS assays using well-characterized proficiency testing samples provided by the College of American Pathologists (CAP) Molecular Oncology Committee. A secondary goal was to compare the use of preanalytic and postanalytic practices.

Design.—: A total of 17 343 responses were obtained from participants in the , , , and the Multigene Tumor Panel surveys across 84 different proficiency testing samples interrogating 16 variants and 3 wild-type sequences. Performance and preanalytic/postanalytic practices were analyzed by method.

Results.—: While both NGS and non-NGS achieved an acceptable response rate of greater than 95%, the overall performance of NGS methods was significantly better than that of non-NGS methods for the identification of variants in (overall 97.8% versus 95.6% acceptable responses, = .001) and (overall 98.5% versus 97.3%, = .01) and was similar for (overall 98.8% and 97.6%, = .10). There were specific variant differences, but in all discrepant cases, NGS methods outperformed non-NGS methods. NGS laboratories also more consistently used preanalytic and postanalytic practices suggested by the CAP checklist requirements than non-NGS laboratories.

Conclusions.—: The overall analytic performance of both methods was excellent. For specific and variants, NGS outperformed non-NGS methods and NGS laboratories report superior adherence to suggested laboratory practices.
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http://dx.doi.org/10.5858/arpa.2018-0394-CPDOI Listing
August 2019

Pediatric Somatic Tumor Sequencing Identifies Underlying Cancer Predisposition.

JCO Precis Oncol 2019 16;3. Epub 2019 Dec 16.

Division of Oncology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Purpose: The diagnosis of cancer predisposition in pediatric patients with cancer is vital for treatment decisions, surveillance, and management of at-risk family members. Somatic tumor testing can identify potential underlying constitutional variants that confer increased cancer risk. Here, we report the characteristics of constitutional variants identified through tumor testing.

Materials And Methods: Data were abstracted from medical record review of 1,023 patients who received inhouse somatic tumor testing over a 28-month period. Patients were identified for testing using referral criteria developed as a collaboration between genomic diagnostics, pathology, and oncology. Characteristics of patients who underwent constitutional testing, including family history and variant loss of heterozygosity, were tracked.

Results: From 1,023 patients who underwent somatic tumor sequencing in a 28-month period, 210 variants were identified in 141 patients (13.8%) that were concerning for cancer predisposition syndromes requiring intervention. A total of 73 variants in 41 patients have undergone clinical confirmatory testing thus far. Of these, 26 variants were confirmed to be constitutionally present (35.6%). Among patients tested, 23 (56.1%) of 41 total patients were diagnosed with a cancer predisposition syndrome.

Conclusion: Our data demonstrate that more than one third of variants in tumor somatic sequencing that were concerning for underlying cancer predisposition were constitutionally confirmed. Overall, somatic tumor testing identified potential cancer predisposition syndromes in pediatric patients, and some would not have been identified on the basis of clinical history alone.
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http://dx.doi.org/10.1200/po.19.00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416724PMC
December 2019

SETD2 mutations in primary central nervous system tumors.

Acta Neuropathol Commun 2018 11 12;6(1):123. Epub 2018 Nov 12.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Mutations in SETD2 are found in many tumors, including central nervous system (CNS) tumors. Previous work has shown these mutations occur specifically in high grade gliomas of the cerebral hemispheres in pediatric and young adult patients. We investigated SETD2 mutations in a cohort of approximately 640 CNS tumors via next generation sequencing; 23 mutations were detected across 19 primary CNS tumors. Mutations were found in a wide variety of tumors and locations at a broad range of allele frequencies. SETD2 mutations were seen in both low and high grade gliomas as well as non-glial tumors, and occurred in patients greater than 55 years of age, in addition to pediatric and young adult patients. High grade gliomas at first occurrence demonstrated either frameshift/truncating mutations or point mutations at high allele frequencies, whereas recurrent high grade gliomas frequently harbored subclones with point mutations in SETD2 at lower allele frequencies in the setting of higher mutational burdens. Comparison with the TCGA dataset demonstrated consistent findings. Finally, immunohistochemistry showed decreased staining for H3K36me3 in our cohort of SETD2 mutant tumors compared to wildtype controls. Our data further describe the spectrum of tumors in which SETD2 mutations are found and provide a context for interpretation of these mutations in the clinical setting.
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http://dx.doi.org/10.1186/s40478-018-0623-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231273PMC
November 2018
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