QIMR Professor Nick Hayward said his team discovered two genes that increase melanoma risk by influencing the number of moles a person has.
In a follow-up study of a further 4,000 people, the researchers went on to show the same two genes also increase the risk of moles developing into melanoma - the deadliest form of skin cancer.
"It has long been known that having a large number of moles is the biggest risk factor," Professor Hayward said.
"Therefore we predicted we would find genes linking moles and melanoma.
"We now have conclusive genetic evidence that having a large number of moles increases an individual's risk of developing melanoma."
The study found that people who carry one of these two gene variants from one parent have a 25 per cent greater chance of developing melanoma, while individuals who carry variants from both parents have double the risk.
Professor Hayward said the study, part of an international project, would help develop screening techniques and ultimately allow scientists to develop new therapies.
"This finding improves our understanding of the genetics of melanoma and therefore the molecular pathways that lead to its development."
Australia has the highest incidence of melanoma in the world, with more than 10,000 new cases and 1,000 people dying from the disease every year.
Queensland is the worst-hit state in Australia, with seven Queenslanders diagnosed with melanoma each day.