World's largest genetic study of 'moliness' helps unravel mysteries of melanoma

by QIMR Berghofer Medical Research Institute

edited by Lisa Lock, reviewed by Robert Egan

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QIMR Berghofer scientists have uncovered hundreds of genes that play a role in the growth of both moles and melanoma, in a discovery that could lead to new ways of preventing and treating the deadliest form of skin cancer. The world's largest genetics study of "moliness," published in Nature Communications, is unraveling the complex causes of both moles and melanomas that are not related to well-known risks caused by sun exposure, skin color and pigmentation.

The team found risk genes linked to biological pathways that could lead to the development of a mole or melanoma. These include an immune response pathway that may be failing to control cell growth, and genes implicated in harmful cell proliferation in other types of cancer, such as breast, prostate and brain cancers.

Working out how to stop these risk pathways could lead to new melanoma drug targets and prevention strategies that go beyond sun protection.

Why new targets are needed

Associate Professor Matthew Law, team head of QIMR Berghofer's Genetics and Skin Cancer Lab, said research has made major inroads, but Australia still has the world's highest incidence of melanoma. About 1,400 Australians lose their lives to the complex disease each year.

"We know how to reduce sun exposure and risk through SunSmart behaviors, and new immunotherapies have greatly improved survival rates. But people still get melanoma and people still die from melanoma," Law said.

"Existing immunotherapies fail to work for half of all patients with late-stage melanoma, so we need to find other ways to target the disease. By studying moles, we're learning more about the biology of melanoma so we can find new ways of controlling it."

Moles and melanomas share the same cellular origin, forming from a pigment-producing cell called a melanocyte that gives skin its color. In moles, the cell multiplies to form a cluster, then stops growing, leaving a harmless spot. In melanoma, the cell growth continues aggressively.

Moliness is strongly influenced by your genes, and having a high mole count is a major risk factor for melanoma. About a third of melanomas develop from a mole.

Genetic clues from mole counts

The QIMR Berghofer research analyzed data from more than 85,000 participants of European ancestry, discovering 24 new genetic regions that determine the number of moles someone has. This is a fivefold increase from the five areas found in an earlier 2018 study, also led by QIMR Berghofer researchers.

All but one of the genetic regions for mole count also play a role in melanoma. The team pinpointed more than 250 key genes in these regions to prioritize for further research.

One of the new genes, SIKE1, regulates immune responses to viral infections. The researchers think it could enable the development of melanomas by malfunctioning and affecting the immune system's ability to detect and destroy melanocytes that are multiplying abnormally. This could be a promising target for a potential immunotherapy that could possibly prevent early-stage melanoma growth.

Lead author Shanika Jayasinghe from QIMR Berghofer said the study builds on decades of world-leading skin cancer research at the institute, which has been involved in every major study of the genetics of moles and melanomas, from twin studies to large-scale genome-wide research.

"I'm really proud to be continuing this long legacy of research. Our study increases understanding of why some people have a lot of moles and why some people develop melanoma so we can better treat and prevent this skin cancer," Jayasinghe said.

What comes next

The researchers used the study insights to create a Polygenic Risk Score (PRS) for moliness to predict those who are genetically more likely to have a large number of moles. This could be integrated into melanoma screening tools in the future to improve their accuracy in finding those at high risk so they can receive extra monitoring.

The next step is to analyze even larger data sets to find more genetic regions involved in moliness and melanoma. The researchers are also searching for existing drugs that could potentially target the newly identified biological pathways.

Publication details

G. J. M. Shanika R. Jayasinghe et al, A large-scale genome-wide association meta-analysis for nevus count provides direct insights into the genetics of melanoma, Nature Communications (2026). DOI: 10.1038/s41467-026-70368-5

Journal information: Nature Communications

Key medical concepts

MelanomaMelanocytesPolygenic Risk Scores

Clinical categories

OncologyDermatologyClinical genetics Provided by QIMR Berghofer Medical Research Institute Who's behind this story?

Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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