A cancer-specific transcriptional signature in human neoplasia
Francesco Nicassio, Fabrizio Bianchi, Maria Capra, Manuela Vecchi, Stefano Confalonieri, Marco Bianchi, Deborah Pajalunga, Marco Crescenzi, Ian Marc Bonapace, Pier Paolo Di Fiore
Francesco Nicassio, Fabrizio Bianchi, Maria Capra, Manuela Vecchi, Stefano Confalonieri, Marco Bianchi, Deborah Pajalunga, Marco Crescenzi, Ian Marc Bonapace, Pier Paolo Di Fiore
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Research Article Oncology

A cancer-specific transcriptional signature in human neoplasia

Abstract

The molecular anatomy of cancer cells is being explored through unbiased approaches aimed at the identification of cancer-specific transcriptional signatures. An alternative biased approach is exploitation of molecular tools capable of inducing cellular transformation. Transcriptional signatures thus identified can be readily validated in real cancers and more easily reverse-engineered into signaling pathways, given preexisting molecular knowledge. We exploited the ability of the adenovirus early region 1 A protein (E1A) oncogene to force the reentry into the cell cycle of terminally differentiated cells in order to identify and characterize genes whose expression is upregulated in this process. A subset of these genes was activated through a retinoblastoma protein/E2 viral promoter required factor–independent (pRb/E2F-independent) mechanism and was overexpressed in a fraction of human cancers. Furthermore, this overexpression correlated with tumor progression in colon cancer, and 2 of these genes predicted unfavorable prognosis in breast cancer. A proof of principle biological validation was performed on one of the genes of the signature, skeletal muscle cell reentry-induced (SKIN) gene, a previously undescribed gene. SKIN was found overexpressed in some primary tumors and tumor cell lines and was amplified in a fraction of colon adenocarcinomas. Furthermore, knockdown of SKIN caused selective growth suppression in overexpressing tumor cell lines but not in tumor lines expressing physiological levels of the transcript. Thus, SKIN is a candidate oncogene in human cancer.

Authors

Francesco Nicassio, Fabrizio Bianchi, Maria Capra, Manuela Vecchi, Stefano Confalonieri, Marco Bianchi, Deborah Pajalunga, Marco Crescenzi, Ian Marc Bonapace, Pier Paolo Di Fiore

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Selected class D genes predict disease outcome in breast cancer. Two cla...
Selected class D genes predict disease outcome in breast cancer. Two class D genes (SKIN and Ch-TOG) were used together as a predictor (see Supplemental Methods) of prognostic outcome on 2 independent data sets, one generated in-house (A), another from van’t Veer (42) (B), and finally on 15 randomly selected breast tumor patients analyzed by Q–RT-PCR (C) (see Table 1 for details). Data are shown as the probability of remaining free of metastatic relapse, in a Kaplan-Meier plot, as a function of a favorable (dashed line) or unfavorable (continuous line) signature. See also Supplemental Table 13 for details. (C) Probability of remaining metastasis free is shown in a Kaplan-Meier plot, as a function of the presence of the favorable (dashed line) or unfavorable (continuous line) signature. In A–C, the P values indicated were calculated with the log-rank test.