UK Health

SCLC line: 'Full genetics of cancer mapped'

News   •   Dec 18, 2009 09:58 GMT

Many newspapers have reported that scientists have ”cracked the code” of cancer with the analysis of the entire genetic sequence of malignant melanoma skin cancer and an aggressive form of lung cancer.

In the past researchers were only able to look at smaller sections of DNA, as sequencing the entire DNA of a cell would have taken a very long time. Recent advances in technology have allowed the analysis of the entire sequence of DNA within a cell much more quickly.However, cancer is a complex disease and not all individuals with cancer will have exactly the same mutations found in this research. Equally, not all of the mutations identified will be contributing to the cancerous nature of the cells. Therefore, future research will be needed to look at DNA from many other individuals to pinpoint which mutations are likely to cause these cancers.

These types of advances may mean that eventually each patient will routinely have their entire cancer genome sequenced. However, this is not likely to happen in the near future and we do not yet know enough to be able to use this knowledge to help tailor indviduals’ treatments, as several newspapers have claimed.

Where did the story come from?

This research was conducted by Dr Erin D Pleasance and colleagues from Wellcome Trust Sanger Institute and other research centres in the UK and the US. It was published as two papers in the peer-reviewed scientific journal Nature. One study was funded by the Wellcome Trust, sources of funding were not stated for the other.

These studies are part of a larger ongoing project called The International Cancer Genome Consortium that is attempting to genetically analyse 50 different tumour types.

What kind of research was this?

This was laboratory research looking at the genetic sequence of various human cancer cells grown in the laboratory. The researchers wanted to identify genetic mutations that might cause cancer.

Previous studies have mostly looked at mutations in small numbers of genes or in small sections of DNA, but this research aimed to read the entire sequence genetic sequence of these cancerous cells. Advances in DNA technology have now made it possible to perform this type of analysis much more quickly and easily than before. The researchers hope that looking at the entire genetic sequence will help them to further understand factors such as how DNA is affected by known cancer risks such as UV rays and tobacco smoke, as well as which mutations might be behind the formation of cancers and how the cells attempt to repair mutated DNA

What did the research involve?

The researchers used cancer cells that had been removed from people with cancer and grown in a laboratory. They looked at the overall pattern of mutations that the cancer cells contained. The cells examined were malignant melanoma cells taken from one person and small cell lung cancer cells (SCLC – a particularly aggressive form of lung cancer) taken from another person. The researchers also analysed the DNA of normal cells from these patients to help identify the mutations in the DNA of the cancerous cells.

The SCLC cells came from a site where the lung cancer had metastasised (spread) to the bone of a 55-year-old man before he received chemotherapy. It was not known whether this man had smoked. The melanoma cells came from a metastasis in a 43-year-old man with malignant melanoma before he received chemotherapy.

The researchers used special techniques that can rapidly read the sequence of letters that make up the code of the DNA in the cells, a technique called sequencing. Advances in DNA technology have made it easier and quicker to sequence the entire genetic code of a cell, called the genome.

The researchers then compared the sequences in the cancer cells to those in normal cells to identify any changes (mutations) in their DNA. These changes can range from changing a single letter in the code to rearranging whole sections of DNA. They looked at the characteristics of these mutations to see whether they were typical of the effects of UV exposure (a known risk factor for skin cancer), or of the 60 chemicals that are found in tobacco smoke (a known risk factor for lung cancer) that might potentially cause mutations. They also looked at what genes (sequences which carry instructions for making proteins) were affected, and whether the mutations were spread evenly throughout the DNA.

What were the basic results?

In the malignant melanoma skin cancer cells, the researchers identified 33,345 single-letter changes in the DNA. The also identified various other mutations involving rearrangements, insertions and deletions of sections of DNA. Most of the mutations identified appeared to be caused by ultraviolet light exposure, which is known to be a risk factor for skin cancer. Mutations were found to be more common in areas where the genetic sequence did not contain any genes, suggesting that the cells’ DNA repair mechanisms had preferentially fixed mutations that affected genes.

In the SCLC line, the researchers identified 22,910 single letter changes in the DNA. This included 134 changes within the pieces of genes that contained the instructions for making proteins. These genes with mutations included those known to play a role in cancer. As was the case in the melanoma cells, they also identified larger mutations involving rearrangements, insertions and deletions of chunks of DNA.

Most of the mutations they identified in the lung cancer cells did not appear to be giving them a ‘selective advantage’ that would help them to survive and divide. The mutations were of varying types, which indicated the effects of the many different cancer–causing chemicals found in cigarette smoke. Again, there was evidence that suggested that the cells’ DNA repair mechanisms had ‘fixed’ some of the mutations that affected genes.

The researchers identified one specific mutation that caused a duplication of a part of a gene called CHD7. Two other SCLC lines were also shown to have mutations that caused part of the CHD7 gene to be inappropriately joined to the PVT1 gene. This suggested that rearrangements in the CHD7 gene may be common in small cell lung cancer.

Based on their results and the average number of cigarettes needed to cause lung cancer, the researchers estimated that cells that eventually become cancerous develop an average of one mutation for every 15 cigarettes smoked.

How did the researchers interpret the results?

The researchers concluded that their results “illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic”. They also say that their findings “illustrate the potential for
next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.”

Conclusion

This research has been made possible by advances in DNA sequencing technology, and understanding the mutations that lie behind cancer may have numerous implications for future research. However, cancer is a complex disease, and not all of the mutations identified in these studies will be contributing to the cancerous nature of the cells. Equally, not all individuals with cancer will have exactly the same mutations. Therefore, future research will be needed to look at DNA from many other individuals to try to identify which mutations are likely to be causing the cancers.

Eventually, these and future advances may mean that sequencing the entire genome of cancer cells from each individual may eventually become a routine part of cancer care. However, this is not likely to be the case in the near future and currently, we do not know enough to be able to use this knowledge to help doctors to tailor treatment to the individual.