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Sequence of mutations leading to melanoma identified

New research has identified the specific sequence of genetic changes that cause benign moles to become malignant skin cancer, and researchers have replicated each step in vitro using CRISPR gene editing. This research has revealed molecular warning signs which could help physicians identify developing cancers earlier, or lead to new targeted therapies, according to a press release from the University of California San Francisco (UCSF).

The research was published in two papers in Cancer Cell (July 9, 2018; 34(1):45-55, and

“It’s a very crude assessment of the progression state of a tumour to measure it with a ruler. 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,” said Dr. Boris Bastian, a UCSF Health skin cancer pathologist and director of the Clinical Cancer Genomics Laboratory for the UCSF Helen Diller Comprehensive Cancer Center. Dr. Bastian was the lead author on the first paper.

The first study looked at a dataset of surgically removed melanoma tissue samples and the benign moles they developed from, taken from 82 patients. In a subset of these, matched samples of metastatic tumours and the primary skin melanomas the metastatic colonies had derived from were obtained.

Molecular differences between benign growths, malignant melanomas, and metastatic colonies could then be compared within the same patients.

The researchers sequenced tumour DNA to identify gene mutations arising at different stages of cancer evolution and also measured changes in RNA to connect these mutations to related changes in gene activity. “This is the first study to profile both DNA and RNA from matching melanoma samples and precursor moles from the same patients,” said Hunter Shain, PhD, an assistant professor in the department of dermatology and cancer geneticist at UCSF who co-led the first study with Dr. Bastian.

They found that as tumours progress, multiple independent gene mutations repeatedly tweak central molecular pathways controlling cell growth, tumour suppression and DNA regulation until enough mutations accumulate to break down cells’ natural protective mechanisms and trigger cancer.

“The field has a tendency to oversimplify how cancers evolve, as if there were just a switch that gets flipped on.” Dr. Shain said, citing the team’s own previous work pointing to early activation of the MAP kinase pathway in melanomas. “Now we see that this pathway is turned on just a little early on, then ramped up over the course of tumour evolution. We think this may allow cancers to avoid cellular alarm bells until enough genetic changes have accumulated that the alarms no longer function.”

One of their findings was that moles consistently developed mutations in the SWI/SNF class of DNA regulatory genes as one step in their transition to malignancy. This could make such mutations a useful clinical marker for identifying dangerous moles, the authors note.

The second part of the research, published in the latter paper, involved inducing recreating and studying each step in melanoma progression in a laboratory setting, in order to learn the specific biological effects of each step and associated mutations. One finding that came from this was that mutations disrupting the central tumour suppressor gene CDKN2A did not simply unleash tumour growth, as had been predicted, but also caused affected cells to become highly mobile, and thereby more prone to invade and spread to other parts of the body. This increased mobility occured through activation of a transcription factor protein called BRN2.

Investigators suggest that in addition to identifying a key mechanism driving melanoma’s ability to metastasize, the new research demonstrates a novel use for CRISPR gene-editing as a laboratory tool for studying melanoma.

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