SUMMARY We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad–mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, BMPR2), and Smads (SMAD2, SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.

Genetic alterations affecting transforming growth factor-b (TGF-b) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-b signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-b pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.

Voges & Proskauer [1898] observed that when strong alkali was added to broth cultures of certain species of bacteria there developed, after an interval of time, a pink colour. Subsequently the work of Harden [1906] and of Harden & Norris [1911] established that the chemical reaction responsible was one between diacetyl and creatine (or certain similar substances). Attempts to make the reaction quantitative [Walpole, 1911; Eggleton & Eggleton, 1928] were only partially successful. The reaction was further studied by Duliere [1929], Lang [1932] and Muller [1935], but it was the discovery by Barritt [1936], that o-naphthol greatly intensifies the colour, which made it possible for the first timne to use this reaction as a means of estimating either creatine or diacetyl. The present paper presents some additional facts about the reaction and methods of estimation based on it.