Melbourne researchers have discovered how melanoma cells are flooded with DNA changes as this skin cancer progresses from early stages that can be treated to a lethal stage disease.
Using genomics, the team tracked DNA changes that occurred in melanoma samples given by patients as their disease progressed, right up to the time the patient died. This revealed dramatic and chaotic genetic changes that accumulated in the melanoma cells as the cancers progressed, evidencing possible new approaches to treating this disease.
The research, published in Nature Communication, led by Professor Mark Shackleton, Professor Director of Oncology at Alfred Health and Monash University; Professor Tony Papenfuss, who heads the WEHI Computational Biology Subject and is in charge of the Peter MacCallum Cancer Center Computational Cancer Biology Program; and Dr Ismael Vergara, computational biologist at WEHI, Peter Mac and the Australian Melanoma Institute.
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- Genomics were used to monitor DNA changes in melanoma samples provided by patients who developed the disease and developed after treatment.
- The research showed that end-stage melanomas experienced dramatic and chaotic genetic changes associated with aggressive disease growth and resistance to treatment.
- Understanding the genetic changes that drive melanoma growth and resistance to treatment could lead to new ways of treating this cancer.
Surveillance for destructive cancer
Melanoma – the third most commonly diagnosed cancer in Australia – is caused by destructive changes occurring in the DNA of skin cells called melanocytes, usually as a result of exposure to ultraviolet (UV) radiation. ) from sunlight. These genetic changes enable uncontrolled growth of the cells, creating melanoma. As the melanoma cells continue to grow, some accumulate even more DNA changes, helping them grow even faster and spread, Dr. Shackleton said.
“In the early stages, melanomas can be treated with surgery. However, they recur and progress to more aggressive forms. While new treatments are excellent in these contexts, for some patients this progressive disease is difficult to treat, “he said.
“We used DNA sequences to record genetic changes that occurred as melanomas recurred and progressed in patients.”
The team obtained genome sequence data from tumors donated by these patients and fed them into a mathematical model. This revealed that as melanomas progress, they undergo ever-increasing genetic changes that greatly contribute to the initial DNA damage from UV radiation that caused the melanoma in the first place, said Professor Papenfuss.
“Primary melanomas showed an early stage of changes in their DNA from UV damage – similar to misspelled words in a book. These changes were enough to allow the melanoma cells to grow uncontrollably in the skin,” he said.
“In contrast, end-stage, highly invasive melanomas, in addition to sustaining most of the original DNA damage, accumulated even more impressive genetic changes. All patients had melanoma cells in the whether the total amount of DNA had doubled – a rare phenomenon not seen in normal cells – but in addition, large sections of DNA were rearranged or lost – such as bent or missing leaves in We believe that this deluge of DNA ‘supercharged’ altered the genes that drove the cancer, making the disease more invasive.
“The genomes in the late-stage melanomas were completely disorganized. We believe that these mutations occur in a large, sudden wave, different from the gradual DNA changes that occur. collection from UV exposure in the form of melanomas at an earlier stage. The melanoma cells that build them. chaotic changes appear to overwhelm the slower, smaller cells, “said the t. -Professor Papenfuss.
New perspectives on melanoma
Professor Shackleton said the research provided an in-depth explanation of how melanomas change as they grow and may also suggest how melanoma might be treated.
“We mapped continuous DNA changes to monitor the spread of the disease in individual cases, creating‘ family trees ’of melanoma cells that grew, spread and evolved over time in each patient. In early melanomas of the skin, the DNA changes were consistent with UV damage, while the changes we observed in later melanoma were completely wild, and associated with growth and spread. more of the disease, and avoid the body ‘s immune defenses. We could also link some DNA changes to the development of resistance to treatment, “he said.
The research also revealed key cancer genes that can contribute to the growth and spread of melanoma.
“Late-stage melanomas of many patients damaged genes that were known to control cell growth and to protect DNA structure during cell growth and division. When these genes do not function properly, the cells grow uncontrolled and the DNA inside cells becomes even more rare – it is a snowball effect.The findings also suggest that treatments that take advantage of these destructive changes could be useful for the treatment of late-stage melanoma, “said Dr. Shackleton.
The study included tumor samples from the Peter Mac Cancer Collection After CAS (CASCADE) program – in which patients voluntarily undergo autopsy shortly after death.
“Our entire team would like to extend our sincere thanks to the patients and families who made the participation in CASCADE this research possible. We hope that the insights we have gained will lead to better treatments for people with melanoma, “said Dr Shackleton.
Source:
Walter and Eliza Hall Institute