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Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.

ABSTRACT: BACKGROUND:Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. METHODS AND FINDINGS:To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. CONCLUSIONS:The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life.

SUBMITTER: Kool M

PROVIDER: S-EPMC2518524 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.

Kool Marcel M Koster Jan J Bunt Jens J Hasselt Nancy E NE Lakeman Arjan A van Sluis Peter P Troost Dirk D Meeteren Netteke Schouten-van NS Caron Huib N HN Cloos Jacqueline J Mrsić Alan A Ylstra Bauke B Grajkowska Wieslawa W Hartmann Wolfgang W Pietsch Torsten T Ellison David D Clifford Steven C SC Versteeg Rogier R

PloS one 20080828 8

<h4>Background</h4>Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classifi ...[more]

PMID: 18769486

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Project description:Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the dataset. Immunohistochemistry for subgroup-specific ‘signature’ genes was used to determine subgroup affiliation for 294 non-overlapping medulloblastomas on two independent tissue microarrays (TMAs). Multiple unsupervised analyses of transcriptional profiles identified four distinct, non-overlapping molecular variants: WNT, SHH, Group C, and Group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (Group C), and KCNA1 (Group D) could reliably and uniquely classify formalin fixed medulloblastomas in ~98% of cases. Group C patients (NPR3 +ve tumors) exhibited a significantly diminished progression free and overall survival irrespective of their metastatic status. Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma sub-classification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma. A total of 103 primary medulloblastoma specimens were profiled by Affymetrix exon array and gene-level analysis was performed.

Project description:BackgroundThe aim of this study is to investigate the clinicopathological features of intrinsic and extrinsic subtypes in adenomyosis. In particular, we focused on the early lesions of adenomyosis.MethodsThis is a single-center, prospective study of women who elected surgery for adenomyosis at the Department of Gynecology, Nara Medical University Hospital, Kashihara, Japan, from April 2008 to March 2018. Adenomyosis was histologically classified as intrinsic, extrinsic, and others, depending on the type of intramural growth. Adenomyosis that occurs at the inner and outer myometrium was defined as an intrinsic and extrinsic type, respectively.ResultsOne hundred eighty-nine patients with histologically confirmed adenomyosis were classified into three different types, 74 intrinsic type, 78 extrinsic type, and 37 other type. Compared to the intrinsic type, the extrinsic type was more likely to have endometriosis, including ovarian endometrioma (OMA), superficial peritoneal endometriosis (SUP), or deep infiltrating endometriosis (DIE). To further identify the clinicopathological features of early-stage adenomyosis, we focused only on patients with intrinsic and extrinsic types of adenomyosis with less than one-third of muscular layer infiltration. Patients with early-stage intrinsic adenomyosis were more likely to experience induced abortions. Patients with early-stage extrinsic adenomyosis were more likely to have endometriosis. The coexistence of endometriosis and the lack of induced abortion were independent predictors of extrinsic adenomyosis. Multivariate logistic regression analysis identified coexistence of endometriosis as independent predictors of the early stage extrinsic adenomyosis.ConclusionThe study suggests that there are at least two types of adenomyosis, where the intrinsic type is closely associated with a history of induced abortion, while the extrinsic type is strongly associated with endometriosis. Adenomyosis might be a gynecological disorder with complex pathogenesis implicating both traumatic and endometriotic factors.

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Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.

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Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.

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