New study finds a long-neglected key factor in triggering multiple types of cancer

The top academic journal "Nature" recently published an important discovery about cancer

This discovery will lay the foundation for the development of new treatments in the clinic, as well as provide new biomarkers for predicting survival in cancer patients

Cancer cell genomes contain a large number of somatic mutations due to various internal or external factors, such as aging or UV radiation

Because the proportion of clustered mutations in all mutations is not high, their "contribution" to the development of cancer has not received enough attention in the past

The finding comes from the team's detailed mapping of aggregated somatic mutations

Next, the researchers developed artificial intelligence methods to analyze the vast amounts of data obtained, detect clustered mutations in patients, and infer the underlying processes by which such events arise

▲ Different forms of clustered mutations are widely present in 30 human cancers (Image source: Reference [1])

Further analysis found that some well-known driver genes, that is, key genes that promote the development of cancer, are popular locations for such clustered mutations, and their occurrence is often correlated with the overall survival rate of patients

For example, patients with clustering mutations in BRAF, a key driver gene commonly seen in melanoma, have a relatively higher overall survival rate than those without clustering mutations

▲ The presence of clustered mutations on several representative driver genes is associated with changes in patient survival (Image source: Reference [1])

The researchers also identified multiple factors that contribute to such aggregated somatic mutations, such as polybasic substitutions mostly produced by smoking or ultraviolet radiation

This enzyme is normally found in human cells and cuts off viruses that dare to break into the cells

As the name suggests, ecDNA is not compressed outside the chromosome like traditional DNA, but exists independently of the chromosome in a circular form

▲The "cyclone" (kyklonas) that causes aggregated mutations in circular ecDNA, the figure also shows another mutation pattern found in chromosomal DNA in the past, which is called "fog" because of its diffuse distribution characteristics ( Also named in Greek, omikli) (Image credit: References [2]; Credit: Catherine Eng)

While previous studies pointed to the presence of cancer driver genes such as EGFR on ecDNAs, this study observed multiple "molecular whirlwinds" on most mutated ecDNAs, including regions containing these cancer genes

Professor Alexandrov pointed out that this is a completely new mode of tumorigenesis

References:

[1] Erik N.

[2] Mapping mutation 'hotspots' in cancer reveals new drivers and biomarkers.