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Cancer May Arise From Epigenetic Changes, Study in Fruit Flies Suggests

NEW YORK – Cancer may stem from transient epigenetic changes, even in the absence of related genetic alterations, according to a new study in fruit flies published in Nature on Wednesday.

"Cancer is generally believed to arise as a consequence of the accumulation of somatic mutations, frequently involving multiple mutational hits," co-senior and co-corresponding author Giacomo Cavalli, a researcher affiliated with the University of Montpellier and CNRS in France, said in an email, adding that "some human cancers have a low or undetectable driver mutation burden."

In addition, he explained, prior studies have hinted that epigenetic shifts can occur in the absence of new genetic alterations in metastatic tumors that develop from primary tumors containing certain driver mutations.

To explore epigenetic effects on cancer risk, Cavalli and colleagues at the University of Montpellier; the Vienna BioCenter; the University of California, Los Angeles; and other international centers performed RNA interference experiments on developing Drosophila larvae, focusing on a conserved gene silencing complex known as Polycomb.

"Over the last decade, substantial evidence has been provided showing that many epigenetic components … are perturbed in many types of cancers," Cavalli said. "[W]hat was not known is whether cancer can be induced by a pure epigenetic perturbation without accompanying driver DNA mutations and how that would work."

Indeed, after using thermosensitive RNAi experiments to reversibly dial down the PH subunit of the Polycomb repressive complex 1 (PRC1) in eye imaginal disc tissue, the team saw tumors form by the third larval stage in the developing fruit flies.

That tumor formation did not appear to be explained by the presence of new genetic mutations, based on whole-genome sequencing analyses of tumor and normal tissue samples from the larvae with or without Polycomb knockdown.

"No genes contained deleterious [single nucleotide variants or small insertions or deletions] in all tumor samples, and similar results were found when considering structural variants or copy number variations," the authors reported, adding that these and other results "argue strongly against the presence of recurrent driver mutations in these tumors."

On the other hand, when the team used approaches such as RNA sequencing, chromatin immunoprecipitation sequencing, and ATAC-seq to track the transcriptomic and chromatin accessibility consequences of the transient PRC1 knockdown, it found reversible expression changes as well as expression shifts that persisted after activity of the Polycomb complex was restored.

"[W]e show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila," the authors reported.

In particular, the researchers suggested that the transient Polycomb silencing led to irreversible regulatory changes to the JAK-STAT signaling pathway and to the fruit fly version of a gene known to be an oncogene in mammals, leading to derepression of these genes in the tumors that they dubbed "epigenetically initiated cancers."

"These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations," the authors wrote, "suggesting that tumors can emerge through epigenetic dysregulation leading to inheritance of altered cell fates."

Based on their subsequent analysis of published data on solid cancer and multiple myeloma cases, the investigators suggested that epigenetic changes may have similar consequences in human cancers, since cases marked by lower-than-usual expression of the PRC1 Polycomb subunit tended to show poorer-than-usual overall survival outcomes.

Cavalli suggested that such findings may ultimately improve investigators' understanding of cancer development. They could also potentially inform treatment strategies used to tackle forms of cancer that are marked by low mutation levels compared to treatments for mutation-rich tumors.

In a related commentary in Nature, University of Freiburg researcher Anne-Kathrin Classen, who was not involved in the study, noted that the results point to the need for profiling both genetic and epigenetic features in tumors to better understand and treat cancer.

"In people, temporary epigenetic changes might arise from environmental influences that are specific to an individual's life history, such as certain diets or medications, or exposure to chemical agents," Classen wrote. "Consequently, approaches to the experimental analyses of tumors need to take these transient events into account and consider their long-term consequences."