title: Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes.
abstract: Cancer genomes maintain a complex array of somatic alterations required for maintenance and progression of the disease, posing a challenge to identify driver genes among this genetic disorder. Toward this end, we mapped regions of recurrent amplification in a large collection (n=392) of primary human cancers and selected 620 genes whose expression is elevated in tumors. An RNAi loss-of-function screen targeting these genes across a panel of 32 cancer cell lines identified potential driver genes. Subsequent functional assays identified SHMT2, a key enzyme in the serine/glycine synthesis pathway, as necessary for tumor cell survival but insufficient for transformation. The 26S proteasomal subunit, PSMB4, was identified as the first proteasomal subunit with oncogenic properties promoting cancer cell survival and tumor growth in vivo. Elevated expression of SHMT2 and PSMB4 was found to be associated with poor prognosis in human cancer, supporting the development of molecular therapies targeting these genes or components of their pathways.
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Genee Y
authors.initials: GY
authors.lastname: Lee
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Noelyn M
authors.initials: NM
authors.lastname: Kljavin
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Bourgon
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: James
authors.initials: J
authors.lastname: Lee
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Howard
authors.initials: H
authors.lastname: Stern
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: David
authors.initials: D
authors.lastname: Davis
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California.
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, Molecular Biology, Bioinformatics, Pathology, and Molecular Oncology, Genentech Inc., South San Francisco, California neve.richard@gene.com.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Neve
mesh_terms: D000818:Animals; D002384:Catalysis; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D056915:DNA Copy Number Variations; D018450:Disease Progression; D017353:Gene Deletion; D016678:Genome; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009857:Oncogenes; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D034622:RNA Interference
chemical_list: C108898:PSMB4 protein, human; D046988:Proteasome Endopeptidase Complex