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Killela P.J.,Duke University | Pirozzi C.J.,Duke University | Reitman Z.J.,Duke University | Jones S.,Personal Genome Diagnostics (PGD) | And 8 more authors.
Oncotarget | Year: 2014

Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from glioblastoma multiforme (GBM) WHO grade IV. To reveal the genetic landscape of this tumor type, we sequenced the exome of a cohort of A3s (n=16). For comparison and to illuminate the genomic landscape of other glioma subtypes, we also included in our study diffuse astrocytoma WHO grade II (A2, n=7), oligoastrocytoma WHO grade II (OA2, n=2), anaplastic oligoastrocytoma WHO grade III (OA3, n=4), and GBM (n=28). Exome sequencing of A3s identified frequent mutations in IDH1 (75%, 12/16), ATRX (63%, 10/16), and TP53 (82%, 13/16). In contrast, the majority of GBMs (75%, 21/28) did not contain IDH1 or ATRX mutations, and displayed a distinct spectrum of mutations. Finally, our study also identified novel genes that were not previously linked to this tumor type. In particular, we found mutations in Notch pathway genes (NOTCH1, NOTCH2, NOTCH4, NOTCH2NL), including a recurrent NOTCH1-A465Tmutation, in 31% (5/16) of A3s. This study suggests genetic signatures will be useful for the classification of gliomas.

Yildiz M.,University of Michigan | Li H.,University of Michigan | Bernard D.,University of Michigan | Amin N.A.,University of Michigan | And 10 more authors.
Blood | Year: 2015

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the Western world. FL cell-intrinsic and cell-extrinsic factors influence FL biology and clinical outcome. To further our understanding of the genetic basis of FL, we performed whole-exome sequencing of 23 highly purified FL cases and 1 transformed FL case and expanded findings to a combined total of 114 Fls. We report recurrent mutations in the transcription factor STAT6 in 11% of FLs and identified the STAT6 amino acid residue 419 as a novel STAT6 mutation hotspot (p.419D/G, p.419D/A, and p.419D/H). FL-associated STAT6 mutations were activating, as evidenced by increased transactivation in HEK293T cell-based transfection/luciferase reporter assays, heightened interleukin-4 (IL-4) -induced activation of target genes in stable STAT6 transfected lymphoma cell lines, and elevated baseline expression levels of STAT6 target genes in primary FL B cells harboring mutant STAT6. Mechanistically, FL-associated STAT6 mutations facilitated nuclear residency of STAT6, independent of IL-4-induced STAT6-Y641 phosphorylation. Structural modeling of STAT6 based on the structure of the STAT1-DNA complex revealed that most FL-associated STAT6 mutants locate to the STAT6-DNA interface, potentially facilitating heightened interactions. The genetic and functional data combined strengthen the recognition of the IL-4/JAK/STAT6 axis as a driver of FL pathogenesis. © 2015 by The American Society of Hematology

Li H.,University of Michigan | Kaminski M.S.,University of Michigan | Li Y.,University of Michigan | Yildiz M.,University of Michigan | And 14 more authors.
Blood | Year: 2014

Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and single nucleotide polymorphism 6.0 array genomic profiling of 11 highly purified FL cases, and 1 transformed FL case and the validation of selected mutations in 102 FL cases. We report the identification of 15 novel recurrently mutated genes in FL. These include frequent mutations in the linker histone genes HIST1H1 B-E (27%) and mutations in OCT2 (also known as POU2F2; 8%), IRF8 (6%), and ARID1A (11%). A subset of the mutations in HIST1H1 B-E affected binding to DNMT3B, and mutations in HIST1H1 B-E and in EZH2 or ARID1A were largely mutually exclusive, implicating HIST1H1 B-E in epigenetic deregulation in FL. Mutations in OCT2 (POU2F2) affected its transcriptional and functional properties as measured through luciferase assays, the biological analysis of stably transduced cell lines, and global expression profiling. Finally, multiple novel mutated genes located within regions of acquired uniparental disomy in FL are identified. In aggregate, these data substantially broaden our understanding of the genomic pathogenesis of FL. © 2014 by The American Society of Hematology.

Zhang L.,Capital Medical University | Chen L.H.,Duke University | Wan H.,Capital Medical University | Yang R.,Duke University | And 22 more authors.
Nature Genetics | Year: 2014

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.© 2014 Nature America, Inc. All rights reserved.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 216.86K | Year: 2015

DESCRIPTION provided by applicant With over million new cases and over deaths annually colorectal cancer CRC is the third most common cancer and the third highest cause of cancer death in the developed world CRC patients are classified into stage I through IV depending on the extent of their disease Approximately of CRC patients are diagnosed with localized stage II cancer amounting to new cases in the developed world and in the U S annually The standard of care for stage II CRC includes surgical removal of the tumor followed by adjuvant therapy in high risk patients The current risk stratification approaches including the standard of care TNM staging method offer only limited accuracy as evidenced by the approximately of stage II CRC patients who recur with predominantly incurable disease and do not receive adjuvant therapy Therefore novel more accurate approaches to identify high risk patients are urgently needed Circulating cell free tumor derived DNA ctDNA is released by tumors and carries tumor exclusive genetic alterations Hypothesis We hypothesize that direct and early detection of minimal residual disease MRD using ctDNA will more accurately identify high risk CRC patients than the current approaches that predict recurrence based on analyses of the resected tumors Preliminary Data We have pioneered the development of technologies for evaluation of ctDNA and established ctDNA as an exquisitely specific and sensitive marker for tumor burden and MRD Most relevant to this proposal we have demonstrated that andgt of localized CRC release detectable ctDNA and that post surgery ctDNA levels are prognostic Specific Aims In this phase I SBIR we propose to develop and validate CRCDetect a molecular test for the detection of MRD using ctDNA in the peripheral blood of stage II CRC patients collected weeks after surgery CRCDetect can identify patients who are not cured by surgery alone have a high risk of recurrence and may benefit from adjuvant therapy In Specific Aims and we will focus on the development and analytical validation of CRCDetect In Specific Aim we will evaluate the prognostic performance of CRCDetect in a cohort of stage II CRC patients Overall Impact Together these studies will demonstrate the feasibility of using CRCDetect to detect MRD in early stage CRC patients from a simple blood draw after surgery thereby identifying the stage II CRC patients with a high risk of recurrence and informing whether a patient should receive adjuvant treatment PUBLIC HEALTH RELEVANCE Colorectal cancer CRC is the third most common cancer with over new cases diagnosed and deaths predicted in in the United States More than of CRC patients including stage I III and some stage IV patients have surgery performed intended to cure their cancer Current standard care for stage II CRC includes surgical removal of tumor followed by chemotherapy treatment for patients who have a high risk of recurrence Although existing approaches attempt to predict the risk of recurrence based on features of the resected tumors they achieve only modest accuracy as evidenced by cancer recurrence in stage II CRC patients Given the high specificity and sensitivity of circulating tumor DNA ctDNA as a cancer marker we propose to develop and validate CRCDetect a non invasive approach for detection of cancer specific mutations in peripheral blood of CRC patients using digital sequencing and polymerase chain reaction PCR methods CRCDetect would identify from a simple blood drawl the stage II CRC patients who have a high recurrence risk and may benefit from chemotherapy The results from CRCDetect would enable physicians to determine the most appropriate treatment course for stage II CRC patients and would improve the outcome and survival of this patient cohort

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