Browsing by Author "Stampfer, Martha R"

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    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.
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    The senescent methylome and its relationship with cancer, ageing and germline genetic variation in humans.
    (Genome Biol, 2015-09-17) Lowe, Robert; Overhoff, Marita G; Ramagopalan, Sreeram V; Garbe, James C; Koh, James; Stampfer, Martha R; Beach, David H; Rakyan, Vardhman K; Bishop, Cleo L
    BACKGROUND: Cellular senescence is a stable arrest of proliferation and is considered a key component of processes associated with carcinogenesis and other ageing-related phenotypes. Here, we perform methylome analysis of actively dividing and deeply senescent normal human epithelial cells. RESULTS: We identify senescence-associated differentially methylated positions (senDMPs) from multiple experiments using cells from one donor. We find that human senDMP epigenetic signatures are positively and significantly correlated with both cancer and ageing-associated methylation dynamics. We also identify germline genetic variants, including those associated with the p16INK4A locus, which are associated with the presence of in vivo senDMP signatures. Importantly, we also demonstrate that a single senDMP signature can be effectively reversed in a newly-developed protocol of transient senescence reversal. CONCLUSIONS: The senDMP signature has significant potential for understanding some of the key (epi)genetic etiological factors that may lead to cancer and age-related diseases in humans.