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Interest in understanding the high chemoresistance and poor prognosis of advanced ovarian clear cell carcinoma (OCCC) is rising. Patient-derived xenografts (PDX) are widely used in vivo models because of their supposedly accurate morphologic and (epi)genetic representation of patient tumors. Here, we established five subcutaneous OCCC PDXs. The PDX.F1 engraftment success rate was over 30% with similar latency time and growth speed of PDX.F2. ARID1A, PTEN, ATM, BRCA1 and PIK3CA mutations were found in matched tumors and PDXs. ARID1A protein loss was further verified by immunohistochemical staining. Cyclophilin A staining depicted the replacement of human stroma by mouse stroma in PDX.F2, while PAS/PAS-D staining confirmed cellular glycogen accumulation in OCCC tumors and PDXs. SNP array and Infinium MethylationEPIC BeadChip array data analysis demonstrated the copy number alterations and DNA methylation signatures of genome-wide and tumor-driver genes in PDXs generally resembled their patients' tumors. Promoter CpG islands of a small number of genes, enriched in PRC2/histone methylation related gene-sets, gained methylation (△β-value > 0.4) in PDXs vs patient tumors. In conclusion, the high phenotypic and molecular similarity allows the established PDXs to serve as potential preclinical models for future translational research of OCCC. [ABSTRACT FROM AUTHOR]

Purpose: To perform a molecular profiling of the metastases from papillary thyroid carcinomas (PTCs) and poorly differentiated thyroid carcinomas (PDTCs). Methods: We retrieved and analyzed the molecular and clinical features of 136 metastases from PTCs and 35 metastases from PDTCs subjected to targeted DNA sequencing, from cBioPortal. The clinicopathological data included the number and location of the metastases, and genomic data included mutations, translocations, copy number alterations and fraction of the genome altered (FGA). Results: Bone metastases from PTCs had a lower frequency of BRAF mutations than the lymph node metastases (LNMs) (43% vs 88%, p < 0.01), and a higher frequency of RBM10 and NRAS mutations than the LNMs (21% vs 3% for both, p < 0.05). The FGA of the bone metastases was higher than the FGA of the lung metastases (5.6% vs 1.3%, p < 0.05). The frequency of RET translocations was higher in the lung metastases from PTCs than the LNMs (15% vs 3%, p < 0.05). The LNMs from PTC patients harboring 4 or more distant metastases (DMs) had a higher frequency of TERT promoter mutations than the LNMs from patients harboring less than 4 DMs (96% vs 65%, p < 0.001). SDHA gene amplifications were enriched in the bone metastases from PDTCs and absent in the LNMs (38% vs 0%, p < 0.05). Conclusion: Metastases from PTCs and PDTCs harbor clinically relevant alterations affecting distinct body locations, such as NRAS and RBM10 mutations, RET translocations and SDHA amplifications that may be explored therapeutically. [ABSTRACT FROM AUTHOR]

Chromosomal Instability (CIN) is a common and evolving feature in breast cancer. Large-scale Transitions (LSTs), defined as chromosomal breakages leading to gains or losses of at least 10 Mb, have recently emerged as a metric of CIN due to their standardized definition across platforms. Herein, we report the feasibility of using low-pass Whole Genome Sequencing to assess LSTs, copy number alterations (CNAs) and their relationship in individual circulating tumor cells (CTCs) of triple-negative breast cancer (TNBC) patients. Initial assessment of LSTs in breast cancer cell lines consistently showed wide-ranging values (median 22, range 4–33, mean 21), indicating heterogeneous CIN. Subsequent analysis of CTCs revealed LST values (median 3, range 0–18, mean 5), particularly low during treatment, suggesting temporal changes in CIN levels. CNAs averaged 30 (range 5–49), with loss being predominant. As expected, CTCs with higher LSTs values exhibited increased CNAs. A CNA-based classifier of individual patient-derived CTCs, developed using machine learning, identified genes associated with both DNA proliferation and repair, such as RB1, MYC, and EXO1, as significant predictors of CIN. The model demonstrated a high predictive accuracy with an Area Under the Curve (AUC) of 0.89. Overall, these findings suggest that sequencing CTCs holds the potential to facilitate CIN evaluation and provide insights into its dynamic nature over time, with potential implications for monitoring TNBC progression through iterative assessments. [ABSTRACT FROM AUTHOR]

Liquid biopsy has recently emerged as an important tool in clinical practice particularly for lung cancer patients. We retrospectively evaluated cell-free DNA analyses performed at our Institution by next generation sequencing methodology detecting the major classes of genetic alterations. Starting from the graphical representation of chromosomal alterations provided by the analysis software, we developed a support vector machine classifier to automatically classify chromosomal profiles as stable (SCP) or unstable (UCP). High concordance was found between our binary classification and tumor fraction evaluation performed using shallow whole genome sequencing. Among clinical features, UCP patients were more likely to have ≥ 3 metastatic sites and liver metastases. Longitudinal assessment of chromosomal profiles in 33 patients with lung cancer receiving immune checkpoint inhibitors (ICIs) showed that only patients that experienced early death or hyperprogressive disease retained or acquired an UCP within 3 weeks from the beginning of ICIs. UCP was not observed following ICIs among patients that experienced progressive disease or clinical benefit. In conclusion, our binary classification, applied to whole copy number alteration profiles, could be useful for clinical risk stratification during systemic treatment for non-small cell lung cancer patients. [ABSTRACT FROM AUTHOR]

This review investigates the role of aneuploidy and chromosome instability (CIN) in the aging brain. Aneuploidy refers to an abnormal chromosomal count, deviating from the normal diploid set. It can manifest as either a deficiency or excess of chromosomes. CIN encompasses a broader range of chromosomal alterations, including aneuploidy as well as structural modifications in DNA. We provide an overview of the state-of-the-art methodologies utilized for studying aneuploidy and CIN in non-tumor somatic tissues devoid of clonally expanded populations of aneuploid cells. CIN and aneuploidy, well-established hallmarks of cancer cells, are also associated with the aging process. In non-transformed cells, aneuploidy can contribute to functional impairment and developmental disorders. Despite the importance of understanding the prevalence and specific consequences of aneuploidy and CIN in the aging brain, these aspects remain incompletely understood, emphasizing the need for further scientific investigations. This comprehensive review consolidates the present understanding, addresses discrepancies in the literature, and provides valuable insights for future research efforts. [ABSTRACT FROM AUTHOR]

Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2Ahigh) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression. These findings support the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas with potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Next-generation sequencing (NGS) has enabled comprehensive genomic profiling to identify gene alterations that play important roles in cancer biology. However, the clinical significance of these genomic alterations in triple-negative breast cancer (TNBC) patients has not yet been fully elucidated. The aim of this study was to clarify the clinical significance of genomic profiling data, including copy number alterations (CNA) and tumor mutation burden (TMB), in TNBC patients. Methods: A total of 47 patients with Stage I–III TNBC with genomic profiling of 435 known cancer genes by NGS were enrolled in this study. Disease-free survival (DFS) and overall survival (OS) were evaluated for their association to gene profiling data. Results: CNA-high patients showed significantly worse DFS and OS than CNA-low patients (p = 0.0009, p = 0.0041, respectively). TMB was not associated with DFS or OS in TNBC patients. Patients with TP53 alterations showed a tendency of worse DFS (p = 0.0953) and significantly worse OS (p = 0.0338) compared with patients without TP53 alterations. Multivariable analysis including CNA and other clinicopathological parameters revealed that CNA was an independent prognostic factor for DFS (p = 0.0104) and OS (p = 0.0306). Finally, multivariable analysis also revealed the combination of CNA-high and TP53 alterations is an independent prognostic factor for DFS (p = 0.0005) and OS (p = 0.0023). Conclusions: We revealed that CNA, but not TMB, is significantly associated with DFS and OS in TNBC patients. The combination of CNA-high and TP53 alterations may be a promising biomarker that can inform beyond standard clinicopathologic factors to identify a subgroup of TNBC patients with significantly worse prognosis. [ABSTRACT FROM AUTHOR]

B cell lineage acute lymphoblastic leukemia is the most common leukemia occurring in children and young adults and is the leading cause of cancer related deaths. The 5 year overall survival outcome in children with B-ALL has improved significantly in the last few decades. In the past, the discovery of various genetic alterations and targeted therapy have played a major role in decreasing disease-related deaths. In addition, numerous advances in the pathogenesis of B-ALL have been found which have provided better understanding of the genes involved in disease biology with respect to diagnostic and prognostic implications. Present review will summarize current understanding of risk stratification, genetic factors including cytogenetics in diagnosis and prognosis of B-ALL. [ABSTRACT FROM AUTHOR]

Purpose of Review: The high prevalence of relapse in pediatric B-lineage acute lymphoblastic leukemia (B-ALL) despite the improvements achieved using current risk stratification schemes, demands more accurate methods for outcome prediction. Here, we provide a concise overview about the key advances that have expanded our knowledge regarding the somatic defects across B-ALL genomes, particularly focusing on copy number alterations (CNAs) and their prognostic impact. Recent Findings: The identification of commonly altered genes in B-ALL has inspired the development of risk classifiers based on copy number states such as the IKZF1plus and the United Kingdom (UK) ALL-CNA classifiers to improve outcome prediction in B-ALL. Summary: CNA-risk classifiers have emerged as effective tools to predict disease relapse; though, their clinical applications are yet to be transferred to routine practice. [ABSTRACT FROM AUTHOR]

Purpose: Choroid plexus tumors comprise of choroid plexus papilloma (CPP, WHO grade I), atypical choroid plexus papilloma (aCPP, WHO grade II) and choroid plexus carcinoma (CPC, WHO grade III). Molecular events driving the majority of choroid plexus tumors remain poorly understood. Recently, DNA methylation profiling has revealed different epigenetic subgroups. Methods: Comprehensive review of epigenetic profiles of choroid plexus tumors in the context of histopathological, genetic, and clinical features. Summary: DNA methylation profiling segregates choroid plexus tumors into three distinct epigenetic subgroups: supratentorial pediatric low-risk choroid plexus tumors (CPP and aCPP), infratentorial adult low-risk choroid plexus tumors (CPP and aCPP), and supratentorial pediatric high-risk choroid plexus tumors (CPP and aCPP and CPC). Epigenetic subgrouping provides additional prognostic information in comparison to histopathological grading. Conclusions: Epigenetic profiling of choroid plexus tumors can be used for the identification of patients at risk of recurrence and is expected to play a role for treatment stratification and patient management in the context of future clinical trials. [ABSTRACT FROM AUTHOR]

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As shown by genomic studies, colorectal cancer (CRC) is a highly heterogeneous disease, where copy number alterations (CNAs) may greatly vary among different patients. To explore whether CNAs may be present also in histologically normal tissues from patients affected by CRC, we performed CGH + SNP Microarray on 15 paired tumoral and normal samples. Here, we report for the first time the occurrence of CNAs as a common feature of the histologically normal tissue from CRC patients, particularly CNAs affecting different oncogenes and tumor-suppressor genes, including some not previously reported in CRC and others known as being involved in tumor progression. Moreover, from the comparison of normal vs paired tumoral tissue, we were able to identify three groups: samples with an increased number of CNAs in tumoral vs normal tissue, samples with a similar number of CNAs in both tissues, and samples with a decrease of CNAs in tumoral vs normal tissue, which may be likely due to a selection of the cell population within the tumor. In conclusion, our approach allowed us to uncover for the first time an unexpected frequency of genetic alteration in normal tissue, suggesting that tumorigenic genetic lesions are already present in histologically normal colonic tissue and that the use in array comparative genomic hybridization (CGH) studies of normal samples as reference for the paired tumors can lead to misrepresented genomic data, which may be incomplete or limited, especially if used for the research of target molecules for personalized therapy and for the possible correlation with clinical outcome. [ABSTRACT FROM AUTHOR]

A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15 % or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a leading cause of morbidity and mortality in women worldwide. About 70 % of breast cancers are estrogen receptor (ER) positive. Blocking estrogen action by tamoxifen has been the treatment of choice in ER positive breast cancers for more than 30 years. In the past, several studies have revealed associations between gene copy number alterations and responsiveness to tamoxifen therapy, but so far no single gene copy number alteration could completely explain the response variation observed between individual breast cancer patients. Here, we set out to perform a simultaneous analysis of copy number alterations of several genes involved in the prognosis and response to therapy by multiplex ligation-dependent probe amplification (MLPA). Methods: A case-control study was designed encompassing 170 non-metastatic ER positive breast cancer patients (case group = 85, control group = 85). All patients in the control group had received standard adjuvant tamoxifen treatment for 5 years without any evidence of recurrence. Patients in the case group had experienced early recurrences while receiving tamoxifen treatment. 76 % of the patients of the case group and 73 % of the patients of the control group had received anthracycline-based adjuvant chemotherapy. Gene copy number alterations detected by MLPA in both groups were compared. Results: Amplification of CCND1 (OR = 3.13; 95 % CI = 1.35 to 7.26; p = 0.006) and TOP2A (OR = 3.05; 95 % CI = 1.13 to 8.24; p = 0.022) were significantly more prevalent in the case group, compared to the control group. In a multivariate analysis CCND1 ( p = 0.01) and TOP2A ( p = 0.041) amplifications remained significant predictors of recurrence. Conclusions: Our results indicate that CCND1 amplification may serve as a useful biomarker for hormone responsiveness, and that TOP2A amplification may serve as a useful prognostic biomarker. [ABSTRACT FROM AUTHOR]

This study was conducted to analyze copy number alterations (CNAs) of the genes involved in the G1/S checkpoint signaling pathway of triple-negative breast cancer (TNBC) and to evaluate their clinical value in the prognosis of TNBC. Quantitative multi-gene fluorescence in situ hybridization was used to study CNAs of the genes involved in the G1/S checkpoint signaling pathway, including cyclin d1 (CCND1), c-Myc, p21, cell-cycle-checkpoint kinase 2 gene, p16, retinoblastoma (Rb1), murine double minute 2 (Mdm2) and p53, in 60 TNBC samples and 60 non-TNBC samples. In comparison with the non-TNBC samples, CNAs of the genes involved in the G1/S checkpoint signaling pathway were more frequently observed in the TNBC samples ( p = 0.000). Out of a total of eight genes, six (CCND1, c-Myc, p16, Rb1, Mdm2, and p53) exhibited significantly different CNAs between the TNBC group and the non-TNBC group. Univariate survival analysis revealed that the gene amplification of c-Myc ( p = 0.008), Mdm2 ( p = 0.020) and the gene deletion of p21 ( p = 0.004), p16 ( p = 0.015), and Rb1 ( p = 0.028) were the independent predictive factor of 5-year OS for patients with TNBC. Cox multivariate analysis revealed that the gene amplification of c-Myc ( p = 0.026) and the gene deletion of p21 ( p = 0.019) and p16 ( p = 0.034) were independent prognostic factors affecting the 5-year OS for TNBC. CNAs of the genes involved in the G1/S checkpoint signaling pathway presented a higher rate of incidence in TNBC than in non-TNBC, which could indicate one of the molecular mechanisms for the specific biological characteristics of TNBC. The genes c-Myc, p21, and p16 were correlated with the prognosis of TNBC and therefore may have potential clinical application values in the prognostic prediction of TNBC. [ABSTRACT FROM AUTHOR]

Decitabine is a hypomethylating agent with proven clinical efficacy in myelodysplastic syndrome (MDS). The current study analyzed the role of single nucleotide polymorphism array (SNP-A)-based karyotyping in prediction of clinical outcome in MDS or chronic myelomonocytic leukemia (CMML) patients following decitabine therapy. A total of 61 MDS/CMML patients treated with decitabine were evaluated with Genome-Wide Human SNP 6.0 Array using DNAs derived from marrow samples. The primary endpoint was the best response rate including complete (CR) and partial response (PR) with overall (OS) and event-free survival (EFS) as secondary endpoints. Best response was noted in 14 patients (26.4 %) out of 53 evaluated patients including 12 CR and two PR with median follow-up of 21.6 months. A total of 81 abnormal SNP lesions were found in 25 out of 61 patients (41.0 %). The patients carrying abnormal SNP lesions showed an inferior CR/PR rate ( p = 0.002) and showed a trend of worse OS ( p = 0.02 in univariate, p = 0.09 in multivariate) compared to those without SNP lesions, but not were associated with inferior EFS. The presence of abnormal SNP lesions in MDS was associated with adverse outcomes following decitabine therapy. Further study is strongly warranted to establish the role of SNP-A karyotyping in MDS. [ABSTRACT FROM AUTHOR]

The current study investigated molecular cytogenetic characteristics of chronic myeloid leukemia (CML) using genome-wide, single nucleotide polymorphism arrays (SNP-A) capable of detecting cryptic submicroscopic genomic aberrations. Genome-Wide Human SNP 6.0 Array (Affymetrix, CA, USA) was performed in 118 patients having CML, chronic phase. Thirty-nine clonal aberrations (CAs) were identified (35 losses, two gains, two copy neutral loss of heterozygosity) that were not detected by metaphase cytogenetics in 25 patients (21%). The 9q34 deletions were found in 10% of cases, while 22q11.2 deletions were observed in 12% of cases. Seven patients (6%) harbored both 5′-ABL and 3′-BCR deletions adjacent to the t(9;22) breakpoint. Copy number gains were identified at 8p and 9p, and losses at 2q, 7q, 8q, 9q, 11q, 13q, 16p, and 22q. When we compared the treatment outcome of imatinib therapy between patients with and without CAs identified by SNP-A, treatment failure and progression to advanced disease were not significantly different ( p > 0.05). In addition, according to the presence of deletions of 9q34 and/or 22q11.2 identified by SNP-A, the treatment outcome did not show any significant differences ( p > 0.05). Our data suggests that SNP-A analysis is a useful tool for detection of clonal aberrations including deletions adjacent to the t(9;22) breakpoint in the CML cancer genome. However, clonal aberrations detected by SNP-A could not improve a prognostic stratification in CML patients with chronic phase. [ABSTRACT FROM AUTHOR]

The outcome of treating chronic myeloid leukemia (CML) with imatinib mesylate (IM) is inferior when therapy is commenced in late chronic or accelerated phase as compared to early chronic phase. This may be attributed to additional genomic alterations that accumulate during disease progression. We sought to identify such lesions in patients showing suboptimal response to IM by performing array-CGH analysis on 39 sequential samples from 15 CML patients. Seventy-four cumulative copy number alterations (CNAs) consisting of 35 losses and 39 gains were identified. Alterations flanking the ABL1 and BCR genes on chromosomes 9 and 22, respectively, were the most common identified lesions with 5 patients losing variable portions of 9q34.11 proximal to ABL1. Losses involving 1p36, 5q31, 17q25, Y and gains of 3q21, 8q24, 22q11, Xp11 were among other recurrent lesions identified. Aberrations were also observed in individual patients, involving regions containing known leukemia-associated genes; CDKN2A/2B, IKZF1, RB1, TLX1, AFF4. CML patients in late stages of their disease, harbor pre-existing and evolving sub-microscopic CNAs that may influence disease progression and IM response. [ABSTRACT FROM AUTHOR]

Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845 Kb-96.2 Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio=12.3; P=0.005), (b) in progressive patients, class II deletions were enriched (P=0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2-49.2 Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (P<0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome. [ABSTRACT FROM AUTHOR]

Glioblastoma Multiforme (GBM) is a malignant brain cancer that develops after accumulating genomic DNA damage that often includes gene amplifications and/or deletions. These copy number changes can be a critical step in brain tumor development. To evaluate glioblastoma genomic copy number changes, we determined the genome-wide copy number alterations in 31 GBMs. Illumina Bead Arrays were used to assay 22 GBMs and Digital Karyotyping was used on 8 GBM cell lines and one primary sample. The common amplifications we observed for all 31 samples was GLI/CDK4 (22.6%), MDM2 (12.9%) and PIK3C2B/MDM4 (12.9%). In the 22 GBM tumors, EGFR was amplified in 22.7% of surgical biopsies. The most common homozygously deleted region contained CDKN2A/CDKN2B (p15 and p16) occurring in 29% of cases. This data was compiled and compared to published array CGH studies of 456 cases of GBMs. Pooling our Illumina data with published studies yielded these average amplification rates: EGFR—35.7%, GLI/CDK4—13.4%, MDM2—9.2%, PIK3C2B/MDM4—7.7%, and PDGFRA—7.7%. The CDKN2A/CDKN2B locus was deleted in 46.4% of the combined cases. This study provides a larger assessment of amplifications and deletions in glioblastoma patient populations and shows that several different copy number technologies can produce similar results. The main pathways known to be involved in GBM tumor formation such as p53 control, growth signaling, and cell cycle control are all represented by amplifications or deletions of critical pathway genes. This information is potentially important for formulating targeted therapy in glioblastoma and for planning genomic studies. [ABSTRACT FROM AUTHOR]