拨动开关：萨尔克科学家揭示“开启”癌基因的遗传变化新见解

拨动开关：萨尔克科学家揭示“开启”癌基因的遗传变化新见解

New research on cancer-causing genetic mutations may lead to improved ways of predicting and treating the disease

加乔拉——癌症是由细胞异常过度生长引起的，是世界第二大死因。索尔克研究所的研究人员已经聚焦于激活癌基因的具体机制。癌基因是发生改变的基因，可以使正常细胞变成癌细胞。.

癌症可能由基因突变引起，但特定类型的影响，例如断裂和重组DNA的结构变异，可能差异很大。该发现发表在 自然 2022年12月7日，表明这些突变的活性取决于特定基因与调控基因的序列之间的距离，并且取决于所涉及的调控序列的活性水平。.

This work advances the ability to predict and interpret which genetic mutations found in cancer genomes are causing the disease.

“If we can better understand why a person has cancer, and what particular genetic mutations are driving it, we can better assess risk and pursue new treatments,” says Salk physician-scientist 杰西·迪克森, senior author of the paper and an assistant professor in the Gene Expression Laboratory.

Most genetic mutations have no impact on a cancer and the molecular incidents that lead to oncogene activation are relatively rare. Dixon’s lab studies how genomes are organized in 3D space and seeks to understand why these changes happen in some, but not the majority, of circumstances. The team also wants to identify factors that might distinguish where and when these events occur.

“A gene is like a light and what regulates it are like the light switches,” says Dixon. “We are seeing that, because of structural variants in cancer genomes, there are a lot of switches that can potentially turn ‘on’ a particular gene.”

Using CRISPR-Cas9 gene editing, the research team introduced genetic mutations by cutting DNA in certain locations of the genome. They found that some of the variants they created had major impacts on the expression of nearby genes, and could ultimately cause cancer, but that most had essentially no impact. Some genes appeared to go haywire when they were brought into environments with novel regulatory sequences, and others were not affected at all. The type of sequence that was introduced appeared to have a huge impact on whether or not the cell became cancerous.

“Our next move is to test whether there are other factors in the genome that contribute to the activation of oncogenes,” says Zhichao Xu, a postdoctoral fellow at Salk and the paper’s co-first author. “We are also excited about a new CRISPR genome editing technology we are developing to make this type of genome engineering work much more efficient.”

Other authors on the study are Sahaana Chandran, Victoria T. Le, Rosalind Bump, Jean Yasis, Sofia Dallarda, Samantha Marcotte, Benjamin Clock, Nicholas Haghani, Chae Yun Cho, Selene Tyndale, Graham McVicker, and Geoffrey M. Wahl of Salk; Dong-Sung Lee of the University of Seoul, South Korea; and Kadir Akdemir and P. Andrew Futreal of the University of Texas MD Anderson Cancer Center.

The research was supported by the National Institutes of Health (DP5OD023071), the Leona M. and Harry B. Helmsley Charitable Trust (2017-PG-MED001), the National Institutes of Health National Cancer Institute (R35 CA197687), and the Breast Cancer Research Foundation.

DOI: 10.1038/s41586-022-05504-4