Try a new search

Format these results:

Searched for:

in-biosketch:yes

person:davolt01

Total Results:

33


How aneuploidy drives cancer [Meeting Abstract]

Davoli, Teresa; Uno, Hajima; Xu, Andrew; Mengwasser, Kristen; Sack, Laura; Park, Peter J; Elledge, Stephen J
ISI:000389941703036
ISSN: 1538-7445
CID: 2668002

A primary melanoma and its asynchronous metastasis highlight the role of BRAF, CDKN2A, and TERT [Case Report]

Hosler, Gregory A; Davoli, Teresa; Mender, Ilgen; Litzner, Brandon; Choi, Jaehyuk; Kapur, Payal; Shay, Jerry W; Wang, Richard C
BACKGROUND: Alterations in pathways including BRAF, CDKN2A, and TERT contribute to the development of melanoma, but the sequence in which the genetic alterations occur and their prognostic significance remains unclear. To clarify the role of these pathways, we analyzed a primary melanoma and its metastasis. METHODS: Immunohistochemistry for BRAF-V600E, Sanger sequencing of BRAF and the TERT promoter, fluorescence in-situ hybridization, and telomere analyses were performed on a primary melanoma and its asynchronous cerebellar metastasis. Using the log-rank test and Cox-proportional model, the cancer genome atlas (TCGA) cohort of melanomas was analyzed for the effect of BRAF mutation and CDKN2A loss on survival. RESULTS: The primary melanoma expressed mutant BRAF-V600E and possessed a homozygous deletion of CDKN2A. In addition to these early defects, the metastatic lesion also possessed evidence of aneuploidy and an activating mutation of the TERT promoter. In the TCGA melanoma cohort, there was a non-significant trend toward poor prognosis in early stage cutaneous melanoma patients with concomitant BRAF mutation and CDKN2A loss. CONCLUSION: BRAF mutation and CDKN2A loss occurred early and TERT promoter mutation later in a case of lethal metastatic melanoma. The effects of these pathways on survival warrant further investigation in early stage cutaneous melanoma patients.
PMCID:4470704
PMID: 25407517
ISSN: 1600-0560
CID: 2667892

Comprehensive identification of host modulators of HIV-1 replication using multiple orthologous RNAi reagents

Zhu, Jian; Davoli, Teresa; Perriera, Jill M; Chin, Christopher R; Gaiha, Gaurav D; John, Sinu P; Sigiollot, Frederic D; Gao, Geng; Xu, Qikai; Qu, Hongjing; Pertel, Thomas; Sims, Jennifer S; Smith, Jennifer A; Baker, Richard E; Maranda, Louise; Ng, Aylwin; Elledge, Stephen J; Brass, Abraham L
RNAi screens have implicated hundreds of host proteins as HIV-1 dependency factors (HDFs). While informative, these early studies overlap poorly due to false positives and false negatives. To ameliorate these issues, we combined information from the existing HDF screens together with new screens performed with multiple orthologous RNAi reagents (MORR). In addition to being traditionally validated, the MORR screens and the historical HDF screens were quantitatively integrated by the adaptation of an established analysis program, RIGER, for the collective interpretation of each gene's phenotypic significance. False positives were addressed by the removal of poorly expressed candidates through gene expression filtering, as well as with GESS, which identifies off-target effects. This workflow produced a quantitatively integrated network of genes that modulate HIV-1 replication. We further investigated the roles of GOLGI49, SEC13, and COG in HIV-1 replication. Collectively, the MORR-RIGER method minimized the caveats of RNAi screening and improved our understanding of HIV-1-host cell interactions.
PMCID:4926641
PMID: 25373910
ISSN: 2211-1247
CID: 2667902

Cumulative dosage effect of TSGs and OGs drives aneuploidy patterns in cancer [Meeting Abstract]

Davoli, Teresa; Xu, Andrew Wei; Mengwasser, Kristen E; Sack, Laura M; Yoon, John C; Park, Peter J; Elledge, Stephen J
ISI:000349906903131
ISSN: 1538-7445
CID: 2667982

How aneuploidy drives tumorigenesis [Meeting Abstract]

Davoli, Teresa; Xu, Wei; Park, Peter; Elledge, Stephen J
ISI:000349910205478
ISSN: 1538-7445
CID: 2667992

Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome

Davoli, Teresa; Xu, Andrew Wei; Mengwasser, Kristen E; Sack, Laura M; Yoon, John C; Park, Peter J; Elledge, Stephen J
Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory to explain the recurring patterns of aneuploidy in cancer has emerged. Here, we develop Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor (TSG) or oncogene (OG). By analyzing >8,200 tumor-normal pairs, we provide statistical evidence suggesting that many more genes possess cancer driver properties than anticipated, forming a continuum of oncogenic potential. Integrating our driver predictions with information on somatic copy number alterations, we find that the distribution and potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy number variation characteristic of cancer genomes. We propose that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity.
PMCID:3891052
PMID: 24183448
ISSN: 1097-4172
CID: 2667912

Haploinsufficiency in cancer [Meeting Abstract]

Davoli, Teresa; Solimini, Nicole L; Pavlova, Natalya N; Xu, Qikai; Mengwasser, Kristen; Sack, Laura M; Liang, Anthony C; Schlabach, Michael R; Luo, Ji; Burrows, Anna E; Anselmo, Anthony N; Li, Mamie Z; Elledge, Stephen J
ISI:000209496600171
ISSN: 1538-7445
CID: 2667962

Genetic Approaches to Cancer [Meeting Abstract]

Elledge, Steve; Pavlova, Natasha; Davoli, Teresa; Solimini, Nicole
ISI:000319883500556
ISSN: 0892-6638
CID: 2667972

STOP gene Phactr4 is a tumor suppressor

Solimini, Nicole L; Liang, Anthony C; Xu, Chunxiao; Pavlova, Natalya N; Xu, Qikai; Davoli, Teresa; Li, Mamie Z; Wong, Kwok-Kin; Elledge, Stephen J
Cancer develops through genetic and epigenetic alterations that allow unrestrained proliferation and increased survival. Using a genetic RNAi screen, we previously identified hundreds of suppressors of tumorigenesis and/or proliferation (STOP) genes that restrain normal cell proliferation. Our STOP gene set was significantly enriched for known and putative tumor suppressor genes. Here, we report a tumor-suppressive role for one STOP gene, phosphatase and actin regulator 4 (PHACTR4). Phactr4 is one of four members of the largely uncharacterized Phactr family of protein phosphatase 1 (PP1)-and actin-binding proteins. Our work suggests that Phactr4 restrains normal cell proliferation and transformation. Depletion of Phactr4 with multiple shRNAs leads to increased proliferation and soft agar colony formation. Phactr4 acts, in part, through an Rb-dependent pathway, because Rb phosphorylation is maintained upon growth factor withdrawal in Phactr4-depleted cells. Examination of tumor copy number analysis and sequencing revealed that PHACTR4 is significantly deleted and mutant in many tumor subtypes. Furthermore,cancer cell lines with reduced Phactr4 expression exhibit tumor suppressor hypersensitivity upon Phactr4 complementation,leading to reduced proliferation, transformation, and tumor formation. Thus, Phactr4 acts as a tumor suppressor that is deleted and mutant in several cancers.
PMCID:3562831
PMID: 23319639
ISSN: 1091-6490
CID: 2269842

Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells

Davoli, Teresa; de Lange, Titia
Human cancers with a subtetraploid karyotype are thought to originate from tetraploid precursors, but the cause of tetraploidization is unknown. We previously documented endoreduplication in mouse cells with persistent telomere dysfunction or genome-wide DNA damage. We now report that endoreduplication and mitotic failure occur during telomere crisis in human fibroblasts and mammary epithelial cells and document the role of p53 and Rb in repressing tetraploidization. Using an inducible system to generate transient telomere damage, we show that telomere-driven tetraploidization enhances the tumorigenic transformation of mouse cells. Similar to human solid cancers, the resulting tumors evolved subtetraploid karyotypes. These data establish that telomere-driven tetraploidization is induced by critically short telomeres and has the potential to promote tumorigenesis in early cancerous lesions.
PMCID:3376354
PMID: 22698402
ISSN: 1878-3686
CID: 2667922