Melanoma: What Are the Gaps in Our Knowledge?

C utaneous malignant melanoma (MM) falls into two main groups, based on aetiology [1–3]. First, a small minority of patients have acral MM, in which the disease occurs on the palms and soles. The incidence of acral MM is similar in people with widely different skin colours (and hence with different amounts of skin melanin), and at different latitudes. The palms and soles have a thick epidermis, and so few harmful photons of ultraviolet radiation (UVR) will penetrate to the germinative layers. Acral melanomas are therefore not believed to be causally related to UVR, and their aetiology remains a mystery. They will not be discussed further in this article. By contrast, more than 90% of MM occurs on non-acral sites and is thought to be caused by UVR [2,4]. The evidence for such causality comes from a variety of fields. MM is most common in those with pale skin, which has a relative lack of melanin, a substance that blocks photons from penetrating deeply into skin [2]. African people with very dark skin are hundreds of times less sensitive to the harmful effects of UVR than white Northern Europeans. Even within white Northern European populations, MM rates vary in relation to more subtle degrees of difference in sun sensitivity. Those with red hair, pale skin, and a tendency to freckle are about three times more likely to develop MM than those without these three features [2,5]. The dramatically elevated rate of MM in those with European ancestry in Australia is therefore what we would expect: susceptibility of the host coupled with enhanced environmental exposure leads to a high disease risk [4]. However, it is not just epidemiology that implicates a key role for UVR. Patients with the rare Mendelian disorder xeroderma pigmentosa (see dramatically increased risk of most types of skin cancer, including MM. This disorder is characterised acutely by sunburn in response to tiny amounts of UVR, and both this sunburn and the elevated cancer rates are a result of an inability to repair the DNA damage induced by UVR. The lesson is quite clear: it is not sunlight per se, but the highly mutagenic UVR part of the electromagnetic spectrum that is important for skin carcinogenesis. Given that we know the major host and environmental factors that lead to non-acral melanomas, one might think that we know enough to reduce the incidence of MM. But our ability to …