Elizabeth Marchionne, MD, examines a mole on a patient's shoulder. Credit: Barbara Ries
UC San Francisco researchers have identified the sequence of genetic changes that transform benign moles to into malignant skin cancer and have used CRISPR gene editing to recreate the steps of melanoma evolution one by one in normal human skin cells in the lab. The research identified key molecular warning signs that could be used by clinicians to catch developing cancers before they spread and could also lead to new targeted therapies.
Melanoma is most commonly triggered by exposure to ultraviolet (UV) rays in sunlight, which damages DNA, creating genetic mutations that cause skin cells to multiply and spread. Often, these cells produce benign moles, pigmented skin growths that are self-limiting in size. While most moles never turn cancerous, some can transform into malignant melanoma and rapidly spread to other parts of the body. Melanomas can almost always be successfully treated if they are caught early, but fewer than 30 percent of patients with metastatic melanoma survive more than 5 years, making melanoma the deadliest form of skin cancer.
The new research, published July 9, 2018, in two companion papers in Cancer Cell, for the first time systematically traced the how new mutations and changes in gene activity break down cellular protective mechanisms, allowing moles to transform into melanoma and begin to spread. The new studies also identify new biomarkers that could be used in the clinic to more reliably detect rapidly progressing melanomas that require additional treatment beyond surgical removal.
Dermatologists currently diagnose melanomas by taking biopsy samples of suspicious skin growths. If the lesion turns out to be a melanoma, pathologists measure its thickness to determine how far it has progressed and whether surgery alone will be enough to eliminate the cancer: The thicker the melanoma, the greater the risk that it has already begun spreading to other parts of the body. But this approach is not very reliable — some thin melanomas metastasize and some thick ones do not.
“It’s a very crude assessment of the progression state of a tumor 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 Boris Bastian, MD, PhD, a UCSF Health skin cancer pathologist who directs the Clinical Cancer Genomics Laboratory for the UCSF Helen Diller Comprehensive Cancer Center and was one of the leaders of the new research.
In the first study, led by Bastian and UCSF cancer geneticist Hunter Shain, PhD, the researchers studied a unique dataset 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. In a subset of patients, the researchers also obtained matched samples of metastatic tumors and the primary melanomas in the skin from which the metastatic colonies had derived. By analyzing these 230 tissue samples, the researchers to compare molecular differences between benign growths, malignant melanomas, and metastatic colonies within the same patients.
The researchers sequenced tumor 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,” Shain said.
Read more at UCSF.edu