Case Of Astrocytoma Research Articles

In Utero and Early-Life Exposure to Ambient Air Toxics and Childhood Brain Tumors: A Population-Based Case-Control Study in California, USA.

Background:Little is known about the influence of environmental factors on the etiology of childhood brain tumors.Objectives:We examined risks for brain tumors in children after prenatal and infant exposure to monitored ambient air toxics.Methods:We ascertained all cases of medulloblastoma, central nervous system primitive neuroectodermal tumor (PNET), and astrocytoma before 6 years of age diagnosed in 1990–2007 from the California Cancer Registry and selected controls randomly from birth rolls matched by birth year. Exposures to air toxics during pregnancy/infancy for 43 PNET, 34 medulloblastoma, and 106 astrocytoma cases and 30,569 controls living within 5 mi of a monitor were determined. With factor analysis we assessed the correlational structures of 26 probable carcinogenic toxics, and estimated odds ratios by brain tumor type in logistic regression models.Results:PNETs (≤ 38 cases) were positively associated with interquartile range (IQR) increases in prenatal exposure to acetaldehyde [odds ratio (OR) = 2.30; 95% CI: 1.44, 3.67], 1,3-butadiene (OR = 2.23; 95% CI: 1.28, 3.88), benzene, and toluene; and with IQR increases in exposure during the first year of life to ortho-dichlorobenzene (OR = 3.27; 95% CI: 1.17, 9.14), 1,3-butadiene (OR = 3.15; 95% CI: 1.57, 6.32), and benzene. All exposures except ortho-dichlorobenzene loaded on the same factor. Medulloblastoma (≤ 30 cases) was associated with prenatal exposure to polycyclic aromatic hydrocarbons (PAHs combined: OR = 1.44; 95% CI: 1.15, 1.80). Exposures to lead and some PAHs during the first year of life were positively associated with astrocytoma, but the confidence intervals included the null value (e.g., for lead, OR = 1.40; 95% CI: 0.97, 2.03).Conclusions:Our data suggest that in utero and infancy exposures to air toxics generated by industrial and road traffic sources may increase the risk of PNET and medulloblastoma, with limited support for increased risks for astrocytoma in children up to age 6.Citation:von Ehrenstein OS, Heck JE, Park AS, Cockburn M, Escobedo L, Ritz B. 2016. In Utero and early-life exposure to ambient air toxics and childhood brain tumors: a population-based case–control study in California, USA. Environ Health Perspect 124:1093–1099; http://dx.doi.org/10.1289/ehp.1408582

Overexpression of Eg5 correlates with high grade astrocytic neoplasm.

To investigate the relationship between Eg5 and histopathological grade of astrocytoma, Eg5 expression was evaluated by immunohistochemical examination on 88 specimens including 25 cases of glioblastoma (WHO grade IV), 22 cases of anaplastic astrocytoma (WHO grade III), 20 cases of diffuse astrocytoma (WHO grade II), and 21 cases of pilocytic astrocytoma (WHO grade I). The histopathological characteristics and Eg5 expression level of each tumor were assessed and statistically analyzed. Astrocytic tumors exhibited significant correlation of expression of Eg5 with higher WHO histopathological grades (p < 0.001). Eg5 is expressed in 51-98% (mean 76.88%) of neoplastic cells in glioblastoma, 34-57% (mean 43.59%) of neoplastic cells in anaplastic astrocytoma, 6-36% (mean 18.60%) of neoplastic cells in diffuse astrocytoma, and 2-28% (mean 13.48%) of neoplastic cells in pilocytic astrocytoma. In conclusion, overexpression of Eg5 associates with high-grade astrocytic neoplasm, and it may represent an independent diagnostic and prognostic factor in grading astrocytic tumors and predicting prognosis of astrocytic tumor patients.

Intramedullary spinal glioblastoma metastasis from anaplastic astrocytoma of cerebellum: A case report and review of the literature

Cerebellar anaplastic astrocytoma is infrequently encountered even nowadays, and drop metastasis with progression into spinal glioblastoma is not reported in the English literature. We report a case of cerebellar anaplastic astrocytoma receiving operation and subsequent concurrent chemoradiotherapy. One year later, progressive weakness of both lower limbs and unsteady gait occurred. Spine magnetic resonance imaging showed cervical and thoracic spine intramedullary tumor. We then performed laminectomy and tumor biopsy. The histopathological report demonstrated primary spinal cord glioblastoma multiforme with positive glial fibrillary acidic protein, high MIB-1 labeling index and negative staining of isocitrate dehydrogenase-1 mutation. After reviewing the English literature to date, most metastatic spinal glioblastoma resulted from previous intracranial glioblastoma, and there are few studies mentioning spinal glioblastoma originating from intracranial low-grade gliomas. Over time, improvement in local control of the primary tumor has raised patient risk of the possibility of spinal metastasis, and clinical physicians should be aware of this aspect so that quicker diagnosis and management will be accomplished, even in patients with lower grade of intracranial gliomas.

Low grade astrocytoma in children under the age of three years: a report from the Canadian pediatric brain tumour consortium

In children under the age of 3years, the most common solid tumors are brain tumors. Low grade astrocytomas represent 30-40% of brain tumours in this age group. This study reviewed the incidence, characteristics, therapy, and outcome of children less than 36months of age diagnosed with a low grade astrocytoma from 1990 to 2005 in Canada. A data bank was established using data collected from Canadian pediatric oncology centers on children less than age 3 diagnosed with brain tumors between 1990 and 2005. Cases of low grade astrocytoma were extracted from this data bank and their characteristics summarized. From the 579 cases in the data bank, 153 cases of low grade astrocytoma (26%) were identified. The mean duration of symptoms prior to presentation was 13weeks, and 53% of patients underwent a greater than 90% resection of their tumor, while 30% underwent 10-90% resection. Seventy-one percent of patients received no further therapy after surgery and of the 45 who received therapy following surgery, 43 received chemotherapy, and 5 received radiation therapy. Sixty-eight patients had recurrence or progression of their tumor. Eighty-seven percent of patients were alive at the time of the survey with a 2year survival rate of 95.3±1.8%, 5year survival rate of 93.1±2.1% and 10year survival rate of 89.1±2.8%. The 5year survival rate for Canadian children less than 36months of age with a low grade astrocytoma was 93.0±2.8% which is similar to that for older children with this tumor.

Impact of tumor histology on resectability and neurological outcome in primary intramedullary spinal cord tumors: a single-center experience with 102 patients.

Surgical outcomes for intramedullary spinal cord tumors are affected by many variables including tumor histology and preoperative neurological function. To analyze the impact of tumor histology on neurological outcome in primary intramedullary spinal cord tumors. A retrospective review of 102 consecutive patients with intramedullary spinal cord tumors treated at a single institution between January 1998 and March 2009. Ependymomas were the most common tumors with 55 (53.9%), followed by 21 astrocytomas (20.6%), 12 hemangioblastomas (11.8%), and 14 miscellaneous tumors (13.7%). Gross total resection was achieved in 50 ependymomas (90.9%), 3 astrocytomas (14.3%), 11 hemangioblastomas (91.7%), and 12 miscellaneous tumors (85.7%). At a mean follow-up of 41.8 months (range, 1-132 months), we observed recurrences in 4 ependymoma cases (7.3%), 10 astrocytoma cases (47.6%), 1 miscellaneous tumor case (7.1%), and no recurrence in hemangioblastoma cases. When analyzed by tumor location, there was no difference in neurological outcomes (P = .66). At the time of their last follow-up visit, 11 patients (20%) with an ependymoma improved, 38 (69%) remained the same, and 6 (10.9%) worsened. In patients with an astrocytoma, 1 (4.8%) improved, 10 (47.6%) remained the same, and 10 (47.6%) worsened. One patient (8.3%) with a hemangioblastoma improved and 11 (91.7%) remained the same. No patient with a hemangioblastoma worsened. In the miscellaneous tumor group, 2 (14.3%) improved, 10 (71.4%) remained the same, and 2 (14.3%) worsened. Preoperative neurological status (P = .02), tumor histology (P = .005), and extent of resection (P < .0001) were all predictive of functional neurological outcomes. Tumor histology is the most important predictor of neurological outcome after surgical resection because it predicts resectability and recurrence.

The clinical characteristics of subependymal giant cell astrocytoma: five cases.

In this study, we reviewed the clinical characteristics of five cases of subependymal giant cell astrocytoma (SEGA) at our hospital between May 1997 and July 2012. The median age was 18 years old (range, 8 to 26). The clinical symptoms were presented as seizure in two patients and headache in three patients. All the tumors were located near the foramen of Monro. The median size of the tumors was 2.5 cm (range, 1.9-4.0). Two patients showed the solitary lesion, and three had subependymal nodules and cortical tubers. The median follow-up duration was 7.4 years (range, 2.0-14.3). Three patients were associated with the tuberous sclerosis complex (TSC). Four patients showed the SEGA at the first presentation and one patient experienced the 1.9 cm-sized growing mass during 7.7 years follow-up after the diagnosis of the TSC. The mass was totally removed in four patients and subtotally in one. Postoperatively, one patient took the medication for the seizure, which was controllable. The subtotally removed mass showed the recurrence postoperative 4.1 years later, and the recurred mass was stable for 4.5 years after the recurrence. The clinical follow-up study of the SEGA showed an indolent behavior before and after the surgery.

頭皮下転移をきたした視床退形成性星細胞腫の1例

頭皮下転移をきたした視床退形成性星細胞腫の1例

Thyroid transcription factor-1 and epithelial membrane antigen expression in four cases of subependymal giant cell astrocytoma.

Thyroid transcription factor-1 and epithelial membrane antigen expression in four cases of subependymal giant cell astrocytoma.

Aggressive Low-Grade Optic Nerve Glioma in Adults

Primary optic nerve gliomas are most commonly benign pilocytic astrocytomas (World Health Organization [WHO] Grade I) occurring in childhood and following an indolent course. Malignant optic gliomas occur in adulthood and follow an extremely aggressive course, with rapid infiltration of the chiasm, blindness, and death typically within months. A third category of optic glioma, occurring in adulthood, histopathologically benign (WHO Grade I–II) but following an aggressive course, has been rarely reported. The authors describe clinical and histopathologic features of clinically aggressive but histopathologically benign optic nerve gliomas of adulthood. Retrospective review of cases of biopsy-proven optic nerve glioma in the neuro-ophthalmology division of the Jules Stein Eye Institute from 1990 to 2011 was carried out. Cases following an aggressive course were selected for review of clinical, neuroradiologic, and histopathologic features. Three cases were selected for detailed study. Ages ranged from 31 to 45 years. All were initially diagnosed with optic nerve inflammation or benign neoplasm based on clinical and neuroradiologic features, but all suffered neuroradiologic extension and rapid deterioration of vision in the affected eye to no light perception over 3–8 weeks. Optic nerve biopsies were undertaken for the suspicion of malignancy. Features ranged from WHO Grade I (pilocytic astrocytoma, ganglioglioma) in two cases, to WHO Grade II in one case (diffuse astrocytoma, histopathologically benign, but associated with aggressive features such as high p53 [13–21%] and Ki-67 [40%]). The diffuse astrocytoma case subsequently developed extensive intracranial extension suspicious for malignant transformation. These findings indicate that benign optic nerve glioma in adults may be initially misdiagnosed as inflammation, be clinically aggressive, and require excision to prevent further intracranial involvement.

N-cadherin, beta-catenin and connexin 43 expression in astrocytic tumours of various grades.

Astrocytic tumors are the most common primary brain tumors, but little is known about their etiology and prognostic factors. N-cadherin and beta-catenin are adhesive proteins, and are often overexpressed in many types of cancers, including breast or colorectal cancer, resulting in better prognosis. Connexin 43 is a gap junction protein involved in cell-cell signaling pathway taking part in the process of carcinogenesis. The aim of the study was to evaluate N-cadherin, beta-catenin and connexin 43 expression in astrocytic tumors of various grades. We examined 131 cases of astrocytic tumors, including 26 cases of diffuse astrocytoma (group I), 44 anaplasic astrocytomas (group II) and 61 glioblastoma cases (group III)--primary and secondary. To evaluate N-cadherin, beta-catenin and connexin 43 expression, we used immunohistochemical reaction with specific antibodies (Santa Cruz Biotechnology). The obtained results were correlated with clinical and morphological features. Beta-catenin expression was observed in 69.3% of diffuse astrocytomas, 75% of anaplastic astrocytomas, and 82% of glioblastoma cases. N-cadherin expression was observed in 92.3% of diffuse astrocytomas, 90.1% of anaplastic astyrocytomas, and in all glioblastoma cases. Connexin 43 was observed in 76.9% of diffuse astrocytomas, and in all cases of anaplastic astrocytomas and glioblastomas. Beta-catenin expression was significant within the nucleus of neoplastic cells in groups I and II. In group III, staining was observed only in the cellular membranes. N-cadherin and connexin 43 expression was observed only in the cells' membranes. In glioblastomas, both primary and secondary, all protein expression was significant within the cells surrounding the necroses and blood vessels and weak or absent in the tumor's margins. Our study shows that beta-catenin nuclear expression in group of diffuse astrocytomas and anaplastic astrocytomas is evidence for transcriptional function of beta-catenin in those groups. Strong N-cadherin and connexin 43 expression in those groups may be evidence for their role in tumor formation and progression. However, in glioblastomas a very important role of all examined proteins is generating intracellular connections to facilitate the escape of tumor cells from the effects of hypoxia or their accumulation around the blood vessels rather than tumor invasion into the brain parenchyma.

Pilocytic astrocytoma presenting with atypical features on magnetic resonance imaging

Pilocytic astrocytoma, which is classified as a grade I astrocytic tumor by the World Health Organization, is the most common type of glioma in children and young adults. Pilocytic astrocytoma generally appears as a well-circumscribed, contrast-enhancing lesion, frequently with cystic components on magnetic resonance imaging (MRI). However, it has been reported that the MRI appearance of pilocytic astrocytoma may be similar to that of high-grade gliomas in some cases. We here report on 6 cases of pilocytic astrocytoma with atypical MRI findings, including small cyst formation, heterogeneously enhancing tumor nodules, irregularly enhancing tumor nodules, and enhancing tumor nodules with internal hemorrhage. All tumors were successfully resected, and the histological diagnoses were pilocytic astrocytoma. When the tumor is located near a cerebral cistern or ventricle, the risk of leptomeningeal dissemination is increased. Furthermore, partial resection has also been associated with a higher risk of recurrence and leptomeningeal dissemination. To date, all but one patient are alive and recurrence-free. Because the preoperative diagnosis influences the decision on the extent of resection and because of the high risk of leptomeningeal dissemination associated with these tumors, careful and correct diagnosis by MRI is important.

EG-08 * IDH MUTATIONS IN GLIOMAS ASSOCIATED WITH ENCHONDROMATOSIS

The enchondromatoses, Ollier's disease and Maffucci syndrome, are non-heritable developmental disorders characterized by multiple enchondromas (Olllier's) in association with hemangiomas (Maffucci). Glial neoplasms are reported in both disorders but a pathogenic mechanism underlying this association has not been identified. We report a case of anaplastic astrocytoma in a 23 year old man with Maffucci syndrome whose tumor carried a substitution mutation of arginine for cysteine at position 132 (R132C) of the isocitrate dehydrogenase 1 (IDH1) protein. This mutation, commonly found in Maffucci-associated enchondromas and hemangiomas, was not detected on routine immunohistochemical (IHC) analysis of the astrocytoma using the R132H mutation-specific antibody, commonly applied in clinical laboratories. The R132C mutation was detected by polymerase chain reaction (PCR) and subsequently confirmed using a SNaPshot assay. Because somatic mosaic IDH mutations are associated with enchondromas and hemangiomas in Maffucci syndrome, we looked for the R132C mutation in a hemangioma, peripheral blood mononuclear cells (PBMNC) and histologically normal brain surrounding the tumor from this patient. The mutation was present in the hemangioma, absent in PBMNC, and present in 2% of alleles in ‘normal’ brain. The low level in surrounding brain tissue is consistent with tumor cell infiltration, not mosaicism, as a S173T p53 mutation in the tumor showed similar results. Using IHC, we further demonstrated that the mutant IDH1 protein in this glioma functions as an oncometabolite. Two repressive histone trimethylation marks were strongly positive in the tumor, supporting a role for 2-hydroxyglutarate in the inhibition of histone demethylation. Together, these data demonstrate that an IDH1 mutation common in enchodromatoses underlies the association of glial tumors reported in both Ollier's disease and Maffucci syndrome.

Low grade glioma in an adult patient with Sotos syndrome

Sotos syndrome is a rare overgrowth syndrome with an increased risk of tumorigenesis. To our knowledge we report the first case of astrocytoma in an adult patient with Sotos syndrome and describe the clinical course.

A case of an infiltrative astrocytoma in a suicidal woman

Astrocytomas are a type of brain tumors. They originate in a particular kind of glial cells, called astrocytes due to their star-shape. There are two broad classes of astrocytomas recognized in literature according to the invasion into brain tissue:

IDH1 mutation and MGMT expression in astrocytoma and the relationship with prognosis after radiotherapy

To study the correlation between IDH1 mutation, MGMT expression, clinicopathologic features and post-radiotherapy prognosis in patients with astrocytoma. Detection of IDH1 mutation and MGMT expression was carried out in 48 cases of astrocytoma (WHO grade II to III) by EnVision method with immunohistochemical staining. Follow-up data, including treatment response and overall survival time, were analyzed. The rates of IDH1 mutation and MGMT expression in astrocytomas were 62.7% (30/48) and 47.9% (23/48), respectively. There was a negative correlation between IDH1 mutation and MGMT expression (r = -0.641, P < 0.01). The age of patients with IDH1 mutation was younger at disease onset. The IDH1 mutation rate in patients with WHO grade II astrocytoma was higher than that in patients with WHO grade III tumor (P < 0.05). The age at onset was an independent factor affecting the expression of mutant IDH1. After radiotherapy, patients with IDH1 mutation+/MGMT- tumor carried a longer overall survival time than patients with IDH1 mutation-/MGMT+ tumor (P < 0.05). There is a correlation between IDH1 mutation and MGMT expression in WHO grade II to III astrocytoma. Age at onset is an independent factor affecting the expression of mutant IDH1. Tumors with IDH1+/MGMT- pattern show better response to radiotherapy than tumors with IDH1-/MGMT+ pattern. Detection of IDH1 mutation and MGMT protein expression can provide some guidance in choice of treatment modalities in patients with astrocytoma.

Abstract 1356: Frequent H3F3A K27M mutations in thalamic gliomas from young adult patients

Abstract Introduction. Mutations in the H3F3A gene, which encodes histone H3.3, were recently reported in cases of pediatric glioblastoma. H3F3A K27M mutations occur in gliomas that arise at midline locations, including the pons, thalamus, and spine; moreover, this particular mutation is found mainly in tumors in children and adolescents. In this study, we aimed to determine the association between H3F3A mutations and adult thalamic glioma. Methods. Genomic H3F3A was sequenced from 20 separate thalamic gliomas. Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 years; range, 17 - 46), and seven were from patients more than 50 years of age. Additionally, for 14 of the 20 gliomas, 639 genes_including cancer-related genes and chromatin-modifier genes_were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome. Results. The H3F3A K27M mutation was present in 10 of (91%) of the 11 younger patients, and absent from all seven older patients. Additionally, H3F3A K27M was not detected in the two diffuse astrocytomas. By additional sequencing, recurrent mutations were identified in TP53, ATRX, NF1, and EGFR. In addition, a KDM6A mutation was found in one case of diffuse astrocytoma and a CREBBP mutation was identified in one case of glioblastoma with the H3F3A K27M mutation. Gliomas with H3F3A K27M from pediatric or young-adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas. Conclusion. We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently have the H3F3A K27M mutation. Citation Format: Akitake Mukasa, Koki Aihara, Kengo Gotoh, Kuniaki Saito, Genta Nagae, Shingo Tsuji, Kenji Tatuno, Shogo Yamamoto, Shunsaku Takayanagi, Yoshitaka Narita, Soichiro Shibui, Hiroyuki Aburatani, Nobuhito Saito. Frequent H3F3A K27M mutations in thalamic gliomas from young adult patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1356. doi:10.1158/1538-7445.AM2014-1356

IMMUNOHISTOCHEMICAL EXPRESSION OF CLUSTER OF DIFFERENTIATION-68(CD-68) AND KI-67 IN ASTROCYTOMAS

Astrocytoma is common primary malignant brain tumors which arise from immortalized astrocytes. In astrocytoma microglia density is higher than in normal brain, and microglia increase in number according to the grade of malignancyIntense CD68 staining was marginally significant prognosticator for shorter survival.Since proliferative activity is a reliable method to assess tumour biology. Ki-67/MIB-1 has proven to be of prognostic and diagnostic power in astrocytic tumours and shown to correlate with tumour grade. Aim: This study was conducted to detect immunohistochemical expression of CD-68 and Ki-67 in astrocytoma and assessing their relation to proliferative activity and prognosis of such tumors. Methods: Thirty representative cases; 30 cases of astrocytoma examined immunohistochemically using antibodies against CD-68 and Ki-67. Results: CD-68 was positive in 73.3% of astrocytoma cases and it was negative in 26.7%. LowKi-67LI was found in low grade astrocytoma and high Ki-67 LI was found in high grade astrocytoma. Conclusion: CD-68 and Ki-67 were the most useful IHC markers in the discrimination of different grades of astrocytoma and predict proliferative activity and prognosis of such tumors. Key words: Astrocytoma, Prognosis, CD-68, Ki-67.

Anorexia: an early sign of fourth ventricle astrocytoma in children.

Paediatric low-grade astrocytomas of the fourth ventricle are rare tumours, generally revealed by hydrocephalus. However, some patients present with a history of severe anorexia. It might be a harbinger, which if recognized, could lead to earlier diagnosis. We decided to examine our database in order to evaluate the incidence and signification of anorexia in this context. Retrospective monocentric study of cases of low-grade astrocytomas of the fourth ventricle operated between 1991 and 2012 in our paediatric neurosurgery department. We particularly observed the clinical presentation and long-term clinical, oncological and radiological evolution. Non-parametrical tests were used (Mann-Whitney, Fisher). We reviewed 34 cases, 31 pilocytic astrocytomas and 3 diffuse astrocytomas, 16 boys and 18 girls, (M/F ratio 0.89). Mean age at diagnosis was 8 years old. Seven presented with notable anorexia, the average BMI in this group was ≤2 standard deviation (SD); with clinical signs evolving for 11.5 months. Twenty-seven children had no anorexia; average BMI in this group was +1 SD, with clinical evolution for 6 months on an average of p < 0.05. We found no significant difference regarding hydrocephalus or tumour location. In all children with anorexia, body mass index improved markedly in the postoperative follow-up, which lasted, on average, for 6 years. Anorexia with stunted body weight curve is a non-exceptional presentation in children with low-grade astrocytomas of the fourth ventricle. Unexplained or atypical anorexia with negative etiologic assessment should prompt cerebral imaging. Clinical improvement after surgical resection, could suggest a possible interaction between tumour tissue and appetite-suppressing peptide secretion.

FREQUENT H3F3A K27M MUTATIONS IN THALAMIC GLIOMAS FROM YOUNG ADULT PATIENTS

BACKGROUND: Mutations in the H3F3A gene, which encodes histone H3.3, were recently reported in cases of pediatric glioblastoma. H3F3A K27M mutations occur in gliomas that arise at midline locations, including the pons, thalamus, and spine; moreover, this particular mutation is found mainly in tumors in children and adolescents. In this study, we aimed to determine the association between H3F3A mutations and adult thalamic glioma. METHODS: Genomic H3F3A was sequenced from 20 separate thalamic gliomas. Additionally, for 14 of the 20 gliomas, 639 genes—including cancer-related genes and chromatin-modifier genes—were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome. RESULTS: Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 years; range, 17–46), and seven were from patients more than 50 years of age. Among the 18 high-grade thalamic gliomas, the H3F3A K27M mutation was present in 10 (91%) of the 11 tumors from patients under 50 years of age, and was absent in all seven tumors from patients over 50 years of age. The H3F3A K27M mutation was not detected in two diffuse astrocytomas. By additional sequencing, recurrent mutations were identified in TP53, ATRX, NF1 and EGFR. In addition, a KDM6A mutation was found in one case of diffuse astrocytoma and a CREBBP mutation was identified in one case of glioblastoma with the H3F3A K27M mutation. Gliomas with H3F3A K27M from pediatric or young-adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas. The patients with high-grade thalamic gliomas harboring the H3F3A K27M mutation that occur frequently in young adults had a poor prognosis similar to those with wild-type H3F3A tumors that occur mainly in older adults. CONCLUSIONS: We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.

DETECTION OF CIRCULATING TUMOR DNA IN EARLY AND LATE STAGE HUMAN MALIGNANCIES

BACKGROUND: The development of minimally-invasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital PCR-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. In particular we studied the plasma of 14 medulloblastoma, 13 WHO grade 2-3 glioma and 14 WHO grade IV astrocytoma cases for levels of ctDNA. METHODS: The basis of our approach is to differentiate DNA shed by normal cells from DNA derived from tumor cells. In order to distinguish the two populations of cell-free DNA, we first identify a tumor-specific alteration. We then query for that exact mutation in matching plasma from the same patient to generate a personalized tumor biomarker. Only DNA derived from the tumor will harbor the genetic alteration. We initially use targeted, exomic, or whole genome sequencing to identify sequence or structural alterations in tumor tissues of 410 individuals. DNA was extracted from less than 5 ml of plasma in each case. The majority of plasma samples were queried for levels of ctDNA using a high fidelity next-generation sequencing approach coined Safe-SeqS. RESULTS: We found that at least one tumor-specific mutant molecule could be identified in 75% of patients with advanced ovarian, colorectal, bladder, gastroesophoageal, pancreatic, breast, melanoma, hepatocellular and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. Approximately 40% of medulloblastoma and 10% of low or high grade glioma cases had detectable levels of ctDNA. In patients with localized non-CNS tumors, ctDNA was detected in 73%, 57%, 48% and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor (EGFR) blockade in 24 colorectal cancer patients who objectively responded to therapy but who subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase (MAPK) pathway. CONCLUSIONS: Taken together, these data suggest that ctDNA is a sensitive, specific and robust biomarker that can be used for a variety of clinical and research purposes in patients with several multiple different types of cancer. For individuals with CNS neoplasms, alternate strategies may need to be developed in order to detect cell-free tumor derived DNA at levels that are clinically meaningful. ABSTRACT CATEGORY: Neuropathology & Tumor Biomarkers.