Successful carcinogenesis involves the integration of both pro- and anti-oncogenic pathways. We postulated that genes critical for balancing these opposing pathways are likely to be precisely controlled in tumors, since even subtle alterations in their activity might cause substantial alterations in tumor growth and survival. Using a novel genomic approach, we identified a 48-gene “Poised Gene Cassette” (PGC) showing tight regulation specifically in human cancers but not in corresponding nonmalignant tissues. We show, using a wide variety of in vitro and in vivo approaches, that small alterations in PGC expression are consistently associated with significant differences in experimental metastasis and patient survival, and we demonstrate a direct functional role for five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6 and SKIP) in cancer invasion. Our findings support the existence of a novel class of ultrasensitive genes that may regulate various cancer-associated phenotypes such as metastasis. Such precisely controlled genes could represent appealing drug targets, since even partial alterations in their activity should prove sufficient to induce potent effects on tumors. Besides cancer, our analytical approach is quite generalizable and likely to be applicable to other disease conditions.
Overall design
Primary human tumor and adjacent normal tissues were obtained from the Tissue Repository of the National Cancer Centre of Singapore (NCCS). Appropriate institutional approvals were obtained from the NCCS Tissue Repository and Ethics Committees. In the operating theater, morphologically visible tumor and adjacent matched normal tissues were removed by surgery and examined by a surgical pathologist to confirm the presence of cancer cells by cryosections. The tissue samples were divided into discrete aliquots, flash frozen and subsequently stored in liquid nitrogen. The detailed information regarding samples is available in Supplementary Information S1. The training set used in this study comprises 341 samples (270 tumors and 71 matched normals) from patients with breast, colon, liver, lung, oesophagal and thyroid cancer (Tissue Type/Tumor/Normal : Lung/18/12, Thyroid/35/16, Liver/9/8, Oesophagus/16/13, Colon/9/9, Breast/183/13.)
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