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PubMed2000

Diagnosis of human papillomavirus gynecologic infections.

The identification in the early 1980s of human papillomavirus (HPV) DNA in cervical carcinoma generated interest in molecular classification of the virus, and prompted studies regarding the oncogenic potential of genital HPVs. Subsequent studies confirming the presence of HPV in greater than 90% of precancerous cervical lesions and close to 100% of cervical cancers has raised concerns regarding the adequacy of Papanicolaou (Pap) smear testing for the detection of precancerous lesions/HPV infection. A variety of detection methods adjunctive to cytologic testing have been described, including detection at the macroscopic level, cerviography, colposcopy, and serologic and molecular-based HPV testing. Recently, there has been intense interest in molecular-based detection and typing of HPV-induced genital lesions. This has resulted in the development of a variety of molecular-based detection methods including Southern transfer, dot blotting, in situ hybridization, hybrid capture, and PCR-based assays. This article provides an overview of each of the molecular methods, and addresses the potential future role of molecular-based HPV testing.

Antibodies, Viral↗
PubMed2006

Cryptotrichosporon anacardii gen. nov., sp. nov., a new trichosporonoid capsulate basidiomycetous yeast from Nigeria that is able to form melanin on niger seed agar.

Five yeast isolates obtained from cashew tree flowers in Nigeria resembled Cryptococcus neoformans phenotypically by producing brown pigmented colonies on niger seed agar, expressing a capsule, and being able to grow at 37 degrees C. However, rRNA gene sequences, including the 18S rRNA gene, the D1/D2 domains of the 26S rRNA gene and the ITS1+2 regions, suggested that these yeasts form a basal lineage within the Trichosporonales (Tremellomycetidae, Hymenomycetes, Basidiomycota, Fungi). Since the isolates could not be identified with any known genus and species within the Trichosporonales, we describe them as Cryptotrichosporon anacardii gen. et sp. nov. with CBS 9551(T) (=NRRL Y-27671) as the type strain. The taxonomic conflict between phenetic and molecular classification schemes within this group of fungi is discussed, and is resolved in favor of the latter.

Agar↗
PubMed2001

Towards a novel classification of human malignancies based on gene expression patterns.

As a result of progress on the human genome project, approximately 19 000 genes have been identified and tens of thousands more tentatively identified as partial fragments of genes termed expressed sequence tags (ESTs). Most of these genes are only partially characterized and the functions of the vast majority are as yet unknown. It is likely that many genes that might be useful for diagnosis and/or prognostication of human malignancies have yet to be recognized. The advent of cDNA microarray technology now allows the efficient measurement of expression for almost every gene in the human genome in a single overnight hybridization experiment. This genomic scale approach has begun to reveal novel molecular-based sub-classes of tumours in breast carcinoma, colon carcinoma, lymphoma, leukaemia, and melanoma. In several instances, gene microarray analysis has already identified genes that appear to be useful for predicting clinical behaviour. This review discusses some recent findings using gene microarray technology and describes how this and related technologies are likely to contribute to the emergence of novel molecular classifications of human malignancies.

Breast Neoplasms↗
PubMed2026

Molecular subtyping of adrenocortical carcinoma reveals distinct subtypes with prognostic and therapeutic implications.

Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with poor survival and limited treatment options. To comprehensively characterize its molecular landscape and identify clinically relevant subtypes, we performed an integrated genomic analysis - including whole-exome sequencing, RNA sequencing, and copy number variation profiling - on 61 Chinese patients with ACC. We identified recurrent mutations in TP53 (25%), CTNNB1 (15%), ZNRF3 (10%), and MEN1 (8%). Unsupervised clustering of transcriptomic data revealed four distinct molecular subtypes: cortisol-driven (CD, 14%), immune-suppressed (IS, 40%), cell cycle-altered (CCA, 22%), and immunomodulatory (IM, 24%). The CD subtype exhibited steroidogenic pathway activation; the IS subtype showed T cell receptor downregulation and the worst disease-free survival; the CCA subtype was marked by chromosomal instability and cell cycle gene overexpression; and the IM subtype displayed enriched immune signaling and favorable outcomes. Copy number analysis further uncovered focal amplifications (e.g. TERT, CDK4) and HLA-II deletions. This study establishes a novel molecular classification of ACC, providing a framework for subtype-specific therapeutic strategies, such as CDK4/6 inhibition for CCA and immunotherapy for IM tumors, while highlighting the clinical challenges of immune-cold IS tumors.

Humans↗
PubMed1995

Detection of CBFB/MYH11 transcripts in patients with inversion and other abnormalities of chromosome 16 at presentation and remission.

The pericentric inversion of chromosome 16 [inv(16)(p13q22)] and t(16;16)(p13;q22) are chromosomal rearrangements frequently associated with AML FAB type M4Eo resulting in the production of a fusion gene CBFB/MYH11. We studied 17 patients with a chromosome 16 abnormality (eight M4Eo, two M1, one M2, three M4 without abnormal eosinophils, three MDS) for the presence of CBFB/MYH11 transcripts using an RT-PCR technique. 10 AML patients with inv(16) tested RT-PCR positive (eight at presentation, one in remission, one in remission and relapse). Three of these patients were originally reported by cytogenetic analysis to have del(16q22) but the positive RT-PCR results prompted a cytogenetic re-examination, resulting in the correction of the reports to inv(16). We show that although inv(16) is closely associated with AML M4Eo, it can also be detected in cases of AML M4 without abnormal eosinophils. Three cases of MDS with inv(16) were also RT-PCR positive. Four patients with other chromosome 16 abnormalities were RT-PCR negative. Four AML patients with inv(16) were studied in remission. All were RT-PCR positive, including one patient in remission for 108 months and one 22 months post allogeneic bone marrow transplant. In the latter two remission patients, RT-PCR evaluation was positive in bone marrow (BM) but not in peripheral blood, suggesting that BM may be the more informative. We conclude that this technique is valuable in the accurate molecular classification of AML, particularly as treatment options may be influenced by such information. Though RT-PCR is highly sensitive in detecting CBFB/MYH11 fusion transcripts during remission, monitoring of minimal residual disease in patients with inv(16) remains to be established.

Acute Disease↗
PubMed2004

Expression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes.

PURPOSE: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. EXPERIMENTAL DESIGN: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. RESULTS: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-kappaB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. CONCLUSIONS: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.

Cell Survival↗
PubMed2000

Relevance of presenting white blood cell count and kinetics of molecular remission in the prognosis of acute myeloid leukemia with CBFbeta/MYH11 rearrangement.

BACKGROUND AND OBJECTIVES: The detection of CBFbeta/MYH11 transcripts by RT-PCR has became a valuable and widely used technique in the accurate cytogenetic and molecular classification of acute myeloid leukemia (AML), but the clinical value of RT-PCR for monitoring minimal residual disease (MRD) during follow-up remains unclear. DESIGN AND METHODS: We analyzed the factors predicting relapse and the value of MRD monitoring by RT-PCR in a series of 16 patients with CBFb/MYH11-positive AML (15 M4Eo; 1 M4). Fifteen were newly diagnosed cases (CR1) and one was studied after first relapse (CR2). Eight patients had clinical relapse at 6 to 19 months from the achievement of CR. RESULTS: Presenting WBC count had a significant prognostic influence on disease-free survival (p=0.001). All four patients with a WBC count >100x10(9)/L relapsed, while only four additional relapses occurred among the eleven patients who had an initial WBC count below 100x10(9)/L. With regards to molecular monitoring, all relapses but one occurred in patients who showed persistent RT-PCR positivity during hematologic remission. By contrast, conversion to a repeatedly PCR-negative status was observed in the seven patients who remained in CR1 after a median follow-up of 48 months (range 31-79 months), as well as in the transplanted patient who was monitored in CR2. In these patients a PCR-positivity could be detected up to 24 months after diagnosis (median time to conversion to PCR-negative: 8 months). INTERPRETATION AND CONCLUSIONS: In conclusion, marked hyperleukocytosis (>100x10(9)/L) confers poor prognosis to the patient with CBFbeta/MYH11-positive AML. In addition, slow kinetics of molecular remission was observed in this subset of AML, but the CBFb/MYH11 fusion transcript is no longer detectable in long-term survivors, indicating that molecular remission is an important therapeutic goal.

Acute Disease↗
PubMed2006

Analysis of needle versus open biopsy for the diagnosis of advanced stage pediatric neuroblastoma.

BACKGROUND: Adequate tissue biopsy is necessary for the appropriate diagnosis and risk stratification of pediatric neuroblastoma (NB). We compared the quality and adequacy of biopsy tissue and complication rates in children with NB who underwent open (OBX) and image-guided needle biopsy (NBX) at our center. METHODS: We retrospectively reviewed all patients diagnosed with stage III and IV NB from September 2001 to August 2004. The 24 patients were divided into two groups: those in whom the diagnosis was initiated using NBX, and those diagnosed using OBX. In addition to demographic data, we collected data pertaining to sufficiency of biopsy tissue for biology studies including: Shimada Classification, MYC-N amplification, and DNA index analysis and complications associated with the procedure. Chi-Square and Student's t-test were used to analyze the categorical and continuous variables, respectively. RESULTS: Of 24 patients, 11 underwent NBX, and 13 patients underwent OBX. Eighteen patients had stage IV disease, 5 patients had stage III disease, and 1 stage IVS. Ten major complications occurred in four NBX patients and six OBX patients. There was no difference in days of narcotic use, time to DAT, or hospital stay between the two groups. Ten patients (seven NBX and three OBX, P = 0.045) had tissue that was insufficient for biology studies. Three of the seven NBX patients underwent a second biopsy for clarification of risk group. CONCLUSIONS: This study demonstrated that more than half of patients undergoing NBX for NB had insufficient tissue for complete histological and molecular classification and that the incidence of procedural complications between NBX and OBX are similar.

Biopsy↗
PubMed2005

Tissues from population-based cancer registries: a novel approach to increasing research potential.

Population-based cancer registries, such as those included in the Surveillance, Epidemiology, and End-Results (SEER) Program, offer tremendous research potential beyond traditional surveillance activities. We describe the expansion of SEER registries to gather formalin-fixed, paraffin-embedded tissue from cancer patients on a population basis. Population-based tissue banks have the advantage of providing an unbiased sampling frame for evaluating the public health impact of genes or protein targets that may be used for therapeutic or diagnostic purposes in defined communities. Such repositories provide a unique resource for testing new molecular classification schemes for cancer, validating new biologic markers of malignancy, prognosis and progression, assessing therapeutic targets, and measuring allele frequencies of cancer-associated genetic polymorphisms or germline mutations in representative samples. The assembly of tissue microarrays will allow for the use of rapid, large-scale protein-expression profiling of tumor samples while limiting depletion of this valuable resource. Access to biologic specimens through SEER registries will provide researchers with demographic, clinical, and risk factor information on cancer patients with assured data quality and completeness. Clinical outcome data, such as disease-free survival, can be correlated with previously validated prognostic markers. Furthermore, the anonymity of the study subject can be protected through rigorous standards of confidentiality. SEER-based tissue resources represent a step forward in true, population-based tissue repositories of tumors from US patients and may serve as a foundation for molecular epidemiology studies of cancer in this country.

Biomarkers, Tumor↗
PubMed2002

Sequencing of porcine enterovirus groups II and III reveals unique features of both virus groups.

The molecular classification of the porcine enterovirus (PEV) groups II and III was investigated. The sequence of the almost complete PEV-8 (group II) genome reveals that this virus has unique L and 2A gene regions. A reclassification of this group into a new picornavirus genus is suggested. PEV group III viruses are typical enteroviruses. They differ from other enteroviruses by a prolonged stem-loop D of the 5'-cloverleaf structure.

3' Untranslated Regions↗
PubMed1989

Pelizaeus-Merzbacher disease: an X-linked neurologic disorder of myelin metabolism with a novel mutation in the gene encoding proteolipid protein.

The nosology of the inborn errors of myelin metabolism has been stymied by the lack of molecular genetic analysis. Historically, Pelizaeus-Merzbacher disease has encompassed a host of neurologic disorders that present with a deficit of myelin, the membrane elaborated by glial cells that encircles and successively enwraps axons. We describe here a Pelizaeus-Merzbacher pedigree of the classical type, with X-linked inheritance, a typical clinical progression, and a pathologic loss of myelinating cells and myelin in the central nervous system. To discriminate variants of Pelizaeus-Merzbacher disease, a set of oligonucleotide primers was constructed to polymerase-chain-reaction (PCR) amplify and sequence the gene encoding proteolipid protein (PLP), a structural protein that comprises half of the protein of the myelin sheath. The PLP gene in one of two affected males and the carrier mother of this family exhibited a single base difference in the more than 2 kb of the PLP gene sequenced, a C----T transition that would create a serine substitution for proline at the carboxy end of the protein. Our results delineate the clinical features of Pelizaeus-Merzbacher disease, define the possible molecular pathology of this dysmyelinating disorder, and address the molecular classification of inborn errors of myelin metabolism. Patients with the classical form (type I) and the more severely affected, connatal variant of Pelizaeus-Merzbacher disease (type II) would be predicted to display mutation at the PLP locus. The other variants (types III-VI), which have sometimes been categorized as Pelizaeus-Merzbacher disease, may represent mutations in genes encoding other structural myelin proteins or proteins critical to myelination.

Amino Acid Sequence↗
PubMed2003

Classification of Dukes' B and C colorectal cancers using expression arrays.

PURPOSE: Colorectal cancer is one of the most common malignancies. Substaging of the cancer is of importance not only to prognosis but also to treatment. Classification of substages based on DNA microarray technology is currently the most promising approach. We therefore investigated if gene expression microarrays could be used to classify colorectal tumors. METHODS: We used the Affymetrix oligonucleotide arrays to analyze the expression of more than 5,000 genes in samples from the sigmoid and upper rectum of the left colon. Five samples were from normal mucosa and five samples from each of the Dukes' stages A, B, C, and D. Expression data were filtered based on either covariance or a selection of the most significantly varying genes between tumor stages. RESULTS: A nearest neighbor classifier was used to classify normal, and Dukes' B and C samples with less than 20% error, whereas Dukes' A and D could not be classified correctly. A number of interesting gene clusters showed a discriminating difference between Dukes' B and C samples. These included mitochondrial genes, stromal remodeling genes, and genes related to cell adhesion. CONCLUSION: Molecular classification based on gene expression of one of the most common malignancies, colorectal cancer, now seems to be within reach. The data indicates that it is possible at least to classify Dukes' B and C colorectal tumors with microarrays.

Adenocarcinoma↗
PubMed2004

Molecular modeling of family GH16 glycoside hydrolases: potential roles for xyloglucan transglucosylases/hydrolases in cell wall modification in the poaceae.

Family GH16 glycoside hydrolases can be assigned to five subgroups according to their substrate specificities, including xyloglucan transglucosylases/hydrolases (XTHs), (1,3)-beta-galactanases, (1,4)-beta-galactanases/kappa-carrageenases, "nonspecific" (1,3/1,3;1,4)-beta-D-glucan endohydrolases, and (1,3;1,4)-beta-D-glucan endohydrolases. A structured family GH16 glycoside hydrolase database has been constructed (http://www.ghdb.uni-stuttgart.de) and provides multiple sequence alignments with functionally annotated amino acid residues and phylogenetic trees. The database has been used for homology modeling of seven glycoside hydrolases from the GH16 family with various substrate specificities, based on structural coordinates for (1,3;1,4)-beta-D-glucan endohydrolases and a kappa-carrageenase. In combination with multiple sequence alignments, the models predict the three-dimensional (3D) dispositions of amino acid residues in the substrate-binding and catalytic sites of XTHs and (1,3/1,3;1,4)-beta-d-glucan endohydrolases; there is no structural information available in the databases for the latter group of enzymes. Models of the XTHs, compared with the recently determined structure of a Populus tremulos x tremuloides XTH, reveal similarities with the active sites of family GH11 (1,4)-beta-D-xylan endohydrolases. From a biological viewpoint, the classification, molecular modeling and a new 3D structure of the P. tremulos x tremuloides XTH establish structural and evolutionary connections between XTHs, (1,3;1,4)-beta-D-glucan endohydrolases and xylan endohydrolases. These findings raise the possibility that XTHs from higher plants could be active not only on cell wall xyloglucans, but also on (1,3;1,4)-beta-D-glucans and arabinoxylans, which are major components of walls in grasses. A role for XTHs in (1,3;1,4)-beta-D-glucan and arabinoxylan modification would be consistent with the apparent overrepresentation of XTH sequences in cereal expressed sequence tags databases.

Amino Acid Sequence↗
PubMed2026

LymphGen-Sig: Integrating Genetic and Transcriptional States to Predict Therapeutic Response in Diffuse Large B-Cell Lymphoma.

PURPOSE: Genetic classification may advance precision medicine in diffuse large B-cell lymphoma (DLBCL), but existing tools like LymphGen (LG) are limited by complexity and incomplete classification and do not incorporate nongenetic features that affect disease biology and therapeutic outcomes. To address these limitations, we developed LG-sig (LGsig), a gene expression-based platform that classifies all DLBCLs and harmonizes both genetic and nongenetic dimensions of the disease. METHODS: LGsig was built on the distinct subtype-specific gene expression signature of each LG class using paired genomic and transcriptomic data (National Cancer Institute/British Columbia Cancer Agency; N = 764). Model development was restricted to DLBCLs classified into MYD88L265P and CD79B mutations (MCD), BCL6 translocation and NOTCH2 mutations (BN2), EZH2 mutations and BCL2 translocation (EZB), or SGK1 and TET2 mutations (ST2). Gene features were selected by differential gene expression, with 294 genes being optimal for classification using a nearest shrunken centroid classifier. LGsig classifications were designated as MCDsig, BN2sig, ST2sig, and EZBsig. The final model was applied to RNAseq from archival samples from the POLARIX trial (N = 678) to assess outcomes after polatuzumab vedotin-R-CHP (pola-R-CHP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for each LGsig subtype. RESULTS: LGsig accurately identified LG subtypes using transcriptional data alone and extended assignments to all previously LG-unclassified cases. Importantly, LG-unclassified DLBCLs reassigned by LGsig mirrored the transcriptional and clinical features of their corresponding LG counterparts, supporting their reclassification. In addition, LGsig reassigned LG A53 DLBCLs, characterized by aneuploidy and TP53 alterations, into more biologically and therapeutically relevant LGsig clusters. Finally, LGsig improved the performance of LG as a biomarker in the POLARIX study, by identifying distinct DLBCL subtypes exhibiting a survival benefit with pola-R-CHP over R-CHOP in both LG-classified and LG-unclassified cases. CONCLUSION: LGsig expands molecular classification beyond current genetic classifiers in DLBCL by integrating both genetic and transcriptional dimensions of the disease to better inform subtype-specific therapeutic strategies.

Journal Article↗
PubMed2006

Erwinia tasmaniensis sp. nov., a non-phytopathogenic bacterium from apple and pear trees.

Bacteria were isolated from flowers and bark of apple and pear trees at three places in Australia. In Victoria, Tasmania and Queensland, strains with white colonies on nutrient agar were screened for dome-shaped colony morphology on agar with sucrose and were found to be closely related by several criteria. The isolates were not pathogenic on apples or pears. They were characterized by a polyphasic approach including microbiological and API assays as well as fatty acid methyl ester analysis, DNA-DNA hybridization and DNA sequencing. For molecular classification, the 16S rRNA cistron and the conserved genes gpd and recA of these bacteria were investigated. Together with other taxonomic criteria, the results of these studies indicate that the bacteria belong to a novel separate species, which we propose to name Erwinia tasmaniensis sp. nov., with the type strain Et1/99(T) (=DSM 17950(T)=NCPPB 4357(T)). From DNA-DNA hybridization kinetics, microbiological characteristics and nucleotide sequence analyses, this species is related to pathogenic Erwinia species, but also to the epiphytic species Erwinia billingiae.

Australia↗
PubMed2003

Using mice to decipher the molecular genetics of brain tumors.

The past decade has dramatically increased our knowledge of genetic and molecular alterations in human central nervous system tumors. Important as these alterations are for the molecular classification of tumors, their actual roles in tumorigenesis and tumor progression have long remained obscure. Lately, several mouse brain tumor models have been developed that use different gene modification strategies to replicate mutations seen in the human counterpart. These genetic models will allow discrimination between mutations that are causally related to tumor formation and mutations that are a result of tumor progression. These models also provide histologically and genetically accurate models for preclinical testing and will perhaps help us identify novel targets for therapies aimed at the mechanistic cause of the disease. We present here a review of current models, with a focus on gliomas and medulloblastomas.

Animals↗
PubMed2026

Molecular profiling of pediatric medulloblastoma in Kazakhstan: Genomic alterations, subgroup distribution, and survival.

Medulloblastoma is the most common malignant pediatric brain tumor and comprises biologically distinct molecular subgroups with different clinicopathologic and prognostic characteristics. Molecular data from Kazakhstan and other underrepresented regions remain limited, and practical approaches for molecular subgroup assignment using formalin-fixed, paraffin-embedded (FFPE) material are needed in settings where advanced molecular classification is not routinely available. We retrospectively analyzed 40 pediatric medulloblastomas diagnosed between 2015 and 2024 at the Corporate Fund "University Medical Center," Kazakhstan. Archived FFPE tumor material underwent histologic review, immunohistochemical evaluation (β-catenin, YAP1, and GAB1), and whole-exome sequencing. Tumors were assigned to WNT, SHH, or non-WNT/non-SHH categories using a combined morphologic, immunophenotypic, and genomic framework, and clinicopathologic variables and overall survival were evaluated across subgroups. WNT medulloblastomas (n = 7, 17.5%) showed the most canonical profile, characterized by classic histology, uniform β-catenin nuclear positivity, recurrent CTNNB1/APC alterations, and frequent chromosome 6 loss. SHH medulloblastomas (n = 10, 25.0%) were enriched for desmoplastic/nodular morphology, frequent YAP1/GAB1 expression, pathogenic PTCH1/SUFU alterations, and additional events involving TP53, TERT, and focal amplifications in a subset. Non-WNT/non-SHH medulloblastomas (n = 23, 57.5%) showed the greatest genomic heterogeneity, including frequent i17q and broader structural complexity. Clinically, WNT tumors occurred predominantly in older children and had the most favorable survival, whereas non-WNT/non-SHH tumors were the only subgroup associated with metastatic disease at presentation and showed the poorest long-term survival. Overall, pediatric medulloblastoma in this cohort demonstrated subgroup-specific patterns consistent with established biology. The integration of pathology, immunohistochemistry, and sequencing enabled clinically meaningful molecular stratification. These findings expand evidence from an underrepresented setting and support pragmatic, resource-adapted profiling in routine practice.

Kazakhstan↗
PubMed2006

Prognostic significance of gene expression profiles of metastatic neuroblastomas lacking MYCN gene amplification.

BACKGROUND: The aggressiveness of metastatic neuroblastomas that lack MYCN gene amplification varies with age--they are least aggressive when diagnosed in patients younger than 12 months and most aggressive when diagnosed in patients older than 24 months. However, age at diagnosis is not always associated with patient survival. We examined whether molecular classification of metastatic neuroblastomas without MYCN gene amplification at diagnosis using gene expression profiling could improve the prediction of risk of disease progression. METHODS: We used Affymetrix microarrays to determine the gene expression profiles of 102 untreated primary neuroblastomas without MYCN gene amplification obtained from children whose ages at diagnosis ranged from 0.1 to 151 months. A supervised method using diagonal linear discriminant analysis was devised to build a multigene model for predicting risk of disease progression. The accuracy of the model was evaluated using nested cross-validations, permutation analyses, and gene expression data from 15 additional tumors obtained at disease progression. RESULTS: An expression profile model using 55 genes defined a tumor signature that distinguished two groups of patients from among those older than 12 months at diagnosis and clinically classified as having high-risk disease, those with a progression-free survival (PFS) rate of 16% (95% confidence interval [CI] = 8% to 28%), and those with a PFS rate of 79% (95% CI = 57% to 91%) (P<.01). These tumor signatures also identified two groups of patients with PFS of 15% (95% CI = 7% to 27%) and 69% (95% CI = 40% to 86%) (P<.01) from among patients who were older than 18 months at diagnosis. The gene expression signature of untreated molecular high-risk tumors was also present in progressively growing tumors. CONCLUSION: Gene expression signatures of tumors obtained at diagnosis from patients with clinically indistinguishable high-risk, metastatic neuroblastomas identify subgroups with different outcomes. Accurate identification of these subgroups with gene expression profiles may facilitate development, implementation, and analysis of clinical trials aimed at improving outcome.

Adolescent↗