Study Identifies Key Steps in Melanoma Transformation, Biomarkers for Metastasis

Through the novel use of CRISPR gene editing, researchers have identified the sequence of genetic changes that allow benign moles to transform into melanoma, according to a recent study. The findings could lead to new targeted therapies and help clinicians detect developing skin cancers before they spread, according to the authors.

The research was published in 2 companion papers in Cancer Cell.

Researchers from UC San Francisco systematically traced how new mutations and changes in gene activity break down cellular protective mechanisms—triggering the transformation and spread of melanoma. In doing this, the researchers identified key molecular biomarkers that could be used by health care providers to detect rapidly progressing melanomas that require additional treatment.

Dermatologists currently assess melanoma progression based on the thickness of the lesion to determine whether surgery alone will be sufficient to eliminate the cancer; however, this approach is not always reliable.

“It’s a very crude assessment of the progression state of a tumor to measure it with a ruler,” study author Boris Bastian, MD, PhD, a UCSF Health skin cancer pathologist, said in a press release. “We’d prefer to be able to measure a mole’s genetic state to assess its risk of turning malignant, but the biology of this transformation has not been fully understood.”

In the first study, the researchers profiled both DNA and RNA from matching melanoma samples and precursor moles from the same patients. The researchers evaluated a unique dataset of 230 surgically removed melanoma tissue samples from 82 patients in which malignant tumors and the benign moles from which they had developed were preserved side by side. The researchers also obtained matched samples of metastatic tumors and the primary melanomas in the skin from which the metastatic colonies had derived.

The researchers sequenced tumor DNA to identify gene mutations arising at different stages of cancer evolution and measured changes in RNA to connect these mutations to related changes in gene activity. According to their findings, multiple gene independent mutations come into play, controlling cell growth, tumor suppression, and DNA regulation until enough mutations accumulate to break down cells’ natural protective mechanisms and trigger cancer.

Additionally, the researchers also found that moles consistently developed mutations in the SWI/SNF class of DNA regulatory genes, indicating that this marker could be used to identify potentially harmful moles in need of treatment.

In the second study, the researchers demonstrated a novel use for CRISPR gene-editing and identified a key mechanism in melanoma’s ability to metastasize.

To recreate and study the steps of melanoma evolution, the researchers precisely inserted the genetic sequence of mutations into normal human skin cells in the lab. They found that mutations disrupting the central tumor suppressor gene CDKN2A did not simply unleash tumor growth, but also caused affected cells to become highly mobile through the activation of a transcription factor protein called BRN2.

The researchers hope that the findings will lead to new research into rapid treatment and diagnosis of melanoma, and be used to develop clinical genetic tests that will be able to identify patients at highest risk.

“Because we haven’t had the tools to identify who is at high risk of metastasis, we have tended to treat everybody as if they were at high risk, exposing them to intense treatment and potential side effects,” Dr Bastian said in the press release. “We anticipate that looking at genetic changes in melanoma samples here at UCSF will allow us to identify melanomas that have progressed to a dangerous state and deploy systemic treatments earlier, which will increase their effectiveness for our patients.”

Reference

Shain AH, Joseph NM, Yu R, et al. Genomic and transcriptomic analysis reveals incremental disruption of key signaling pathways during melanoma evolution. 2018. https://doi.org/10.1016/j.ccell.2018.06.005

Zeng H, Jorapur A, Shain AH, et al. Bi-allelic loss of CDKN2A initiates melanoma invasion via BRN2 activation. 2018. https://doi.org/10.1016/j.ccell.2018.05.014

Evolution of Melanoma Reveals Opportunities for Intervention [news release]. UCSF’s website. https://www.ucsf.edu/news/2018/07/411051/evolution-melanoma-reveals-opportunities-intervention. Accessed July 10, 2018.