Distinct Groups Of Tumors Research Articles

Molecular classification of ovarian high-grade serous/endometrioid carcinomas through multi-omics analysis: JGOG3025-TR2 study.

Considerable interobserver variability exists in diagnosis of ovarian high-grade endometrioid carcinoma (HGEC) and high-grade serous carcinoma (HGSC) due to histopathological similarities. While homologous recombination deficiency (HRD) correlates with drug sensitivity in HGSC, the molecular features of HGEC are unclear. Fresh-frozen samples from 15 ovarian HGECs and 274 ovarian HGSCs in the JGOG-TR2 cohort were submitted to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array. We additionally analyzed 555 ovarian HGSCs from TCGA-OV and 287 endometrial high-grade carcinomas from TCGA-UCEC. Unsupervised clustering using copy number signatures identified four distinct tumor groups (C1, C2, C3 and C4). C1 (n = 41) showed CCNE1 amplification and poor survival. C2 (n = 160) and C3 (n = 59) showed high BRCA1/2 alteration frequency with low and moderate ploidy, respectively. C4 (n = 22) was characterized by favorable outcome, higher HGEC proportion, no BRCA1/2 alteration or CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene expression. Notably, C4 exhibited a normal endometrium-like DNA methylation profile, thus, defined as "HGEC-type" tumors, which were also identified in TCGA-OV and TCGA-UCEC. Ovarian "HGEC-type" tumors present a non-HRD status, favorable prognosis, and endometrial differentiation, possibly constituting a subset of clinically diagnosed HGSCs.

Abstract 4530: Single-cell analysis of oral squamous cell carcinoma (OSCC) from smoker vs. non-smoker patients highlights two groups of tumors with distinct immune microenvironments

Abstract Background and Rationale: OSCC is the most frequent head and neck cancer. While it is mainly affecting patients with a smoking and/or alcohol history (SD), 10% to 15% of OSCC are diagnosed in patients with not known risk factors (NSND). We and others have shown that OSCC from NSND patients are characterized by an enrichment in interferon gamma (IFNγ) response and PD-1 signaling pathways together with a higher intratumor T-cell infiltrate. Herein, we seek to gain more insights into the immune and non-immune tumor microenvironment (TME) of OSCC in SD vs. NSND patients. Material and Methods: We made use of single-cell RNA seq (10x Genomics) from non-sorted and CD45 negative enriched cell suspensions of OSCC biopsies from 11 treatment naïve patients, human papillomavirus negative, including 6 SD and 5 NSND patients. Results: All samples were characterized by a strong immune cell infiltrate. Consistent with our previous results, the analysis of 51,629 immune cells confirmed that NSND patients’ samples displayed a significantly higher proportion of T cells (p = 0.005) compared to SD patients. NK cells were also increased, with 2% in SD patients versus 6% in NSND patients (p = 0.008). T cells strongly expressed IFNγ and remarkably, both myeloid cells and tumor cells from NSND patients had an increased enrichment in IFNγ response pathway in NSND as compared to SD patients. The TME of SD patients was characterized by the presence of 15% of plasma cells vs. 3% in NSND patients (p = 0.003). Thus, tumors from NSND versus SD patients represent two distinct groups of tumors characterized by a different immune TME. Moreover, tumors from SD patients displayed 2% vs. 4% Cancer Associated Fibroblasts (CAFs) (p = 0.01). In addition, among CAFs subpopulations, myofibroblast CAFs, defined as the subpopulation producing extracellular matrix proteins were found only in tumors from SD patients, suggesting that distinct CAFs subpopulations may shape the immune TME by affecting the recruitment and function of adaptive immune cells in SD versus NSND patients. Finally, we analyzed tumor cells using non-negative matrix factorization to find Meta Programs (MP), which are set of genes coordinately upregulated. We identified 5 MP associated with different biological functions: epithelial differentiation, stress, cell cycle (G2/M), partial epithelial-to-mesenchymal transition, and epithelial senescence. While the epithelial differentiation MP was found in all patients, the remaining ones were more frequently found in SD patients. Conclusion: Our results show that the TME of OSCC from NSND vs. SD differs in terms of T, NK, and plasma cells composition, CAFs, and tumor cells MP. Integration with spatial transcriptomics is ongoing. Those biological differences may represent an opportunity to refine the therapeutic approaches in the two populations of patients. Citation Format: Yannick Le Meitour, Béatrice Vanbervliet, Sonia Canjura-Rodriguez, Cyril Degletagne, Laurie Tonon, Lucas Michon, Jebrane Bouaoud, Philippe Zrounba, Aude Excoffier, Karène Mahtouk, Pierre Saintigny. Single-cell analysis of oral squamous cell carcinoma (OSCC) from smoker vs. non-smoker patients highlights two groups of tumors with distinct immune microenvironments. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4530.

Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome.

The WHO 2021 classification of central nervous system cancers distinguishes diffuse gliomas that arise in adults (referred to as the "adult type") and those that arise in children (defined as "paediatric") based on clinical and molecular characteristics."). However, paediatric-type gliomas may occasionally be present in younger adults and occasionally adult-type gliomas may occur in children. Diffuse low-grade paediatric glioma includes diffuse astrocytoma altered by MYB or MYBL1, low-grade polymorphic juvenile neuroepithelial tumour, angiocentric glioma, and diffuse low-grade glioma with an altered MAPK pathway. Here, we examine these newly recognised entities according to WHO diagnostic criteria and propose an integrated diagnostic approach that can be used to separate these clinically and biologically distinct tumor groups.

DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with no effective drugs to date. Mutation-based precision oncology approaches are limited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease drivers—master regulator proteins (MRs)—in DIPG to expand treatment options. Using the metaVIPER algorithm, we interrogated an integrated low grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective in murine proneural gliomas in which TOP2 was identified as a MR while RRM2—targetable by drugs such as cladribine—has been shown to be a positive regulator of glioma progression whose knock-down inhibits tumor growth. We also prioritized drugs by their ability to reverse MR-activity signatures using a large drug-perturbation database. Patients clustered by predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which have early evidence in treating gliomas. We will refine this analysis in a multi-institutional study of >100 patient gene expression profiles to define MR signatures driving known biological/molecular disease subtypes, use DIPG cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.

PATH-29. POTENTIAL OF RAMAN SPECTROSCOPY IN ONCOLOGICAL NEUROSURGERY

Abstract Raman spectroscopy (RS) has gained increasing interest for the analysis of biological tissues within the recent years. It is a label-free, non-destructive method providing insights in biochemical properties of tumor cells. It is possible to compare RS signals with histological properties of identical tissue parts. Therefore, RS bears promising potentials in neurosurgical neurooncology. On one hand, it could potentially be used for both intraoperative tumor diagnostics and resection control. On the other hand, it could provide important knowledge on tumor biochemistry and used for a subclassification of tumors with a potential impact on personalized therapy approaches. Within our group, we analyzed over 3000 measurement points in different brain tumors ex vivo with a robotized RS system and correlated the spectral curves with histopathological results. We separated and subclassified the data by AI-based methods. Additionally, we compared the latter results with those of a handheld probe, which is potentially navigatable for in vivo, intraoperative applications. We could demonstrate, that it is possible to separate distinct tumor groups only based on RS signals, especially by using computer-based signal analysis. Furthermore, we could demonstrate the differences of the spectra of deep-frozen and formalin-fixed tissues versus non-fixed tissues. Based on our results, we will highlight the potentials of RS for intraoperative neurosurgical application in resection control for brain tumors, as well as we will focus on the potentials for brain tumor diagnostics based purely on this method or by using it as an adjunct. Those methods bear additional potentials in the field of personalized chemotherapy approaches.

The ABCs of brain tumor prognosis

Cancer Meningiomas are brain tumors that are typically benign and curable by surgery. In about 20% of cases, however, the tumors recur, and then patient prognosis is poor. Tumor histopathology is currently used to predict which patients might benefit from more aggressive treatment, but this method can be inaccurate. Patel et al. used clinical, gene expression, and sequencing data to classify meningiomas from 140 patients. Their analysis identified three distinct groups of tumors (A, B, and C), with type C being the most likely to recur. Type C tumors were characterized by altered activity of a protein complex that controls cell cycle progression. Importantly, this molecular classification system was a better predictor of prognosis than the method currently used in clinics. Proc. Natl. Acad. Sci. U.S.A. 116 , 21715 (2019).

Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes.

Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort. Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein expression (n = 22). Gene ontology and network enrichment analysis were used to relate over- and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings. Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm2 could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup. Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.

RHOA mutations and CLDN18-ARHGAP fusions in intestinal-type adenocarcinoma with anastomosing glands of the stomach

A subtype of intestinal-type adenocarcinoma of the stomach, characterized by low-grade cytological atypia and anastomosing glands, has been described in several reports under different names. One of the remarkable features of these lesions, herein referred to as intestinal-type adenocarcinoma with anastomosing glands, is the frequent association of poorly differentiated adenocarcinoma components. Here we analyzed 44 intestinal-type adenocarcinomas with anastomosing glands focusing on the molecular abnormalities that are common in diffuse-type gastric cancers. Next-generation sequencing identified RHOA and CDH1 mutations in 22 (50%) and one lesion (2%), respectively. Reverse transcription-PCR detected CLDN18-ARHGAP fusions in three lesions (7%). Immunohistochemically, none of the lesions showed abnormal p53 expression patterns whereas focal and diffuse loss of ARID1A was observed in four and one lesion, respectively. Examination of 37 lesions of dysplasia and 26 usual-type intramucosal adenocarcinomas identified one RHOA mutation in adenocarcinoma and no CLDN18-ARHGAP fusions, indicating that these genetic alterations are highly specific to intestinal-type adenocarcinomas with anastomosing glands among differentiated-type intramucosal neoplasms. The present study showed that intestinal-type adenocarcinoma with anastomosing glands represents a genetically distinct group of tumors with the frequent presence of RHOA mutations and CLDN18-ARHGAP fusions, which are thought to be specific to diffuse-type gastric cancers.

P1.11-02 Pathologic Comparison of Prevalent vs. Incident CT Lung Screen Detected Cancer in NCCN High-Risk Subjects: Are They Different?

CT lung screening (CTLS) detects two overlapping but potentially distinct groups of tumors. Prevalent tumors, found at baseline screening, are thought to be enriched with slow-growing, potentially indolent cancers while incident tumors, found on annual repeat scans, are thought to be more uniformly fast-growing and aggressive. Pathologically, squamous cell carcinomas, small cell carcinomas (SCC) and large cell neuroendocrine carcinomas (LCNEC) are uniformly fast-growing and aggressive while adenocarcinomas are more heterogenous in their growth-rates, behavior and histology. By comparing pathologic subtypes, I-ELCAP investigators reported a higher frequency of adenocarcinomas compared to squamous cell carcinomas in prevalent compared to incident tumors (ratio 8:1 vs. 3.4:1) and conversely a 4-fold lower frequency of SCC/LCNEC (7% vs. 30%, respectively). Based partly on these data, some worry about the risk of over diagnosis in CTLS subjects undergoing baseline screening in which the proportion of slow-growing potentially indolent adenocarcinomas may be enriched. Current guidelines recommend screening specific high-risk subjects for which pathologic comparisons of prevalent and incident cancers have not been thus far described. The pathology of 134 CTLS cancers detected at Lahey Hospital and Medical Center was reviewed, including 93 detected at baseline and 41 at annual repeat screening. All individuals met the NCCN Guidelines Lung Cancer Screening v1.2012 high-risk criteria, were asymptomatic, had no known metastatic disease and were free of lung cancer for at least 5-years. Detailed pathologic analysis was performed for 65 stage I resected adenocarcinomas whereas lineage alone was determined for the cytologically diagnosed tumors. The proportion of adenocarcinomas to squamous cell carcinomas was similar in prevalent compared to incident tumors (ratio 2.6:1 vs. 3.1:1). Small cell carcinomas were only half as frequent among prevalent vs. incident cancers (5% vs. 12%). Among stage I adenocarcinomas, a similar proportion of prevalent vs. incident cancers exhibited a ≥5% solid pattern (32% vs. 30%), ≥5% micropapillary pattern (23% vs. 22%), ≥10% cribriform pattern (30% vs. 26%), intermediate/high mitotic grade (57% vs. 57%), angiolymphatic invasion (43% vs. 48%), and STAS (36% vs. 39%). Visceral pleural invasion was actually higher in the prevalent cancers (27% vs. 17%) however no statistically significant differences were observed. Pathologic comparison of prevalent vs. incident CTLS cancers among NCCN defined high-risk subjects reveals less variability than previously described by I-ELCAP. In particular, histologically indolent adenocarcinomas are not enriched in prevalent compared to incident tumors and thus the risk of over diagnosis in baseline detected cancers may be less than once thought.

Histopathology of Neuroendocrine Neoplasms of the Gastrointestinal System

Tumors arising from neuroendocrine cells are defined as epithelial neoplasms with predominantly neuroendocrine differentiation. They comprise a distinct group of tumors with a characteristic histological structure and functional properties that develop at various sites, particularly the gastrointestinal system (67%) and lungs (25%). Although such tumors are usually slow-growing and indolent, almost all have malignant potential and most can produce active hormones. Clinical signs vary, and many are dependent on the site at which the tumor develops. Although these tumors were identified more than 130 years, their classification remains unclear. This review provides a comprehensive overview of the human neuroendocrine system and its neoplasms, from their discovery to current terminology and classifications. In addition, the clinical symptomatology and macroscopic/microscopic features of tumors arising from endocrine cells of the gastrointestinal tract are described, with an emphasis on their classification, diagnostic criteria for their grading and TNM (tumor, node, metastasis) staging, and how these tumors differ according to their localization in the gastrointestinal tract. Tumors arising from neuroendocrine cells are rare and can cause typical symptoms of carcinoid syndrome. However, most of these tumors are asymptomatic, which, together with their typical small size and localization in the gut, makes them difficult to access endoscopically and often leads to diagnosis at an advanced stage. To successfully diagnose and treat tumors arising from neuroendocrine cells, they should be assessed using a differential diagnostic procedure and be histopathologically classified, graded, and staged according to specified criteria and the latest classifications and guidelines. Although the terms "carcinoid", "neuroendocrine tumor", and "neuroendocrine carcinoma" are often used synonymously in the literature and by professionals, more precise terminology is required for nomenclature and classification. Key words: gastrointestinal neuroendocrine neoplasms - neuroendocrine tumors - neuroendocrine carcinomas - classification - NET - NEC The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 3. 2018 Accepted: 16. 4. 2018.

Local network component analysis for quantifying transcription factor activities.

LNCA was implemented as a Matlab package, which is available at http://sysbio.sibcb.ac.cn/cb/chenlab/software.htm/LNCApackage_0.1.rar.

Recurrent fusion transcripts in squamous cell carcinomas of the vulva.

Juxtaposition of two different genes or gene parts due to chromosomal rearrangement is a well-known neoplasia-associated pathogenetic mechanism. The detection and characterization of such tumorigenic fusions is of great importance both research-wise, diagnostically because they may be specific for distinct tumor entities, and because they may serve as therapeutic targets for antioncogenic drugs that interact directly with the molecular changes responsible for neoplastic transformation.At present, more than 10,000 fusion transcripts have been reported in different types of neoplasia, with one tenth of them being identified in squamous cell carcinomas (SCC) of different locations. No recurrent fusion gene has to date been identified in SCC of the vulva.We performed high-throughput paired-end RNA-sequencing of 12 vulvar SCC and found two recurrent fusions with the STIP1-CREB3L1 and ZDHHC5-GPR137 being present in two tumors each. The transcripts were detected only in the tumor samples, not in normal vulvar tissue from healthy donors used as control. The CREB3L1 and ZDHHC5 genes encode proteins involved in transcription suggesting that the chimeras may alter downstream events in their respective pathways. Expression analysis of the CREB3L1 gene showed the presence of two distinct groups of tumors, one having fusion and downregulation of the gene and the other showing upregulation of CREB3L1.

Expression Patterns of Growth and Survival Genes with Prognostic Implications in Advanced Pancreatic Cancer.

The aim of this study was to evaluate the mRNA expression pattern of growth- and survival-related genes and assess their prognostic significance in patients with advanced pancreatic cancer. In total, 98 patients were included in this retrospective translational research study and were evaluated for Kirsten rat sarcoma viral oncogene homolog (KRAS) mutational status, and v-akt murine thymoma viral oncogene homolog 1 (AKT1), AKT serine/threonine kinase 2 (AKT2), AKT serine/threonine kinase 3 (AKT3), cyclin D1 (CCND1), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), hepatocellular growth factor receptor (MET), avian myelomatosis viral oncogene homolog (MYC), nuclear factor kappa B subunit 1 (NFKb1), phosphatase and tensin homolog (PTEN) and mechanistic target of rapamycin (FRAP1) genes mRNA expression. Among these patients, 73 received first-line gemcitabine combined with erlotinib (N=57) or gefitinib (N=16). KRAS mutation did not correlate with mRNA gene expression. Unsupervised hierarchical clustering according to mRNA gene expression successfully distinguished four prognostically distinct groups of tumors. Overexpression of all genes was associated with best prognosis, while suppression or heterogeneous expression patterns of the examined genes were associated with expression patterns of growth- and survival-related genes, classifying pancreatic tumors into distinct groups with possibly different outcomes.

Quantitative imaging analysis of posterior fossa ependymoma location in children.

Imaging descriptions of posterior fossa ependymoma in children have focused on magnetic resonance imaging (MRI) signal and local anatomic relationships with imaging location only recently used to classify these neoplasms. We developed a quantitative method for analyzing the location of ependymoma in the posterior fossa, tested its effectiveness in distinguishing groups of tumors, and examined potential associations of distinct tumor groups with treatment and prognostic factors. Pre-operative MRI examinations of the brain for 38 children with histopathologically proven posterior fossa ependymoma were analyzed. Tumor margin contours and anatomic landmarks were manually marked and used to calculate the centroid of each tumor. Landmarks were used to calculate a transformation to align, scale, and rotate each patient's image coordinates to a common coordinate space. Hierarchical cluster analysis of the location and morphological variables was performed to detect multivariate patterns in tumor characteristics. The ependymomas were also characterized as "central" or "lateral" based on published radiological criteria. Therapeutic details and demographic, recurrence, and survival information were obtained from medical records and analyzed with the tumor location and morphology to identify prognostic tumor characteristics. Cluster analysis yielded two distinct tumor groups based on centroid location The cluster groups were associated with differences in PFS (p=.044), "central" vs. "lateral" radiological designation (p=.035), and marginally associated with multiple operative interventions (p=.064). Posterior fossa ependymoma can be objectively classified based on quantitative analysis of tumor location, and these classifications are associated with prognostic and treatment factors.

American Brain Tumor Association Adolescent and Young Adult Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012.

Brain and central nervous system (CNS) tumors found in adolescents and young adults (AYA) are a distinct group of tumors that pose challenges not only to treatment but also to reporting. Overall, cancer that occurs in this age group is biologically distinct from those that occur in both younger and older age groups1,2 posing significant challenges for clinicians. The most commonly diagnosed histologies in AYA vary from those in both children age (0-14 years), and older adults (40+ years).3,4 Prognosis and expected survival also varies between younger and older adults, with those who are diagnosed with brain and CNS tumors at younger ages having significantly longer survival. Despite this survival advantage, recent analyses have reported that while cancer survival has been improving overall, AYA have not experienced these same increases in survival and in some cases may have worse survival than those cancers diagnosed in persons over age 40 years.5 This report provides an in depth analyses of the epidemiology of brain and CNS tumors in adolescents and young adults in the United States (US), and is the first report to provide histology-specific statistics in this population for both malignant and non-malignant brain and other CNS tumors. In 2006, the National Institutes of Health, the National Cancer Institute (NCI) and the LiveStrong Young Adult Alliance conducted a Progress Review Group to investigate AYA Oncology entitled Research and care imperatives for adolescents and young adults with cancer: A Report of the Adolescent and Young Adult Oncology Progress Review Group. This group established the standard age range for the AYA group as 15-39 years. This is the age range used by the Surveillance Epidemiology and End Results (SEER) program of the NCI, as well as in the 2015 CBTRUS Statistical Report.3,6 Brain tumors and other CNS tumors are less common in AYA than in older adults, but they have a higher incidence than brain tumors in children (age 0-14 years).3 Non-malignant tumors are significantly more common in AYA than children (Average annual age adjusted incidence in age 15-39 years: 6.17 per 100,000; age 0-14 years: 0.79 per 100,000), while malignant tumors are slightly more common in those age 0-14 years (Average annual age adjusted incidence in 15-39 years old: 3.26 per 100,000; 0-14 years old: 3.73 per 100,000). While a rare cancer overall, brain and CNS tumors are among the most common cancers occurring in this age group (4.4% of all cancers in those age 15-39 years as compared to 32.4% in children age 0-14 years, and 2.2% of cancers in adults age 40+ years).3,4,7 Malignant brain and CNS tumors are the 11th most common cancer and the 3rd most common cause of cancer death7,8 in the AYA population. Incidence rates of brain tumors overall as well as specific histologies vary significantly by age. It is, therefore, important to provide an accurate statistical assessment of brain and other CNS tumors in the adolescent and young adult population to better understand their impact on the US population and to serve as a reference for afflicted individuals, for researchers investigating new therapies and for clinicians treating patients.

EPID-05EPIDEMIOLOGY OF BRAIN AND CENTRAL NERVOUS SYSTEM TUMORS IN ADOLESCENTS AND YOUNG ADULTS IN THE UNITED STATES

BACKGROUND: Brain and central nervous system (CNS) tumors in adolescents and young adults (AYA) are a distinct group of tumors that pose challenges to treatment and reporting. Cancer that occurs in this age group is biologically distinct from those in other age groups and poses significant challenges for clinicians. While cancer survival has been improving overall, AYA have not experienced these same increases and in some cases may have worse survival than those over 40 years. METHODS: Using data from 51 central cancer registries from 2007-2011, we calculated the average annual age-adjusted incidence rates (AAIR) per 100,000 population of brain and CNS tumors in AYA by histologic type. We also calculate the relative survival after diagnosis using data from 18 SEER registries from 1995-2011. RESULTS: Approximately 15% of all brain and CNS tumors occur in the AYA age group, 51,118 total tumors from 2007-2011. The most common histologies are tumors of the pituitary (AAIR: 2.90), meningioma (AAIR: 1.68), and nerve sheath tumors (AAIR: 0.88). Gliomas account for ∼29% of all tumors. AYA have higher rates of relative survival than adults 40+ for all histologic types. One-year relative survival for most tumor types is higher for AYA than children <15 years old, but 10-year survival is usually higher for children as compared to AYA. CONCLUSION: Brain tumors are a significant source of cancer-related morbidity and mortality in adolescents and young adults. This age group is diagnosed with unique groups of cancers that require separate reporting in order to accurately portray their impact in these populations.

Abstract 1120: Glioblastoma whole transcriptome analysis: molecular mechanisms related to recurrence-free survival (RFS)

Abstract Introduction. Diffusely infiltrating astrocytomas represent the most frequent intracranial neoplasms, with the glioblastoma (GB) as the most malignant phenotypic endpoint. Surgical resection, radiotherapy and adjuvant chemotherapy currently represent the standard of care for this disease. From a practical perspective, controlling growth and spreading of the recurrence may have a great impact on disease-free survival. The invasive nature of glioblastoma cells represents a major cause of therapeutic failure, so clarification of the molecular mechanisms associated with cellular migration and invasion is crucial to allow better prediction of these patient. Our study had the intent to provide novel information on glioblastoma behavior, with regard to the type of genetic changes involved in length of recurrence free survival time. Materials and Methods. We used whole-transcriptome RNA sequencing (Ion Proton system) to analyze 12 primary formalin fixed, paraffin embedded GBs specifically selected for different length of time of first recurrence. Results. A total of 83 genes resulted to have a statistical significant differential expression, which allowed us to distinguish three distinct groups of tumors with different recurrence free survival times: the short term group (S) with recurrence free survival time less than 6 months (n = 6), the medium group (M) between 16 and 23 months (n = 3), and the long term group (L) with more than 25 months (n = 3). Gene expression comparison analysis identified 51, 21, 26 significant genes between L/S, L/M and S/M respectively. Interestingly the highest number of genes differentialy expressed was found between the two extreme groups (S vs L). Two genes, BOD1L1 and GLUD2 were identified as significantly upregulated in the L group. Conclusions. The analysis of the whole transcriptome of GBs, with different recurrence free survival time, revealed that many of the genes that seem to be related to time of recurrence, after first surgery, are involved in the epigenetic landscape of the transcriptional potential of the cell such as histone and miRNA expression dis-regulation. Two genes were confirmed such as BOD1L1, which is mostly unknown and seems to be involved in the bio-orientation of chromosomes, and the mitochondrial enzyme GLUD2 which has been recently reported as involved in glioma growth. Moreover, some of the upregulated genes, in the group with the worst prognosis, had been related to the Rho family of GTPases which are key mediators of GB invasion. More thorough analyses are ongoing. A comprehensive better understanding of the molecular mechanisms underlying GB recurrence free survival would make a long step forward in the improvement of the clinical management of patients with such deadly disease. Citation Format: Sara Franceschi, Francesca Lessi, Paolo Aretini, Francesco G. Carbone, Cristian Scatena, Marco La Ferla, Valerio Ortenzi, Riccardo Vannozzi, Generoso Bevilacqua, Antonio G. Naccarato, Chiara M. Mazzanti. Glioblastoma whole transcriptome analysis: molecular mechanisms related to recurrence-free survival (RFS). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1120. doi:10.1158/1538-7445.AM2015-1120

Abstract 5270: IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas

Abstract Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II-III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and wild-type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR) = 1.21, 95% confidence interval (CI) = 0.91-1.61] compared to IDH-wild type tumors (HR = 1.74, 95% CI = 0.95-3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank p&amp;lt;0.01, HR = 4.41, 95% CI = 2.55-7.63), it was not associated with outcome in IDH-mutant tumors (log-rank p = 0.471, HR = 1.10, 95% CI = 0.80-1.51), and could demonstrate a statistical interaction (p&amp;lt;0.01) between IDH mutation and mitotic index. Patient age, an established prognostic factor in diffuse glioma, was associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II-III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II-II gliomas as independent entities. Citation Format: Adriana Olar, Khalida Wani, Kristin Diefes, Lindsey Heathcock, Hinke van Thuijl, Mark Gilbert, Terri Armstrong, Erik Sulman, Daniel Cahill, Jaap Reijneveld, Bauke Ylstra, Pieter Wesseling, Kenneth Aldape. IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5270. doi:10.1158/1538-7445.AM2015-5270

Myoepithelioma-like Tumors of the Vulvar Region: A Distinctive Group of SMARCB1-deficient Neoplasms.

We describe 9 tumors that resemble soft tissue myoepitheliomas but possess certain traits that do not fit perfectly into this category. These tumors, herein referred to as "myoepithelioma-like tumors of the vulvar region," occurred in the subcutis of the vulva and surrounding regions of adult women aged 24 to 65 years. Histologically, the tumors measured 2 to 7.7 cm and were well circumscribed, focally encapsulated, and lobulated. Tumor cells had an epithelioid to spindled shape, with fine amphophilic cytoplasm, and uniform nuclei with vesicular chromatin and nucleoli. The tumor stroma was relatively hypervascular, and comprised a mixture of myxoid and nonmyxoid components. Myxoid areas accounted for <5% to 95% of the tumor volume, wherein cells proliferated singly or in a loosely cohesive manner. In nonmyxoid areas, tumors cells grew in diffuse sheets or storiform arrangements. Immunohistochemically, all tested tumors were positive for vimentin, epithelial membrane antigen, and estrogen receptor; most tumors expressed actin. All tumors were negative for S100 protein, glial fibrillary acidic protein, and CD34. Cytokeratin expression was absent in all but 2 tumors, which showed rare positivity. SMARCB1 expression was deficient in all cases. EWSR1, FUS, and NR4A3 rearrangements were absent. All tumors were treated through surgery. Although 3 tumors regrew or recurred after intralesional excision, all 9 patients were alive without metastases at a mean follow-up of 66 months. Myoepithelioma-like tumors of the vulvar region constitute a distinct group of tumors, although future research is required to determine whether they are an unusual subtype of soft tissue myoepitheliomas or a separate disease.

Transcript Profiling Distinguishes Complete Treatment Responders With Locally Advanced Cervical Cancer

Cervical cancer (CC) mortality is a major public health concern since it is the second cause of cancer-related deaths among women. Patients diagnosed with locally advanced CC (LACC) have an important rate of recurrence and treatment failure. Conventional treatment for LACC is based on chemotherapy and radiotherapy; however, up to 40% of patients will not respond to conventional treatment; hence, we searched for a prognostic gene signature able to discriminate patients who do not respond to the conventional treatment employed to treat LACC. Tumor biopsies were profiled with genome-wide high-density expression microarrays. Class prediction was performed in tumor tissues and the resultant gene signature was validated by quantitative reverse transcription–polymerase chain reaction. A 27-predictive gene profile was identified through its association with pathologic response. The 27-gene profile was validated in an independent set of patients and was able to distinguish between patients diagnosed as no response versus complete response. Gene expression analysis revealed two distinct groups of tumors diagnosed as LACC. Our findings could provide a strategy to select patients who would benefit from neoadjuvant radiochemotherapy-based treatment.