Deluge of DNA changes drives progression of fatal melanomas

Date:
March 22, 2021
Source:
Walter and Eliza Hall Institute
Summary:
Australian researchers have revealed how melanoma cells are
flooded with DNA changes as this skin cancer progresses from early,
treatable stages through to fatal end-stage disease.



FULL STORY ========================================================================== Melbourne researchers have revealed how melanoma cells are flooded with
DNA changes as this skin cancer progresses from early, treatable stages
through to fatal end-stage disease.


========================================================================== Using genomics, the team tracked DNA changes occurring in melanoma
samples donated by patients as their disease progressed, right through
to the time the patient died. This revealed dramatic and chaotic genetic changes that accumulated in the melanoma cells as the cancers progressed, providing clues to potential new approaches to treating this disease.

The research, published in Nature Communications, was led by Professor
Mark Shackleton, Professor Director of Oncology at Alfred Health
and Monash University; Professor Tony Papenfuss, who leads WEHI's
Computational Biology Theme and co-heads the Computational Cancer
Biology Program at Peter MacCallum Cancer Centre; and Dr Ismael Vergara,
a computational biologist at WEHI, Peter Mac and the Melanoma Institute Australia.

At a glance
* Genomics has been used to track DNA changes in melanoma samples
donated
by patients whose disease recurred and progressed after treatment.

* The research revealed that end-stage melanomas acquired dramatic and
chaotic genetic changes that are associated with aggressive disease
growth and treatment resistance.

* Understanding the genetic changes that drive melanoma growth and
treatment resistance could lead to new approaches to treating
this cancer.

Tracking a devastating cancer Melanoma -- the third most commonly
diagnosed cancer in Australia -- is caused by damaging 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, forming
a melanoma. As the melanoma cells keep dividing, some accumulate even
more DNA changes, helping them to grow even faster and spread, said
Professor Shackleton.



==========================================================================
"At early stages, melanomas can be cured with surgery. However, they
sometimes recur and progress to more aggressive forms. While there
are excellent new therapies in these contexts, for some patients this progressing disease is difficult to treat," he said.

"We used DNA sequencing to document genetic changes that occurred as
melanomas recurred and progressed in patients." The team obtained genome sequencing data from tumours that had been donated by these patients
and fed it into a mathematical model. This revealed that, as melanomas progress, they acquire increasingly dramatic genetic changes that add substantially to the initial DNA damage from UV radiation that caused
the melanoma in the first place, said Professor Papenfuss.

"Early-stage primary melanomas showed changes in their DNA from UV
damage - - akin to mis-spelt 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 aggressive melanomas, in addition to maintaining most of the original DNA damage, accumulated even more
dramatic genetic changes. Every patient had melanoma cells in which the
total amount of DNA had doubled -- a very unusual phenomenon not seen in
normal cells -- but on top of that, large segments of DNA were rearranged
or lost -- like jumbled or missing pages in a book. We think this deluge
of DNA changes 'supercharged' the genes that were driving the cancer,
making the disease more aggressive.



==========================================================================
"The genomes in the late-stage melanomas were completely chaotic. We
think these mutations occur in a sudden, huge wave, distinct from to the gradual DNA changes that accumulate from UV exposure in form earlier-stage melanomas. The melanoma cells that acquire these chaotic changes seem to overwhelm the earlier, less-abnormal, slower growing cells," Professor Papenfuss said.

New insights into melanoma Professor Shackleton said the research
provided an in-depth explanation of how melanomas change as they grow
and may also provide clues about how melanoma could be treated.

"We mapped sequential DNA changes to track the spread of the disease in individual cases, creating 'family trees' of melanoma cells that grew,
spread and changed over time in each patient. In early-stage melanomas
in the skin, the DNA changes were consistent with UV-damage, while the
changes we saw in later-stage melanoma were totally wild, and associated
with increased growth and spread of the disease, and evasion of the body's immune defences. We could also link some DNA changes to the development
of treatment resistance," he said.

The research also revealed key cancer genes that may contribute to the
growth and spread of the melanoma.

"Many patients' late-stage melanomas had damage to genes known to
control cell growth and to protect the structure of DNA during cell
growth and division.

When these genes don't work properly, cell growth becomes uncontrolled
and the DNA inside cells becomes even more abnormal -- it's a snowball
effect. The findings also suggest that therapies which exploit these
damaging changes might be useful for treating late-stage melanoma,"
Professor Shackleton said.

The study included tumour samples from Peter Mac's Cancer tissue
Collection After Death (CASCADE) program -- in which patients volunteer
to undergo a rapid autopsy following their death.

"Our whole team would like to extend our sincere gratitude to the
patients and their families whose participation in CASCADE made this
research possible. We hope that the insights we have gained will lead
to better treatments for people with melanoma," Professor Shackleton said.

The research was supported by the Lorenzo and Pamela Galli Charitable
Trust, the Australian NHMRC, Pfizer Australia, veski, the Victorian Cancer Agency, a European Commission Horizon 2020 grant, the Victorian Institute
of Forensic Medicine, Tobin Brothers Funerals, the Peter MacCallum Cancer Foundation, Bioplatforms Australia, the Melanoma Institute of Australia,
Cancer Council of Victoria, the Victorian Cancer Biobank, the Melbourne Melanoma Project and the Victorian Government.

========================================================================== Story Source: Materials provided by Walter_and_Eliza_Hall_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ismael A. Vergara, Christopher P. Mintoff, Shahneen Sandhu, Lachlan
McIntosh, Richard J. Young, Stephen Q. Wong, Andrew Colebatch,
Daniel L.

Cameron, Julia Lai Kwon, Rory Wolfe, Angela Peng, Jason Ellul,
Xuelin Dou, Clare Fedele, Samantha Boyle, Gisela Mir Arnau,
Jeanette Raleigh, Athena Hatzimihalis, Pacman Szeto, Jennifer Mooi,
Daniel S. Widmer, Phil F. Cheng, Valerie Amann, Reinhard Dummer,
Nicholas Hayward, James Wilmott, Richard A. Scolyer, Raymond J. Cho,
David Bowtell, Heather Thorne, Kathryn Alsop, Stephen Cordner,
Noel Woodford, Jodie Leditschke, Patricia O'Brien, Sarah-Jane
Dawson, Grant A. McArthur, Graham J. Mann, Mitchell P. Levesque,
Anthony T. Papenfuss, Mark Shackleton. Evolution of late-stage
metastatic melanoma is dominated by aneuploidy and whole genome
doubling. Nature Communications, 2021; 12 (1) DOI: 10.1038/s41467-
021-21576-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/03/210322085513.htm

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