POLE-mutated Endometrial "Carcinosarcoma".

The molecular subtype classification of endometrial carcinomas has conceptually changed our approach to this disease. However, open questions remain about how to integrate certain histotype diagnoses with the molecular subtype. We report 2 cases with morphologic suspicion for endometrial carcinosarcoma, that still fell short of the essential criteria for diagnosing carcinosarcoma. On subsequent molecular testing pathogenic POLE mutations were detected and a descriptive diagnosis of endometrial endometrioid carcinomas, low-grade with a homologous sarcoma component was rendered. This challenges the existence of POLE-mutated "carcinosarcoma."

Future Role of Health Technology Assessment for Genomic Medicine in Oncology: A Canadian Laboratory Perspective.

Genome-based testing in oncology is a rapidly expanding area of health care that is the basis of the emerging area of precision medicine. The efficient and considered adoption of novel genomic medicine testing is hampered in Canada by the fragmented nature of health care oversight as well as by lack of clear and transparent processes to support rapid evaluation, assessment, and implementation of genomic tests. This article provides an overview of some key barriers and proposes approaches to addressing these challenges as a potential pathway to developing a national approach to genomic medicine in oncology.

Large, Nested Variant of Urothelial Carcinoma Is Enriched with Activating Mutations in Fibroblast Growth Factor Receptor-3 among Other Targetable Mutations.

The large, nested variant of urothelial carcinoma (LNVUC) is characterized by bland histomorphology mimicking that of benign von Brunn nests. In the current study, we aimed to investigate the Fibroblast Growth Factor Receptor-3 (FGFR-3) activation and missense mutation in 38 cases, including 6 cases diagnosed with LNVUC and 32 with metastatic invasive urothelial carcinoma (UC). Initially, six formalin-fixed paraffin-embedded (FFPE) tissue samples of the LNVUC were subjected to whole-exome sequencing (WES), and then we performed targeted sequencing on 32 cases of metastatic invasive UC of various morphological subtypes, which were interrogated for the FGFR3. Our results revealed 3/6 (50%) LNVUC cases evaluated by WES in our study showed an activating mutation in FGFR-3, 33% showed an activating mutation in PIK3CA, and 17% showed activating mutation in GNAS or MRE11. Additionally, 33% of cases showed a truncating mutation in CDKN1B. All LNVUC in our study that harbored the FGFR-3 mutation showed additional activating or truncating mutations in other genes. Overall, 6/32 (18.75%) cases of random metastatic invasive UC showed missense mutations of the FGFR-3 gene. The LNVUC variant showed the higher incidence of FGFR-3 mutations compared to other types of mutations. Additionally, all LNVUC cases show additional activating or truncating mutations in other genes, thus being amenable to novel targeted therapy.

Recommendations for the implementation of genetic testing for metastatic prostate cancer patients in Canada.

INTRODUCTION: Genetic testing in advanced prostate cancer is rapidly moving to become standard of care. Testing for genetic alterations in genes involved in DNA repair pathways, particularly those implicated in the homologous recombination repair (HRR) pathway, in patients with metastatic prostate cancer (mPCa) can inform selection of optimal therapies, as well as provide information about familial cancer risks; however, there are currently no consistent Canadian guidelines in place for genetic testing in mPCa. METHODS: A multidisciplinary steering committee guided the process of an environmental scan to define the current landscape, as well as the perceived challenges, through interviews with specialists from 14 sites across Canada. The challenges most commonly identified include limited testing guidelines and protocols, inadequate education and awareness, and insufficient resources. Following the environmental scan, an expert multidisciplinary working group with pan-Canadian representation from medical oncologists, urologists, medical geneticists, genetic counsellors, pathologists, and clinical laboratory scientists convened in virtual meetings to discuss the challenges in implementation of genetic testing in mPCa across Canada. RESULTS: Key recommendations from the working group include implementation of germline and tumor HRR testing for all patients with mPCa, with a mainstreaming model in which non-geneticist clinicians can initiate germline testing. The working group defined the roles and responsibilities of the various healthcare providers (HCPs) involved in the genetic testing pathway for mPCa patients. In addition, the educational needs for all HCPs involved in the genetic testing pathway for mPCa were defined. CONCLUSIONS: As genetic testing for mPCa becomes standard of care, additional resources and investments will be required to implement the changes that will be needed to support the necessary volume of genetic testing, to ensure equitable access, and to provide education to all stakeholders.

Mixed Endometrioid Adenocarcinoma and Müllerian Adenosarcoma of the Uterus and Ovary: Clinicopathologic Characterization With Emphasis on its Distinction From Carcinosarcoma.

Mullerian adenosarcoma is a biphasic neoplasm composed of benign or atypical Müllerian epithelium and a malignant mesenchymal component that is usually, but not always, of low grade. Focal architectural or cytologic atypia of the epithelial component resembling atypical hyperplasia may uncommonly be present and foci of adenocarcinoma have been rarely reported. Whether the coexistence of these 2 tumor components is a result of independent primaries (collision tumor), adenocarcinoma arising from the epithelial component of the adenosarcoma, an unusual form of carcinosarcoma or some other mechanism is uncertain. To establish the diagnostic criteria and clinical significance of the coexistence of adenocarcinoma in close association with Müllerian adenosarcoma, we conducted a multi-institutional study of these rare tumors. Twenty-six patients were identified with "mixed" adenosarcoma and adenocarcinoma; they ranged in age from 43 to 87 years (median: 66 y). Tumors occurred in the uterine corpus (n=22), ovary (n=2), and the pelvis (n=2). All but 6 had International Federation of Gynecology and Obstetrics (FIGO) stage I disease. All extrauterine tumors were associated with endometriosis. The tumor size ranged from 2 to 25 cm (median: 7.9 cm). The sarcomatous component was of low grade in 18 and high grade in 8 (the majority demonstrating rhabdomyoblastic differentiation); 9 had stromal overgrowth. Twenty-five carcinomas were endometrioid in type (23 FIGO grade 1; 3 FIGO grade 2) and 1 carcinoma was dedifferentiated with FIGO grade 1 endometrioid adenocarcinoma component; 33% of the uterine neoplasms were associated with adjacent endometrial hyperplasia. Next-generation sequencing in 2 tumors identified similar molecular abnormalities in the sarcomatous and carcinomatous components supporting a clonal relationship. Of 10 patients with available follow-up (median: 18 mo), 8 had no evidence of disease and 2 died of recurrent sarcoma at 7 and 8 months. Endometrioid adenocarcinomas that arise in close spatial association with Müllerian adenosarcoma appear to be clonally related to the sarcoma. Unlike carcinosarcomas, these tumors are usually early stage at presentation. The prognosis appears to be driven by the sarcomatous component. These tumors should be distinguished from carcinosarcomas, dedifferentiated endometrial carcinomas, and corded and hyalinized endometrioid carcinomas.

Clinical Validation of a Myeloid Next-Generation Sequencing Panel for Single-Nucleotide Variants, Insertions/Deletions, and Fusion Genes.

Myeloid neoplasms are a heterogeneous group of neoplasms including acute myeloid leukemia (AML), myeloproliferative neoplasms, myelodysplastic syndrome, and myeloproliferative neoplasms/myelodysplastic syndrome. Genetic abnormalities are used as diagnostic, prognostic, and predictive biomarkers in patients with these diseases. Herein, we describe the clinical validation of the Oncomine Myeloid Research (OMR) next-generation sequencing panel that interrogates for 40 genes and 29 fusion genes commonly seen in myeloid neoplasms. Our validation set of 77 DNA samples included acute and chronic myeloid neoplasms, with 91 single-nucleotide variants and small insertions/deletions. The 71 RNA samples from patients with AML included most of the AML-defining translocations. The OMR on the Ion Torrent S5 platform shows good performance in terms of depth of coverage, on-target reads, and uniformity. The panel achieved 91.3% and 100% concordance with reference DNA and RNA samples, respectively, with a clinical sensitivity and specificity of 96.7% and 100% for DNA and 99.8% and 100% for RNA, respectively. Precision and reproducibility were 100%, and the lower limit of detection was generally 5% variant allele fraction for DNA and 2-log reduction from initial value for RNA fusion genes. In conclusion, the OMR panel is a highly accurate and reproducible next-generation sequencing panel for the detection of common genetic alterations in myeloid neoplasms.

Clinical Utility of GlioSeq Next-Generation Sequencing Test in Pediatric and Young Adult Patients With Brain Tumors.

Brain tumors are the leading cause of death in children. Establishing an accurate diagnosis and therapy is critical for patient management. This study evaluated the clinical utility of GlioSeq, a next-generation sequencing (NGS) assay, for the diagnosis and management of pediatric and young adult patients with brain tumors. Between May 2015 and March 2017, 142 consecutive brain tumors were tested using GlioSeq v1 and subset using GlioSeq v2. Out of 142 samples, 63% were resection specimens and 37% were small stereotactic biopsies. GlioSeq sequencing was successful in 100% and 98.6% of the cases for the detection of mutations and copy number changes, and gene fusions, respectively. Average turnaround time was 8.7 days. Clinically significant genetic alterations were detected in 95%, 66.6%, and 66.1% of high-grade gliomas, medulloblastomas, and low-grade gliomas, respectively. GlioSeq enabled molecular-based stratification in 92 (65%) cases by specific molecular subtype assignment (70, 76.1%), substantiating a neuropathologic diagnosis (18, 19.6%), and diagnostic recategorization (4, 4.3%). Fifty-seven percent of the cases harbored therapeutically actionable findings. GlioSeq NGS analysis offers rapid detection of a wide range of genetic alterations across a spectrum of pediatric brain tumors using formalin-fixed, paraffin-embedded specimens and facilitates integrated molecular-morphologic classification and personalized management of pediatric brain tumors.

Epithelial-Myoepithelial Carcinoma: Frequent Morphologic and Molecular Evidence of Preexisting Pleomorphic Adenoma, Common HRAS Mutations in PLAG1-intact and HMGA2-intact Cases, and Occasional TP53, FBXW7, and SMARCB1 Alterations in High-grade Cases.

We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n=39) were analyzed for morphologic and molecular evidence of preexisting PA (PLAG1, HMGA2 status by fluorescence in situ hybridization, FISH, and FGFR1-PLAG1 fusion by next-generation sequencing, NGS). Twenty-three EMCAs were further analyzed by NGS for mutations and copy number variation in 50 cancer-related genes. On the basis of combined morphologic and molecular evidence of PA, the following subsets of EMCA emerged: (a) EMCAs with morphologic evidence of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 alterations (10/39, 26%), and (d) de novo carcinomas, without morphologic or molecular evidence of PA (8/39, 21%). Twelve high-grade EMCAs (12/39, 31%) occurred across all subsets. The median disease-free survival was 80 months (95% confidence interval, 77-84 mo). Disease-free survival and other clinicopathologic parameters did not differ by the above defined subsets. HRAS mutations were more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. 1/14, P<0.001). Other genetic abnormalities (TP53 [n=2], FBXW7 [n=1], SMARCB1 deletion [n=1]) were seen only in high-grade EMCAs with intact PLAG1 and HMGA2. We conclude that most EMCAs arose ex PA (31/39, 80%) and the genetic profile of EMCA varies with the absence or presence of preexisting PA and its cytogenetic signature. Progression to higher grade EMCA with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion.

Depletion of Beta Cell Intranuclear Rodlets in Human Type II Diabetes.

Intranuclear rodlets (INRs) are rod-shaped intranuclear bodies of unknown function present in the nuclei of pancreatic beta cells. Previous studies have demonstrated a significant depletion of INRs from beta cells in mouse models of type II diabetes, suggesting that they may have pathological significance. The objective of the present study was to determine whether beta cell INRs show quantitative alterations in human type II diabetes. In sections of non-neoplastic pancreas from 23 diabetic patients and 23 controls who had undergone complete or partial pancreatectomy, we detected a significant reduction in the proportion of INRs in insulin-immunoreactive beta cells. In addition, we showed that beta cell INRs are immunoreactive for the RNA-binding protein HuR. The results of this study confirm and extend our previous study and implicate this enigmatic nuclear structure in the cellular pathophysiological mechanisms underlying the development of type II diabetes in humans.

Value of histopathology for predicting the post-operative complications of ileo-anal anastomosis (J-pouch) procedure in children with refractory ulcerative colitis.

The J-pouch is a surgical procedure offered to children with refractory ulcerative colitis (UC) who have undergone subtotal colectomy to reconstruct a reservoir function with ileo-anal anastomosis. Unfortunately, post-operative complications may occur and can compromise the pouch function. We assessed rectal histopathology to determine whether severity of inflammation in the rectum prior to the creation of the J-Pouch was associated with post-operative complications. We retrospectively reviewed the histopathology of all J-pouch procedure specimens from paediatric patients during the period 2000-2013 using an objective grading system that assesses the chronicity and activity of the UC disease. We analysed the parameters for association with the post-operative complications. A classification tree algorithm was generated to predict the risk of complication based on histopathological parameters. A total of 28 paediatric patients were identified, among whom 10 developed post-operative complications (35%). The activity score at the recto-anal margin was higher among the patients with post-operative complications (mean 7.3±3.1 versus 4.8±3.1; p=0.04). The involvement of more than 5% colonic crypts with epithelial neutrophilic infiltration at the recto-anal margin was found to be an independent parameter that would stratify the patients into low-risk or high-risk group for developing complications (17% versus 64%; p=0.04). An association between UC disease activity at the recto-anal margin and post-operative J-pouch complications was determined. Potentially, this association suggests that a histopathological assessment of the recto-anal transitional zone may have value in guiding the surgeon on the risk of post-operative complications.

Evaluation of apparent diffusion coefficient and MR volumetry as independent associative factors for extra-prostatic extension (EPE) in prostatic carcinoma.

BACKGROUND: To assess mean apparent diffusion coefficient (ADC) and MR-derived tumor volume (Vt) as associative factors for extra-prostatic extension (EPE) in prostate cancer (PCa). METHODS: With institutional review board approval, 73 consecutive patients diagnosed with PCa at trans-rectal ultrasound biopsy underwent preoperative multi-parametric (T2W+DWI+DCE) 3 Tesla MRI before radical prostatectomy between 2012 and 2014; 52% (38/73) patients had EPE. Clinical parameters including: age, prostate serum antigen (PSA), digital rectal examination (DRE) and percentage positive cores (PPC) were recorded. Two blinded radiologists subjectively evaluated for EPE using PI-RADS with T2W-MRI. A third blinded radiologist recorded: mean ADC (mm(2) /s) of tumor and tumor volume on ADC and T2W (derived from planar volumetry). VtMAX (the largest volume on ADC or T2W) was documented. Multivariate and receiver operator characteristic analyses were performed. RESULTS: There were no significant differences in age, DRE, or Gleason score between groups (P = 0.52, 0.06, 0.61, 0.36). PSA approached significance being higher with EPE (12.9 ± 12.6 versus 8.2 ± 7.4; P = 0.06). PPC was higher with EPE (60.9 ± 21.9% versus 38.3 ± 21.6%; P < 0.01) with an area under the curve (AUC) of 0.78 and sensitivity/specificity = 75.7/75% when PPC ≥ 45%. AUC for T2W-MRI was 0.46-0.51 with sensitivity/specificity = 40.0-42.9/48.6-57.1% (R1, R2). Inter-observer agreement was fair, k = 0.39. There was no difference in mean ADC between groups (0.89 ± 0.25 versus 0.88 ± 0.19 [EPE] mm(2) /s), P = 0.70. T2W-Vt, ADC-Vt, and VtMAX were larger with EPE (5.1 ± 7.4, 5.8 ± 6.5, 6.3 ± 7.4 cm(3) versus 1.6 ± 1.8, 1.8 ± 1.3, 2.1 ± 1.8), P < 0.01. VtMAX AUC was 0.77 with sensitivity/specificity = 78.4/73.5% when VtMAX ≥ 2.1 cm(3) which outperformed all other parameters (P > 0.05) except PPC (P = 0.6) for the diagnosis EPE. CONCLUSION: MR volumetry and percentage of positive core biopsies are associated with EPE; whereas, in this study, other clinical and MR parameters including mean ADC and subjective T2W-MR analysis were not useful for assessment of EPE.

Cribriform morphology predicts upstaging after radical prostatectomy in patients with Gleason score 3 + 4 = 7 prostate cancer at transrectal ultrasound (TRUS)-guided needle biopsy.

Selected patients with transrectal ultrasound (TRUS)-guided biopsies containing Gleason score 3 + 4 = 7 prostate cancer (PCa) may be considered candidates for active surveillance (AS). The purpose of this study was to determine if there are features that predict PCa upstaging and/or upgrading after radical prostatectomy (RP) in patients with Gleason score 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsies. We searched our institution's database for patients with Gleason score 3 + 4 = 7 PCa diagnosed on TRUS-guided biopsy who underwent subsequent RP between January 2010 and January 2015. Two blinded genitourinary pathologists independently reviewed and assessed the following on biopsies: (a) nuclear size, nucleolar size and distribution of macronucleoli of PCa, which were subjectively graded using a semi-quantitative scale from 1 to 3, and (b) PCa with cribriform morphology and the size of cribriform disease. Patient age, serum prostate-specific antigen (PSA) and PSA density (PSAD) were also recorded. The Gleason score and stage (presence or absence of organ-confined disease (OCD)) were retrieved from RP reports. Comparisons were performed between groups using the chi-square test and Spearman correlation. One hundred and four patients were identified to have met inclusion criteria. The mean age was 63 (±6.1) years. Mean PSA and PSAD at diagnosis were 7.5 (±4.2) and 0.25 (±0.15) ng/mL, respectively. Gleason scores were upgraded to greater than 3 + 4 = 7 in 26.9 % (28/104) of patients, and 44.2 % (46/104) of patients had no OCD after RP. There was no correlation between age, PSA, PSAD or percent of biopsies with Gleason pattern 4 for either Gleason score upgrading or absence of OCD at the time of RP (p > 0.05). Thirty patients had cribriform morphology on TRUS-guided biopsy of which 60 % (18/30) had no OCD at RP (p = 0.04) while 36.7 % (11/30) were upgraded to Gleason score ≥3 + 4 = 7 after RP (p = 0.15). There was no association between nuclear size, nucleolar size and/or distribution of macronucleoli with upgrading and/or absence of OCD (p > 0.05). The size of cribriform pattern was not associated with the absence of OCD (p = 0.43) or Gleason score upgrade (p = 0.28). A proportion of patients with Gleason score 3 + 4 = 7 PCa at needle biopsy do not have OCD or are upgraded to higher Gleason scores after RP. In our study, patients with Gleason score 3 + 4 = 7 PCa with the presence of cribriform pattern 4 had a significantly increased chance of being found to have no OCD at the time of RP. There were no clinical or pathologic parameters at the time of TRUS-guided biopsy that identified risk factors for Gleason score upgrading at RP in this study. Cribriform morphology detected on biopsy in patients with Gleason score 3 + 4 = 7 PCa is associated with tumour upstaging after RP and may be considered a contraindication to active surveillance.

Evaluation of Quantitative Digital Pathology in the Assessment of Barrett Esophagus-Associated Dysplasia.

OBJECTIVES: Barrett esophagus (BE) is a precursor lesion that confers an increased risk of esophageal adenocarcinoma. Two issues confront the diagnosis of patients with BE: (1) sampling error at the time of endoscopy and (2) variability among pathologists in grading dysplasia. The purpose of our study was to evaluate quantitative digital pathology (QDP) as a marker of dysplasia and stratification from low-grade to high-grade dysplasia to intramucosal adenocarcinoma in BE. METHODS: Sixty-one esophageal biopsy specimens with BE were selected and divided into six groups according to the dysplasia grade. QDP image analysis was carried out by an in-house automated quantitative system on sections. The values of 110 nuclear features that analyze the morphology and chromatin texture were generated for each nucleus. RESULTS: A progressive correlation was found between nuclear morphometric features and chromatin features with BE dysplasia. The chromatin texture was the best discriminator of the class diagnosis. There was a significant difference between the chromatin features of isolated low-grade dysplasia vs low-grade dysplasia that was associated with higher grade lesions in other biopsy tissue fragments. CONCLUSIONS: QDP is a promising tool in the new era of digital pathology. Pending clinical validation studies, analysis of chromatin texture could contribute to the differential diagnosis of BE class and the detection of concomitant high-grade lesions if not sampled.

Tumor and endothelial cell hybrids participate in glioblastoma vasculature.

BACKGROUND: Recently antiangiogenic therapy with bevacizumab has shown a high but transient efficacy in glioblastoma (GBM). Indeed, GBM is one of the most angiogenic human tumors and endothelial proliferation is a hallmark of the disease. We therefore hypothesized that tumor cells may participate in endothelial proliferation of GBM. MATERIALS AND METHODS: We used EGFR FISH Probe to detect EGFR amplification and anti-CD31, CD105, VE-cadherin, and vWF to identify endothelial cells. Endothelial and GBM cells were grown separately, labeled with GFP and DsRed lentiviruses, and then cocultured with or without contact. RESULTS: In a subset of GBM tissues, we found that several tumor endothelial cells carry EGFR amplification, characteristic of GBM tumor cells. This observation was reproduced in vitro: when tumor stem cells derived from GBM were grown in the presence of human endothelial cells, a fraction of them acquired endothelial markers (CD31, CD105, VE-cadherin, and vWF). By transduction with GFP and DsRed expressing lentiviral vectors, we demonstrate that this phenomenon is due to cell fusion and not transdifferentiation. CONCLUSION: A fraction of GBM stem cells thus has the capacity to fuse with endothelial cells and the resulting hybrids may participate in tumor microvascular proliferation and in treatment resistance.

A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry.

Glioblastoma is one of the most angiogenic human tumours and endothelial proliferation is a hallmark of the disease. A better understanding of glioblastoma vasculature is needed to optimize anti-angiogenic therapy that has shown a high but transient efficacy. We analysed human glioblastoma tissues and found non-endothelial cell-lined blood vessels that were formed by tumour cells (vasculogenic mimicry of the tubular type). We hypothesized that CD133+ glioblastoma cells presenting stem-cell properties may express pro-vascular molecules allowing them to form blood vessels de novo. We demonstrated in vitro that glioblastoma stem-like cells were capable of vasculogenesis and endothelium-associated genes expression. Moreover, a fraction of these glioblastoma stem-like cells could transdifferentiate into vascular smooth muscle-like cells. We describe here a new mechanism of alternative glioblastoma vascularization and open a new perspective for the antivascular treatment strategy.

ASPM-associated stem cell proliferation is involved in malignant progression of gliomas and constitutes an attractive therapeutic target.

BACKGROUND: ASPM (Abnormal Spindle-like Microcephaly associated) over-expression was recently implicated in the development of malignant gliomas. RESULTS: To better characterize the involvement of ASPM in gliomas, we investigated the mRNA expression in 175 samples, including 8 WHO Grade II, 75 WHO Grade III and 92 WHO Grade IV tumors. Aspm expression was strongly correlated with tumor grade and increased at recurrence when compared to the initial lesion, whatever the initial grade of the primary tumor. ASPM expression also increased over serial passages in gliomaspheres in vitro and in mouse xenografts in vivo. Lentivirus-mediated shRNA silencing of ASPM resulted in dramatic proliferation arrest and cell death in two different gliomasphere models. CONCLUSION: These data suggest that ASPM is involved in the malignant progression of gliomas, possibly through expansion of a cancer stem cell compartment, and is an attractive therapeutic target in glioblastoma multiforme.

Diagnostic and prognostic markers in gliomas.

PURPOSE OF REVIEW: This review summarizes recent studies on diagnostic and prognostic markers in gliomas such as the BRAF fusion gene in pilocytic astrocytomas and 1p/19q codeletion, O-6-methylguanine-DNA methyltransferase status and isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations in diffuse gliomas. RECENT FINDINGS: In pilocytic astrocytomas, the BRAF fusion gene has been recently identified as a specific and frequent event leading to potentially targetable mitogen-activated protein kinase pathway activation. In grade II/III gliomas and in glioblastomas, chromosome 1p/19q codeletion and O-6-methylguanine-DNA methyltransferase status remain the most important prognostic and predictive markers. Recently identified mutations in IDH1/IDH2, however, are specific for diffuse gliomas, occur frequently in grade II/III gliomas and are of prognostic value in grade III gliomas, as well in glioblastomas in which they characterize secondary glioblastomas. SUMMARY: Extensive molecular studies have enabled the discovery of new diagnostic and prognostic markers that are refining the histomolecular classification of gliomas.

Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas.

PURPOSE: Unexpected mutations affecting the isocitrate dehydrogenase (IDH1) gene at codon 132 have been found in 12% of glioblastomas. PATIENTS AND METHODS: IDH1 codon 132 sequencing was performed in a series of 404 patients with glioma (100 grade 2, 121 grade 3, and 183 grade 4 gliomas) and correlated with histology, genomic profile, methylguanyl methyltransferase (MGMT) promoter methylation status, and outcome. RESULTS: A total of 155 codon 132 mutations were found, of which 131 were Arg132His (88.5%). The IDH1 mutation was inversely correlated with grade, affecting 77% of grade 2, 55% of grade 3, and 6% of grade 4 gliomas (P < 10(-15)). The IDH1 mutation was tightly associated with a 1p19q codeleted genotype (P < 10(-14)) and an MGMT methylated status (P < .001) but mutually exclusive with EGFR amplification (P < 10(-15)) and loss of chromosome 10 (P < 10(-15)). The presence (v absence) of IDH1 mutation was associated with a better outcome in grade 2 (150.9 v 60.1 months, respectively; P = .01), grade 3 (81.1 v 19.4 months, respectively; P < .001), and grade 4 gliomas (27.4 v 14 months, respectively; P < .01). After adjustment for grade, age, MGMT status, genomic profile, and treatment, multivariate analysis confirmed that IDH1 mutation was an independent favorable prognostic marker (hazard ratio = 0.297; 95% CI, 0.157 to 0.564, P = .00021). CONCLUSION: This study indicates that IDH1 codon 132 mutation is closely linked to the genomic profile of the tumor and constitutes an important prognostic marker in grade 2 to 4 gliomas.