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Chan, Jennifer

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Chan

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Jennifer

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Chan, Jennifer
Author's Publications: search.filters.isAuthorOfPublication.c07e41d6-6e27-4310-96aa-e6cbfeca4dc5

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    CDK8 Is a Colorectal Cancer Oncogene That Regulates β-Catenin Activity
    (Springer Nature, 2008) Firestein, Ron; Bass, Adam; Kim, So Young; Dunn, Ian; Silver, Serena J.; Guney, Isil; Freed, Ellen; Ligon, Azra; Vena, Natalie; Ogino, Shuji; Chheda, Milan; Tamayo, Pablo; Finn, Stephen; Shrestha, Yashaswi; Boehm, Jesse S.; Jain, Supriya Rani; Bojarski, Emeric; Mermel, Craig; Barretina, Jordi; Chan, Jennifer; Baselga, Jose; Tabernero, Josep; Root, David E.; Fuchs, Charles; Loda, Massimo; Shivdasani, Ramesh; Meyerson, Matthew; Hahn, William
    Aberrant activation of the canonical Wnt/β-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival. Although dysregulated β-catenin activity drives colon tumorigenesis, additional genetic perturbations are required to elaborate fully malignant disease. To identify genes that both modulate β-catenin activity and are essential for colon cancer cell proliferation, we conducted two loss-of-function screens in human colon cancer cells and compared genes identified in these screens with an analysis of copy-number alterations in colon cancer specimens. One of these genes, CDK8, which encodes a member of the mediator complex, is located at 13q12.13, a region of recurrent copy number gain in a substantial fraction of colon cancers. Suppression of CDK8 expression inhibited proliferation in colon cancer cells characterized by high levels of CDK8 and β-catenin hyperactivity. CDK8 kinase activity was necessary for β-catenin driven transformation and expression of several β-catenin transcriptional targets. Together these observations suggest that therapeutic interventions targeting CDK8 may confer clinical benefit in β-catenin-driven malignancies.
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    Ataxia, Dementia, and Hypogonadotropism Caused by Disordered Ubiquitination
    (New England Journal of Medicine (NEJM/MMS), 2013) Margolin, David H.; Kousi, Maria; Chan, Yee-Ming; Lim, Elaine T.; Schmahmann, Jeremy; Hadjivassiliou, Marios; Hall, Janet E.; Adam, Ibrahim; Dwyer, Andrew; Plummer, Lacey; Aldrin, Stephanie V.; O, Julia; Kirby, Andrew; Lage, Kasper; Milunsky, Aubrey; Milunsky, Jeff M.; Chan, Jennifer; Hedley-Whyte, E.; Daly, Mark; Katsanis, Nicholas; Seminara, Stephanie
    In recent years, we have seen great advances in the elucidation of genetic causes of cerebellar ataxia, with newly identified genes regulating a wide spectrum of cellular functions, including intracellular signaling, tau regulation, and mitochondrial function.1 However, a genetic defect cannot be found in approximately 40% of patients with ataxia,1 including those in whom ataxia is associated with reproductive endocrine failure, a syndrome first reported by Gordon Holmes in 1908.2 Most patients with this syndrome have a hypogonadotropic condition, with defective secretion of gonadotropins by the pituitary gland.3-12 Strikingly, genes associated with ataxia have little functional overlap with genes associated with hypogonadotropic hypogonadism, which encode proteins involved in the biologic function of the neurons that secrete gonadotropin-releasing hormone (GnRH).13 A decade ago, we described a consanguineous family with a syndrome of cerebellar ataxia, dementia, and hypogonadotropic hypogonadism.12 Here we report the results of whole-exome and targeted sequencing performed to identify mutations that underlie the syndrome in this kindred and in unrelated patients.
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    Analysis of the 10q11 Cancer Risk Locus Implicates MSMB and NCOA4 in Human Prostate Tumorigenesis
    (Public Library of Science, 2010) Chanock, Stephen J.; Schafer, Eric J.; Tabernero, Josep; Baselga, José; Oh, William K.; Pomerantz, Mark; Shrestha, Yashaswi; Flavin, Richard John; Regan, Meredith; Penney, Kathryn; Mucci, Lorelei; Stampfer, Meir; Hunter, David; Chan, Jennifer; Richardson, Andrea; Loda, Massimo; Kantoff, Philip; Hahn, William; Freedman, Matthew
    Genome-wide association studies (GWAS) have established a variant, rs10993994, on chromosome 10q11 as being associated with prostate cancer risk. Since the variant is located outside of a protein-coding region, the target genes driving tumorigenesis are not readily apparent. Two genes nearest to this variant, MSMB and NCOA4, are strong candidates for mediating the effects of rs109939934. In a cohort of 180 individuals, we demonstrate that the rs10993994 risk allele is associated with decreased expression of two MSMB isoforms in histologically normal and malignant prostate tissue. In addition, the risk allele is associated with increased expression of five NCOA4 isoforms in histologically normal prostate tissue only. No consistent association with either gene is observed in breast or colon tissue. In conjunction with these findings, suppression of MSMB expression or NCOA4 overexpression promotes anchorage-independent growth of prostate epithelial cells, but not growth of breast epithelial cells. These data suggest that germline variation at chromosome 10q11 contributes to prostate cancer risk by influencing expression of at least two genes. More broadly, the findings demonstrate that disease risk alleles may influence multiple genes, and associations between genotype and expression may only be observed in the context of specific tissue and disease states.
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    Profiling Critical Cancer Gene Mutations in Clinical Tumor Samples
    (Public Library of Science, 2009) Campbell, Catarina D.; Kehoe, Sarah M.; Hatton, Charles; Niu, Lili; Yao, Keluo; Hanna, Megan; Mondal, Chandrani; Luongo, Lauren; Baker, Alissa C.; Philips, Juliet; Goff, Deborah J.; Rubin, Mark A.; Corso, Gianni; Roviello, Franco; MacConaill, Laura; Bass, Adam; Davis, Matt; Emery, Caroline Margaret; Fiorentino, Michelangelo; Polyak, Kornelia; Chan, Jennifer; Wang, Yufang; Fletcher, Jonathan; Santagata, Sandro; Shivdasani, Ramesh; Kieran, Mark W.; Ligon, Keith; Stiles, Charles; Hahn, William; Meyerson, Matthew; Garraway, Levi; Jones, Chris
    Background: Detection of critical cancer gene mutations in clinical tumor specimens may predict patient outcomes and inform treatment options; however, high-throughput mutation profiling remains underdeveloped as a diagnostic approach. We report the implementation of a genotyping and validation algorithm that enables robust tumor mutation profiling in the clinical setting. Methodology: We developed and implemented an optimized mutation profiling platform (“OncoMap”) to interrogate ∼400 mutations in 33 known oncogenes and tumor suppressors, many of which are known to predict response or resistance to targeted therapies. The performance of OncoMap was analyzed using DNA derived from both frozen and FFPE clinical material in a diverse set of cancer types. A subsequent in-depth analysis was conducted on histologically and clinically annotated pediatric gliomas. The sensitivity and specificity of OncoMap were 93.8% and 100% in fresh frozen tissue; and 89.3% and 99.4% in FFPE-derived DNA. We detected known mutations at the expected frequencies in common cancers, as well as novel mutations in adult and pediatric cancers that are likely to predict heightened response or resistance to existing or developmental cancer therapies. OncoMap profiles also support a new molecular stratification of pediatric low-grade gliomas based on BRAF mutations that may have immediate clinical impact. Conclusions: Our results demonstrate the clinical feasibility of high-throughput mutation profiling to query a large panel of “actionable” cancer gene mutations. In the future, this type of approach may be incorporated into both cancer epidemiologic studies and clinical decision making to specify the use of many targeted anticancer agents.