A new study offers insight into what happens in cancer cells as they develop over time and become more and more dangerous. Mutations, changes in genome structure and genome duplication all contribute to cancer development and the potential to metastasise. Researchers have now mapped what the cancer cells do first – and what follows.
When human cells develop into cancer cells, they change to become virtually unrecognisable – both in relation to their appearance but also to their genetics.
Genes are often sliced up, cut out, doubled and swapped around, all of which help the cancer grow and spread to the rest of the body.
Researchers have long been interested in how the genetics of cancer cells change as the cancer develops, and now researchers have determined what happens step by step.
The research shows that cancer does not always go directly from A to B but often takes detours to get to a stage at which the genetic set-up enables it to grow and spread most easily.
“This study contributes to the comprehensive research currently underway to improve understanding of how tumours develop and why cancer metastasises,” explains a researcher behind the study, Toby Baker, Postdoctoral Fellow, Department of Medicine, University of California, Los Angeles, USA.
The research has been published in Cancer Discovery.
Thorough investigation of cancer mutations
Investigating how the genome develops as cancer develops might theoretically be possible by taking a new biopsy from a person with cancer every day and examining it for genetic changes.
This is neither practical nor ethical, so instead the researchers examined the genomes in 6,091 tumours and compared them with the genomes in healthy cells from the same people.
Comparing genetic information between diseased and healthy cells can identify differences between the two and thereby determine which mutations are related to cancer development.
Tumours have point mutations in which individual building blocks in the DNA are replaced by others. These can inactivate a gene, such as one that suppresses tumour development, but they can also increase the effect of a gene, such as one that controls cell growth. Both benefit cancer cells.
However, the genetic landscape also undergoes major changes, including in the number of copies of the entire genome or parts thereof.
Cells normally have two copies of each chromosome, but cancer cells may have one copy that has been removed or have three, four or more copies of whole chromosomes or parts thereof if this benefits the tumour.
“We investigated the frequent changes in the number of copies of the whole genome or parts thereof in cancer cells. For example, about 50% of breast tumours contain an extra chromosome 1q. We also aimed to investigate when the cancer cells undergo these genetic changes as cancer develops,” says Toby Baker.
Differences in mutations affect the development of cancer cells
The researchers studied point mutations to allocate changes in the number of genomes into a relative time scale – approximately rhythmic over time.
This means few differences initially between the number of mutations on a chromosome in a healthy cell and on a chromosome in a cancer cell.
Over time, the differences in mutations will increase exponentially and so will the differences between chromosomes.
If a chromosome has been copied an extra time in a cancer cell, researchers can use the difference in the number of mutations on the two copies of the chromosome to determine when the chromosome was copied.
If the mutations on the two copies are quite similar, the extra copy is probably relatively new. But if the number of mutations differs greatly between the two copies, this means that the extra copy arose early in the development of the cancer.
“We have developed an algorithm that can pinpoint the timing of the various genetic changes, including the more complex ones in which the whole genome or parts thereof are doubled. This is useful because metastatised tumours have more doubled genetic material,” explains Toby Baker.
Pinpoints the time when mutations occur
The algorithm now enables the researchers to get a much clearer picture of how the major genetic changes contribute to cancer development and at what point they occur.
The study also improves understanding of the complexity of the genetic structure of cancer cells. For example, a cancer cell can make major genetic changes in a chromosome, which is then copied into twice the number of chromosomes.
If, for example, a genome doubles, a cancer cell has three genomes instead of two, but then these genomes can further double, and then a cancer cell has six genomes.
The effect of this depends on when other cancer-related mutations arose in the specific chromosome. If they occurred early, the cancer-related changes will be present in all six genomes versus only in a few if they occurred later.
All these factors affect the expression of cancer, and the research put all these events into a timeline.
Cancer seldom goes directly
The research reveals that cancer cells do not always go directly from the initial cancer development to the most advanced stages.
If, for example, a tumour changes from two to three copies of chromosome 1, this could mean that the tumour has made an extra copy. But the tumour could have doubled the number of chromosomes from two to four and then jettisoned one.
“This is interesting from an evolutionary perspective because development happens over time and not as directly as one might imagine. One of our findings is that cancer development is much more arbitrary,” says Toby Baker.
Mutations and the doubling of genomes occurs in a specific order
Finally, the research also improves understanding of genes known to be associated with cancer and when mutations in them contribute to cancer development.
For example, TP53 in its normal form helps to suppress cancer development. This gene very often mutates in tumours to ensure the cancer cells’ unrestricted growth, thereby enabling them to evade a well-functioning gene.
If the cancer cells mutate TP53 on one chromosome and then double the genome, the number of well-functioning TP53 will also increase.
Therefore, the typical sequence is that the tumour initially jettisons the genome with the well-functioning TP53 and then starts copying the one that is mutated.
“This helps to understand how cancer cells develop from the earliest stages onwards, and we can use this to treat people with cancer in various stages to determine the prognosis for individuals,” concludes Toby Baker.
