The von Hippel-Lindau tumour suppressor gene product (pVHL) associates with the elongin B and C and Cul2 proteins to form a ubiquitin-ligase complex (VCBC). To date, the only VCBC substrates identified are the hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha). However, pVHL is thought to have multiple functions and the significance of HIF-1alpha and HIF-2alpha regulation for tumour suppressor activity has not been defined. VHL disease is characterized by distinct clinical subtypes. Thus haemangioblastomas (HABs) and renal cell carcinoma (RCC) but not phaeochromocytoma (PHE) occur in type 1 VHL disease. Type 2 subtypes are characterized by PHE susceptibility but differ with respect to additional tumours (type 2A, PHE+HAB but not RCC; type 2B, PHE+ HAB+RCC; type 2C, PHE only). We investigated in detail the effect of 13 naturally occurring VHL mutations (11 missense), representing each phenotypic subclass, on HIF-alpha subunit regulation. Consistent effects on pVHL function were observed for all mutations within each subclass. Mutations associated with the PHE-only phenotype (type 2C) promoted HIF-alpha ubiquitylation in vitro and demonstrated wild-type binding patterns with pVHL interacting proteins, suggesting that loss of other pVHL functions are necessary for PHE susceptibility. Mutations causing HAB susceptibility (types 1, 2A and 2B) demonstrated variable effects on HIF-alpha subunit and elongin binding, but all resulted in defective HIF-alpha regulation and loss of p220 (fibronectin) binding. All RCC-associated mutations caused complete HIF-alpha dysregulation and loss of p220 (fibronectin) binding. Our findings are consistent with impaired ability to degrade HIF-alpha subunit being required for HAB development and RCC susceptibility.

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Prior attempts to subgroup medulloblastoma (MB) using genomics have identified 4-6 distinct molecular subtypes, including two subgroups driven by activated Wnt and Shh signaling. We performed an integrative analysis on a cohort of 103 primary MBs using a combination of Affymetrix expression and SNP genotyping arrays to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. Both unsupervised hierarchical clustering and principal component analysis of expression data reveals very high confidence for the existence of four medulloblastoma subgroups: WNT, SHH, Group C, and Group D. Additional bioinformatic analyses using non-negative matrix factorization (NMF) and subclass mapping (SubMap) further strengthens the support for the four subgroups. These subgroups exhibit distinct demographics: SHH tumors occur in infants and adults, Group C tumors are restricted to children, and WNT and Group D tumors are found across all age groups. While the sex ratio for the entire cohort is ∼1.5:1 (M:F), the sex ratio for WNT group tumors was ∼1:3. We identified a number of previously uncharacterized, subgroup-specific regions of chromosomal abnormality including 9p, 3q, 20q, and 21q gain in SHH tumors, 1q gain and 5q, 16q, and 10q loss in Group C tumors, and near universal isochromosome 17q and frequent loss of the X chromosome in Group D tumors. These regions likely harbor subgroup-specific oncogenes and tumor suppressor genes that could be targets for rationale therapy. Our demographic, transcriptional, and genetic data support the non-overlapping character of these four subgroups of MB. We identified ‘signature’ genes over-expressed in each subgroup for which there are high quality commercial antibodies available. Staining two separate MB tissue microarrays containing 294 non-overlapping tumors for DKK1 (WNT), SFRP1 (SHH), NPR3 (Group C), and KCNA1 (Group D) demonstrated that 288/294 (98%) tumors stained positive for only a single marker. Analysis of the demographics in these patients validated the results observed in our discovery series studied at the RNA level. Leptomeningeal dissemination was highly over-represented in Group C (47%) followed by Group D (30%) patients. A multivariate analysis that included age, extent of resection, histology, M stage, and subgroup revealed that only LCA histology and Group C affiliation were prognostic. As M0 Group C tumors have a very poor prognosis, we suggest that Group C patients include many of the children with ‘average-risk’ MB who relapse after current therapies. Our data highly support the existence of four independent subtypes of MB that differ in their demographics, transcription, genetic events, rate of metastases, and clinical outcome. Our novel ‘4 antibody’ technique is capable of determining MB subgroup through immunohistochemistry on formalin-fixed, paraffin-embedded material suggesting that it will be broadly generalizable across the globe. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4347.

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Table of contents O1 Regulation of genes by telomere length over long distances Jerry W. Shay O2 The microtubule destabilizer KIF2A regulates the postnatal establishment of neuronal circuits in addition to prenatal cell survival, cell migration, and axon elongation, and its loss leading to malformation of cortical development and severe epilepsy Noriko Homma, Ruyun Zhou, Muhammad Imran Naseer, Adeel G. Chaudhary, Mohammed Al-Qahtani, Nobutaka Hirokawa O3 Integration of metagenomics and metabolomics in gut microbiome research Maryam Goudarzi, Albert J. Fornace Jr. O4 A unique integrated system to discern pathogenesis of central nervous system tumors Saleh Baeesa, Deema Hussain, Mohammed Bangash, Fahad Alghamdi, Hans-Juergen Schulten, Angel Carracedo, Ishaq Khan, Hanadi Qashqari, Nawal Madkhali, Mohamad Saka, Kulvinder S. Saini, Awatif Jamal, Jaudah Al-Maghrabi, Adel Abuzenadah, Adeel Chaudhary, Mohammed Al Qahtani, Ghazi Damanhouri O5 RPL27A is a target of miR-595 and deficiency contributes to ribosomal dysgenesis Heba Alkhatabi O6 Next generation DNA sequencing panels for haemostatic and platelet disorders and for Fanconi anaemia in routine diagnostic service Anne Goodeve, Laura Crookes, Nikolas Niksic, Nicholas Beauchamp O7 Targeted sequencing panels and their utilization in personalized medicine Adel M. Abuzenadah O8 International biobanking in the era of precision medicine Jim Vaught O9 Biobank and biodata for clinical and forensic applications Bruce Budowle, Mourad Assidi, Abdelbaset Buhmeida O10 Tissue microarray technique: a powerful adjunct tool for molecular profiling of solid tumors Jaudah Al-Maghrabi O11 The CEGMR biobanking unit: achievements, challenges and future plans Abdelbaset Buhmeida, Mourad Assidi, Leena Merdad O12 Phylomedicine of tumors Sudhir Kumar, Sayaka Miura, Karen Gomez O13 Clinical implementation of pharmacogenomics for colorectal cancer treatment Angel Carracedo, Mahmood Rasool O14 From association to causality: translation of GWAS findings for genomic medicine Ahmed Rebai O15 E-GRASP: an interactive database and web application for efficient analysis of disease-associated genetic information Sajjad Karim, Hend F Nour Eldin, Heba Abusamra, Elham M Alhathli, Nada Salem, Mohammed H Al-Qahtani, Sudhir Kumar O16 The supercomputer facility “AZIZ” at KAU: utility and future prospects Hossam Faheem O17 New research into the causes of male infertility Ashok Agarwa O18 The Klinefelter syndrome: recent progress in pathophysiology and management Eberhard Nieschlag, Joachim Wistuba, Oliver S. Damm, Mohd A. Beg, Taha A. Abdel-Meguid, Hisham A. Mosli, Osama S. Bajouh, Adel M. Abuzenadah, Mohammed H. Al-Q...