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Shrestha, Yashaswi

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Shrestha

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Yashaswi

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Shrestha, Yashaswi
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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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    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.