Melbourne researchers have uncovered how melanoma cells overwhelm DNA changes as this skin cancer progresses from the early, treatable stages through to the final, lethal stage.
Using genomics, the team tracked the DNA changes that occur in melanoma samples donated by patients as their disease progresses, right up to the time of the patient’s death. This revealed chaotic and exciting genetic changes that built up in melanoma cells as the cancers progressed, providing clues to potential new approaches to treating the disease.
Research published in Nature Communications, Led by Professor Mark Shackleton, Professor of Oncology at Alfred Health and Monash University. Professor Tony Papenfoss, who leads the computational biology topic at WEHI and co-chairs the Computational Cancer Biology Program at the Peter McCallum Cancer Center; Dr. Ismail Vergara, computational biologist at WEHI, Peter Mack and Australian Melanoma Institute.
In a glance
- Genomics has been used to track DNA changes in melanoma samples donated by patients whose disease has recurred and progressed after treatment.
- The research revealed that end-stage melanomas have acquired dramatic and chaotic genetic changes associated with aggressive disease growth and treatment resistance.
- Understanding the genetic changes that drive skin cancer growth and treatment resistance could lead to new ways to treat this cancer.
Track a devastating cancer
Skin cancer – the third most common type of cancer diagnosed in Australia – results from harmful changes in the DNA of skin cells called melanocytes, and is usually the result of exposure to ultraviolet rays from sunlight. These genetic changes enable the uncontrolled growth of cells, and the formation of melanoma. Professor Shackleton said that as melanoma cells continue to divide, some of them accumulate more DNA changes, helping them grow faster and spread.
“In the early stages, melanomas can be treated with surgery. However, they sometimes recur and progress to more aggressive forms. While there are excellent new treatments in these contexts, this advanced disease is difficult to treat for some patients.”
“We used DNA sequencing to document the genetic changes that occurred when melanomas recurred and advanced in patients.”
The team obtained genome sequencing data from tumors donated by these patients and inserted it into a mathematical model. This revealed that as melanomas progressed, they acquire increasingly dramatic genetic changes that significantly add to the initial DNA damage from the ultraviolet rays that caused the melanoma in the first place, Professor Pappenfoss said.
“The primary melanomas in the early stages showed DNA changes from damage from UV rays – similar to the misspelled words in the book. These changes were enough to allow melanoma cells to grow uncontrollably in the skin,” he said.
“In contrast, highly aggressive end-stage melanomas, in addition to preserving most of the original DNA damage, accumulated even more dramatic genetic changes. Each patient had melanoma cells in which the total amount of DNA was doubled – a phenomenon Unusually not seen in normal cells – but on top of that, large chunks of DNA have been rearranged or lost – like mixed or lost pages in a book.We think this flood of DNA alters the genes that were driving cancer, making disease even more aggression.
The genomes of late stage melanoma were completely messy. We believe that these mutations occur in a sudden, massive wave, different from the gradual changes in DNA that accumulate from UV exposure in the form of early stage melanomas. The melanoma cells that acquire these chaotic changes appear to overwhelm the early, less abnormal, slower-growing cells.
New insights into skin cancer
Professor Shackleton said the research provided an in-depth explanation of how melanomas change as they grow and may also provide clues on how to treat skin cancer.
“We have mapped DNA-sequence changes to track disease spread in individual cases, and to create ‘family trees’ of melanoma cells that have grown, proliferated and changed over time in each patient. In the early stages of melanomas in the skin, the DNA changes were consistent with damage Ultraviolet rays, while the changes we saw in later-stage melanoma were completely wild, associated with increased growth and spread of disease, and avoidance of the body’s immune defenses. We could also link some DNA changes to the development of treatment resistance.
The research also revealed key cancer genes that may contribute to the growth and spread of skin cancer.
“Many of the patients’ late-stage melanomas have damaged genes that are known to control cell growth and protect DNA structure during cell growth and division. When these genes do not function properly, cell growth becomes uncontrolled and the DNA inside cells becomes more abnormal – It’s the snowball effect. The results also indicate that treatments that exploit these harmful changes may be beneficial in treating skin cancer in its later stages, “said Professor Shackleton.
The study included tumor samples from the Peter Mack Post-Death Tissue Collection Program (CASCADE) – where patients volunteer to undergo a rapid autopsy after they die.
“Our entire team would like to express our sincere gratitude to the patients and their families whose participation in CASCADE made this research possible. Professor Shackleton said: “We hope that the insights we have gained lead to better treatments for people with skin cancer.
The research was supported by the Lorenzo and Pamela Galli Charitable Trust, Australian NHMRC, Pfizer Australia, veski, Victorian Cancer Agency, European Commission Horizon Scholarship 2020, Victorian Institute of Forensic Medicine, Tobin Brothers Funerals and the Peter MacCallum Cancer Foundation. , Bioplatforms Australia, the Melanoma Institute of Australia, Cancer Council of Victoria, Victorian Cancer Biobank, the Melbourne Melanoma Project and Victorian Government.
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