Browsing by Author "Ng, Alvin WT"

Now showing 1 - 2 of 2
  • Thumbnail Image
    ItemOpen Access
    Experimental and pan-cancer genome analyses reveal widespread contribution of acrylamide exposure to carcinogenesis in humans.
    (Genome research, 2019-03-07) Zhivagui, Maria; Ng, Alvin WT; Ardin, Maude; Churchwell, Mona I; Pandey, Manuraj; Renard, Claire; Villar, Stephanie; Cahais, Vincent; Robitaille, Alexis; Bouaoun, Liacine; Heguy, Adriana; Guyton, Kathryn Z; Stampfer, Martha R; McKay, James; Hollstein, Monica; Olivier, Magali; Rozen, Steven G; Beland, Frederick A; Korenjak, Michael; Zavadil, Jiri
    Humans are frequently exposed to acrylamide, a probable human carcinogen found in commonplace sources such as most heated starchy foods or tobacco smoke. Prior evidence has shown that acrylamide causes cancer in rodents, yet epidemiological studies conducted to date are limited and, thus far, have yielded inconclusive data on association of human cancers with acrylamide exposure. In this study, we experimentally identify a novel and unique mutational signature imprinted by acrylamide through the effects of its reactive metabolite glycidamide. We next show that the glycidamide mutational signature is found in a full one-third of approximately 1600 tumor genomes corresponding to 19 human tumor types from 14 organs. The highest enrichment of the glycidamide signature was observed in the cancers of the lung (88% of the interrogated tumors), liver (73%), kidney (>70%), bile duct (57%), cervix (50%), and, to a lesser extent, additional cancer types. Overall, our study reveals an unexpectedly extensive contribution of acrylamide-associated mutagenesis to human cancers.
  • Thumbnail Image
    ItemOpen Access
    Mutational processes in cancer preferentially affect binding of particular transcription factors.
    (Scientific reports, 2021-02-08) Liu, Mo; Boot, Arnoud; Ng, Alvin WT; Gordân, Raluca; Rozen, Steven G
    Protein binding microarrays provide comprehensive information about the DNA binding specificities of transcription factors (TFs), and can be used to quantitatively predict the effects of DNA sequence variation on TF binding. There has also been substantial progress in dissecting the patterns of mutations, i.e., the "mutational signatures", generated by different mutational processes. By combining these two layers of information we can investigate whether certain mutational processes tend to preferentially affect binding of particular classes of TFs. Such preferential alterations of binding might predispose to particular oncogenic pathways. We developed and implemented a method, termed "Signature-QBiC", that integrates protein binding microarray data with the signatures of mutational processes, with the aim of predicting which TFs' binding profiles are preferentially perturbed by particular mutational processes. We used Signature-QBiC to predict the effects of 47 signatures of mutational processes on 582 human TFs. Pathway analysis showed that binding of TFs involved in NOTCH1 signaling is strongly affected by the signatures of several mutational processes, including exposure to ultraviolet radiation. Additionally, toll-like-receptor signaling pathways are also vulnerable to disruption by this exposure. This study provides a novel overview of the effects of mutational processes on TF binding and the potential of these processes to activate oncogenic pathways through mutating TF binding sites.