So far, two familial melanoma genes have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases1, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds2. To identify other familial melanoma genes, here we conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log odds ratio (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case–control sample. Likewise, it was similarly associated in an independent case–control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international two-stage meta-analysis of 11 genome-wide association studies (GWAS, five unpublished) of CMM and Stage two datasets, totaling 15,990 cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5×10−8) as did two previously-reported but un-replicated loci and all thirteen established loci. Novel SNPs fall within putative melanocyte regulatory elements, and bioinformatic and eQTL data highlight candidate genes including one involved in telomere biology.

Clinical research has established exercise as a safe and effective intervention to counteract the adverse physical and psychological effects of cancer and its treatment. This article summarises the position of the Clinical Oncology Society of Australia (COSA) on the role of exercise in cancer care, taking into account the strengths and limitations of the evidence base. It provides guidance for all health professionals involved in the care of people with cancer about integrating exercise into routine cancer care. Main recommendations: COSA calls for: exercise to be embedded as part of standard practice in cancer care and to be viewed as an adjunct therapy that helps counteract the adverse effects of cancer and its treatment; all members of the multidisciplinary cancer team to promote physical activity and recommend that people with cancer adhere to exercise guidelines; and best practice cancer care to include referral to an accredited exercise physiologist or physiotherapist with experience in cancer care. Changes in management as a result of the guideline: COSA encourages all health professionals involved in the care of people with cancer to: discuss the role of exercise in cancer recovery; recommend their patients adhere to exercise guidelines (avoid inactivity and progress towards at least 150 minutes of moderate intensity aerobic exercise and two to three moderate intensity resistance exercise sessions each week); and refer their patients to a health professional who specialises in the prescription and delivery of exercise (ie, accredited exercise physiologist or physiotherapist with experience in cancer care).

ith more than 1.5 million new cases estimated in 2020, skin cancers are the most commonly diagnosed group of cancers worldwide. Malignant melanomas (hereafter melanoma) account for approximately 1 in 5 of these cancers, with approximately 325 000 cases estimated globally in 2020. Historically a rare disease, melanoma incidence rates have been increasing during the last 50 years in fair-skinned populations of European ancestry. 1,2 Much of this increase is likely due to increased exposure of vulnerable populations to UV radiation, a strong and ubiquitous risk factor for melanoma, emitted naturally by the sun but also from artificial sources. 3,4 According to recent global estimates, more than three-quarters of all newly diagnosed melanoma cases can be attributed to UV radiation. 5 Although the risk of melanoma generally increases with age and incidence is greater among older populations, melanoma is among the most common cancers in young adults. 6 Incidence rates have stabilized or decreased among recent birth cohorts in a few countries, such as Australia and the US. 1,7 The reasons for these decreases in incidence are still debated and are likely associated with a combination of changes in lifestyle and social behavior, ethnic heterogeneity, and population admixture (ie, in which previously diverged or isolated genetic lineages mix). Yet with generational increases in melanoma incidence reported in most other high-risk populations and uniform increases observed in older age groups, the rates and number of melanoma diagnoses are projected to increase in the coming decades, 8,9 emphasizing the urgent need IMPORTANCE Despite many cases being preventable, cutaneous melanoma remains the most serious skin cancer worldwide. Understanding the scale and profile of the disease is vital to concentrate and reinforce global prevention efforts.OBJECTIVE To examine global patterns of cutaneous melanoma in 2020 and to provide projected estimates of cases and deaths by 2040. DESIGN, SETTING, AND PARTICIPANTSThis population-based study used the GLOBOCAN 2020 database for global epidemiological assessment of new cases and deaths due to invasive melanoma.MAIN OUTCOMES AND MEASURES Age-standardized incidence and mortality rates were calculated per 100 000 person-years by country, world region, and 4-tier level of human development. Estimated numbers of cases and deaths were calculated for the year 2040.RESULTS A worldwide total of 325 000 new melanoma cases (174 000 males, 151 000 females) and 57 000 deaths (32 000 males, 25 000 females) was estimated for 2020. Large geographic variations existed across countries and world regions, with the highest incidence rates among males (42 per 100 000 person-years) and females (31 per 100 000 person-years) observed in Australia/New Zealand, followed by Western Europe (19 per 100 000 person-years for males and females), North America (18 per 100 000 person-years for males, 14 per 100 000 person-years for females), and Northern Europe (17 per 100 000 person-years for males, 18 per 100 000 perso...