title: Conserved mechanisms across development and tumorigenesis revealed by a mouse development perspective of human cancers.
abstract: Identification of common mechanisms underlying organ development and primary tumor formation should yield new insights into tumor biology and facilitate the generation of relevant cancer models. We have developed a novel method to project the gene expression profiles of medulloblastomas (MBs)--human cerebellar tumors--onto a mouse cerebellar development sequence: postnatal days 1-60 (P1-P60). Genomically, human medulloblastomas were closest to mouse P1-P10 cerebella, and normal human cerebella were closest to mouse P30-P60 cerebella. Furthermore, metastatic MBs were highly associated with mouse P5 cerebella, suggesting that a clinically distinct subset of tumors is identifiable by molecular similarity to a precise developmental stage. Genewise, down- and up-regulated MB genes segregate to late and early stages of development, respectively. Comparable results for human lung cancer vis-a-vis the developing mouse lung suggest the generalizability of this multiscalar developmental perspective on tumor biology. Our findings indicate both a recapitulation of tissue-specific developmental programs in diverse solid tumors and the utility of tumor characterization on the developmental time axis for identifying novel aspects of clinical and biological behavior.
authors.affiliation: Children's Hospital Informatics Program, Children's Hospital Boston, MA 02115, USA.
authors.forename: Alvin T
authors.initials: AT
authors.lastname: Kho
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Cai
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.forename: John Y H
authors.initials: JY
authors.lastname: Kim
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Kohane
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002531:Cerebellum / Q000254:growth & development / Q000378:metabolism; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D015854:Up-Regulation
chemical_list: D005819:Genetic Markers