Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

Transition to palliative care for people living with metastatic melanoma : preliminary findings from a grounded theory study

Melanoma is the most aggressive form of skin cancer. Five-year survival rates for patients with metastatic melanoma are less than 10%, with a median survival of 6 to 9 months. Despite a number of clinical trials for metastatic melanoma, the treatment options for patients are limited. Palliation is often the main goal of treatment. This constructivist grounded theory study is seeking to examine how people with metastatic melanoma negotiate the transition to palliative care. The method of sampling is purposive and data have been generated through semi-structured interviews with those with metastatic melanoma and partners. Open, focused and theoretical coding of data from 13 interviews conducted to date has produced analytical concepts that reflect how the transition is negotiated. These concepts depict ways in which individuals interact with a fragmented health care system and how meanings are constructed around the rapid progression of the disease and uncertain treatment decisions. The preliminary findings reported upon here are being further explored with a larger sample. The findings to date highlight the need for improved coordination of services for those living with metastatic melanoma, and improved support for individuals dealing with uncertainty.

Re-think, Re-generate, Re-envisage fashionable sun-safe apparel

Design is a way of thinking and working that systematically can create immense societal change. In particular, fashion design is one of the most progressively forward-looking creative and commercial generators that can envisage and initiate meaningful visual and social transformation. If we look back in time at the authority of fashion, many trends have significantly induced visual norms aligning glamour and health with tanned skin - numerous examples exist, including Vogue magazine proclaiming (front-cover) that ‘The 1929 girl must be tanned’. Indeed, in a contemporary landscape, fashion trends continue to re-generate apparel that, in-the-main, has limited design resolution connected to sun safety, and surprisingly many designers elect to ignore this vital and potentially lucrative market segment. In a context with soaring skin cancer rates, how can this powerful design medium of fashion make a positive difference to sun protection; what is the untapped potential for young design talent to connect with the health sector for skin cancer prevention; and, how can fashion designers be swayed to design and produce fashionable sun-safe apparel, that address pertinent issues including heat build up, comfort and transformability? Through a case study approach, examining emergent fashion designers, this paper will propose that astute and novel avenues exist for fashion to re-think sun protective apparel, including: generation of crucial design standards for sun-safe apparel, exploration of co-branding opportunities, advancement of fashion forecasting to connect modesty of body coverage to fashion trends and alignment of the market segment to re-envisage a critical mass for fashionable sun-safe apparel.

The epidemiology of basal cell carcinoma

Basal cell carcinoma (BCC) is a skin cancer of particular importance to the Australian community. Its rate of occurrence is highest in Queensland, where 1% to 2% of people are newly affected annually. This is an order of magnitude higher than corresponding incidence estimates in European and North American populations. Individuals with a sun-sensitive complexion are particularly susceptible because sun exposure is the single most important causative agent, as shown by the anatomic distribution of BCC which is in general consistent with the levels of sun exposure across body sites. A distinguishing feature of BCC is the occurrence of multiple primary tumours within individuals, synchronously or over time, and their diagnosis and treatment costs contribute substantially to the major public health burden caused by BCC. A primary knowledge gap about BCC pathogenesis however was an understanding of the true frequency of multiple BCC occurrences and their body distribution, and why a proportion of people do develop more than one BCC in their life. This research project sought to address this gap under an overarching research aim to better understand the detailed epidemiology of BCC with the ultimate goal of reducing the burden of this skin cancer through prevention. The particular aim was to document prospectively the rate of BCC occurrence and its associations with constitutional and environmental (solar) factors, all the while paying special attention to persons affected by more than one BCC. The study built on previous findings and recent developments in the field but set out to confirm and extend these and propose more adequate theories about the complex epidemiology of this cancer. Addressing these goals required a new approach to researching basal cell carcinoma, due to the need to account for the phenomenon of multiple incident BCCs per person. This was enabled by a 20 year community-based study of skin cancer in Australians that provided the methodological foundation for this thesis. Study participants were originally randomly selected in 1986 from the electoral register of all adult residents of the subtropical township of Nambour in Queensland, Australia. On various occasions during the study, participants were fully examined by dermatologists who documented cumulative photodamage as well as skin cancers. Participants completed standard questionnaires about skin cancer-related factors, and consented to have any diagnosed skin cancers notified to the investigators by regional pathology laboratories in Queensland. These methods allowed 100% ascertainment of histologically confirmed BCCs in this study population. 1339 participants had complete follow-up to the end of 2007. Statistical analyses in this thesis were carried out using SAS and SUDAAN statistical software packages. Modelling methods, including multivariate logistic regressions, allowed for repeated measures in terms of multiple BCCs per person. This innovative approach gave new findings on two levels, presented in five chapters as scientific papers: 1. Incidence of basal cell carcinoma multiplicity and detailed anatomic distribution: longitudinal study of an Australian population The incidence of people affected multiple times by BCC was 705 per 100,000 person years compared to an incidence rate of people singly affected of 935 per 100,000 person years. Among multiply and singly affected persons alike, site-specific BCC incidence rates were far highest on facial subsites, followed by upper limbs, trunk, and then lower limbs 2. Melanocytic nevi and basal cell carcinoma: is there an association? BCC risk was significantly increased in those with forearm nevi (Odds Ratios (OR) 1.43, 95% Confidence Intervals (CI) 1.09-1.89) compared to people without forearm nevi, especially among those who spent their time mainly outdoors (OR 1.6, 95%CI 1.1-2.3) compared to those who spent their time mainly indoors. Nevi on the back were not associated with BCC. 3. Clinical signs of photodamage are associated with basal cell carcinoma multiplicity and site: a 16-year longitudinal study Over a 16-year follow-up period, 58% of people affected by BCC developed more than one BCC. Among these people 60% developed BCCs across different anatomic sites. Participants with high numbers of solar keratoses, compared to people without solar keratoses, were most likely to experience the highest BCC counts overall (OR 3.3, 95%CI 1.4-13.5). Occurrences of BCC on the trunk (OR 3.3, 95%CI 1.4-7.6) and on the limbs (OR 3.7, 95%CI 2.0-7.0) were strongly associated with high numbers of solar keratoses on these sites. 4. Occurrence and determinants of basal cell carcinoma by histological subtype in an Australian community Among 1202 BCCs, 77% had a single growth pattern and 23% were of mixed histological composition. Among all BCCs the nodular followed by the superficial growth patterns were commonest. Risk of nodular and superficial BCCs on the head was raised if 5 or more solar keratoses were present on the face (OR 1.8, 95%CI 1.2-2.7 and OR 4.5, 95%CI 2.1-9.7 respectively) and similarly on the trunk in the presence of multiple solar keratoses on the trunk (OR 4.2, 95%CI 1.5-11.9 and OR 2.2, 95%CI 1.1-4.4 respectively). 5. Basal cell carcinoma and measures of cumulative sun exposure: an Australian longitudinal community-based study Dermal elastosis was more likely to be seen adjacent to head and neck BCCs than trunk BCCs (p=0.01). Severity of dermal elastosis increased on each site with increasing clinical signs of cutaneous sun damage on that site. BCCs that occurred without perilesional elastosis per se, were always found in an anatomic region with signs of photodamage. This thesis thus has identified the magnitude of the burden of multiple BCCs. It does not support the view that people affected by more than one BCC represent a distinct group of people who are prone to BCCs on certain body sites. The results also demonstrate that BCCs regardless of site, histology or order of occurrence are strongly associated with cumulative sun exposure causing photodamage to the skin, and hence challenge the view that BCCs occurring on body sites with typically low opportunities for sun exposure or of the superficial growth pattern are different in their association with the sun from those on typically sun-exposed sites, or nodular BCCs, respectively. Through dissemination in the scientific and medical literature, and to the community at large, these findings can ultimately assist in the primary and secondary prevention of BCC, perhaps especially in high-risk populations.

Study protocol : a randomised controlled trial of a theory-based online intervention to improve sun safety among Australian adults

Background The effects of exposure to ultraviolet radiation are a significant concern in Australia which has one of the highest incidences of skin cancer in the world. Despite most skin cancers being preventable by encouraging consistent adoption of sun-protective behaviours, incidence rates are not decreasing. There is a dearth of research examining the factors involved in engaging in sun-protective behaviours. Further, online multi-behavioural theory-based interventions have yet to be explored fully as a medium for improving sun-protective behaviour in adults. This paper presents the study protocol of a randomised controlled trial of an online intervention based on the Theory of Planned Behaviour (TPB) that aims to improve sun safety among Australian adults. Methods/Design Approximately 420 adults aged 18 and over and predominantly from Queensland, Australia, will be recruited and randomised to the intervention (n = 200), information only (n = 200) or the control group (n = 20). The intervention focuses on encouraging supportive attitudes and beliefs toward sun-protective behaviour, fostering perceptions of normative support for sun protection, and increasing perceptions of control/self-efficacy over sun protection. The intervention will be delivered online over a single session. Data will be collected immediately prior to the intervention (Time 1), immediately following the intervention (Time 1b), and one week (Time 2) and one month (Time 3) post-intervention. Primary outcomes are intentions to sun protect and sun-protective behaviour. Secondary outcomes are the participants’ attitudes toward sun protection, perceptions of normative support for sun protection (i.e. subjective norms, group norms, personal norms and image norms) and perceptions of control/self-efficacy toward sun protection. Discussion The study will contribute to an understanding of the effectiveness of a TPB-based online intervention to improve Australian adults’ sun-protective behaviour. Trials registry Australian and New Zealand Trials Registry number ACTRN12613000470796

A qualitative exploration of sun safety beliefs among Australian adults

Informed broadly by the theory of planned behaviour, this study used qualitative methodology to understand Australian adults' sun-protective decisions. Forty-two adults participated in focus groups where they discussed behavioural (advantages and disadvantages), normative (important referents), and control (barriers and facilitators) beliefs, as well as potential social influences and images of tanned and non-tanned people. Responses were analysed using the consensual qualitative research approach to determine the dominant themes. Themes of fashion and comfort were prominent, the important role of friends and family in sun safe decision-making was highlighted, as was the availability of sun-protective measures (e.g., in an accessible place or in the environment). Additional themes included the need to model sound sun-protective behaviours to (current and future) children, the emphasis on personal choice and personal responsibility to be sun safe, and the influence of Australian identity and culture on tanning and socially acceptable forms of sun protection. These beliefs can be used to inform interventions and public health campaigns targeting sun safety among Australians, a population with the highest skin cancer incidence in the world.

A pilot trial of mobile, patient-performed teledermoscopy

BACKGROUND Early detection by skin self-examination (SSE) could improve outcomes from melanoma. Mobile teledermoscopy may aid this process. OBJECTIVES To establish clinical accuracy of SSE plus mobile teledermoscopy compared to clinical skin examination (CSE) and test whether providing people with detailed SSE instructions improves accuracy. METHODS Men and women 50-64 years (n=58) performed SSE plus mobile teledermoscopy in their homes between May and November 2013 and were given technical instructions plus detailed SSE instructions (intervention) or technical instructions only (control). Within three months, they underwent a CSE. Outcome measures included: a) body sites examined, lesions photographed, and missed; b) sensitivityof SSE plus mobile teledermoscopy compared to in-person CSE using either patients or lesions as denominator, and; c) concordance of telediagnosis with CSE. RESULTS: 49 of 58 randomised participants completed the study, and submitted 309 lesions to the teledermatologist (156 intervention; 153 control group). Intervention group participants were more likely to submit lesions from their legs compared to control (p=0.03), no other differences between groups in number or site of missed lesions.11 participants (22%) did not photograph 14 pigmented lesions the dermatologist considered worthwhile photographing or requiring clinical monitoring. Sensitivity of SSE plus mobile teledermoscopy was 81.8% (95% confidence interval 64.5-93.0) using the patient as the denominator and 41.9 (27.6-56.2) using the lesion as denominator.-There was substantial agreement between telediagnosis and CSE (Kappa =0.90) accounting for differential diagnoses. CONCLUSIONS SSE plus mobile teledermoscopy is promising for surveillance of particular lesions even without provision of detailed SSE instructions, but in the format tested in this study, consumers may overlook lesions and send many non-pigmented lesions. This investigation demonstrates that high quality dermoscopic images can be taken by patients at home and for those sent, telediagnosis is highly accurate.

Automated melanoma diagnosis system

An automated melanoma diagnosis system, the so-called Skin Polar-probe, was developed to improve the chances of early detection of skin cancers and help save the lives of melanoma victims. The system will offer unique benefits to aid early detection of melanoma - the key to reducing deaths caused by this cancer.

Predicting Australian adults' sun-safe behaviour : examining the role of personal and social norms

Objectives To address the scarcity of comprehensive, theory-based research in the Australian context, this study, using a theory of planned behaviour (TPB) framework, investigated the role of personal and social norms to identify the key predictors of adult Australians' sun-safe intentions and behaviour. Design The study used a prospective design with two waves of data collection, 1 week apart. Methods Participants were 816 adults (48.2% men) aged between 18 and 88 years recruited from urban, regional, and rural areas of Australia. At baseline, participants completed a questionnaire assessing the standard TPB predictors (attitude, subjective norm, and perceived behavioural control [PBC]), past behaviour, behavioural intention, and additional measures of group norm for the referent groups of friends and family, image norm, personal norm, personal choice/responsibility, and Australian identity. Seventy-one per cent of the participants (n = 577) reported on their sun-safe behaviour in the subsequent week. Results Via path modelling, past behaviour, attitude, group norm (friends), personal norm, and personal choice/responsibility emerged as independent predictors of intentions which, in turn, predicted sun-safe behaviour prospectively. Past behaviour, but not PBC, had direct effects on sun-safe behaviour. The model explained 61.6% and 43.9% of the variance in intention and behaviour, respectively. Conclusions This study provides support for the use of a comprehensive theoretical decision-making model to explain Australian adults' sun-safe intentions and behaviours and identifies viable targets for health-promoting messages in this high-risk context.

Consumer preferences for teledermoscopy screening to detect melanoma early

- Introduction ‘Store and forward’ teledermoscopy is a technology with potential advantages for melanoma screening. Any large-scale implementation of this technology is dependent on consumer acceptance. - Aim To investigate preferences for melanoma screening options compared to skin selfexamination in adults considered to be at increased risk of developing skin cancer. - Methods A discrete choice experiment (DCE) was completed by 35 consumers, all of whom had prior experience with the use of teledermoscopy, in Queensland, Australia. Participants made 12 choices between screening alternatives described by seven attributes including monetary cost. A mixed logit model was used to estimate the relative weights that consumers place on different aspects of screening, along with the marginal willingness to pay for teledermoscopy as opposed to screening at a clinic. - Results Overall, participants preferred screening/diagnosis by a health professional rather than skin self-examination. Key drivers of screening choice were for results to be reviewed by a dermatologist; a higher detection rate; fewer non-cancerous moles being removed in relation for every skin cancer detected; and less time spent away from usual activities. On average, participants were willing to pay AU$110 to have teledermoscopy with dermatologist review available to them as a screening option. - Discussion & Conclusions Consumers preferentially value aspects of care that are more feasible with a teledermoscopy screening model, as compared to other skin cancer screening and diagnosis options. This study adds to previous literature in the area which has relied on the use of consumer satisfaction scales to assess the acceptability of teledermoscopy.

Mobile medical applications for melanoma risk assessment: False assurance or valuable tool?

With the smartphone revolution, consumer-focused mobile medical applications (apps) have flooded the market without restriction. We searched the market for commercially available apps on all mobile platforms that could provide automated risk analysis of the most serious skin cancer, melanoma. We tested 5 relevant apps against 15 images of previously excised skin lesions and compared the apps' risk grades to the known histopathologic diagnosis of the lesions. Two of the apps did not identify any of the melanomas. The remaining 3 apps obtained 80% sensitivity for melanoma risk identification; specificities for the 5 apps ranged from 20%-100%. Each app provided its own grading and recommendation scale and included a disclaimer recommending regular dermatologist evaluation regardless of the analysis outcome. The results indicate that autonomous lesion analysis is not yet ready for use as a triage tool. More concerning is the lack of restrictions and regulations for these applications.

Varying sun protection of young children by migrant and Australian-born mothers

OBJECTIVE: To compare sun protection by Australian-born and migrant mothers of three-year-old children. METHODS: Australian-born and migrant mothers taking part in the Environments for Healthy Living prospective birth-cohort study were asked standard questions about their child's sun protection. Children were given a skin cancer susceptibility score based on grandparents' ethnic origin. Logistic regression was used to estimate odds ratios (ORs) to measure the association of sun protection of children according to mothers' migrant status adjusted for socio-demographic characteristics. RESULTS: A total of 613 Australian-born and 224 migrant mothers of three-year-old children were studied. Mothers who had migrated less than four years ago were more likely to allow their three-year-old to spend more than two hours outdoors between 10 am and 3 pm compared to Australian-born mothers (OR=2.80, 95%CI 1.20-6.57). Mothers from high latitude countries (>45 degrees) were more likely to apply sunscreen to their child than those from lower latitude countries (OR=3.15, 95%CI 1.03-9.61). CONCLUSIONS AND IMPLICATIONS: Strategies should aim to increase general awareness about the need for sun protection of young children, and recent migrants should be alerted to the harms of excessive sun exposure.

Early detection of melanoma metastases using microRNAs as novel biomarkers

Early detection of melanoma skin cancer, prior to metastatic spread, is critical to improve survival outcomes in patients. This study identified a melanoma-related panel of blood markers that can detect the presence of melanoma with high sensitivity and accuracy which is superior to currently used markers for melanoma progression, recurrence, and survival. Overall, the findings discussed in this thesis may lead to more precise measurement of disease progression allowing for better treatments and an increase in overall survival.

Teledermatology: Its use in the detection and management of actinic keratosis

Teledermatology can profoundly improve access to medical services for those who may have limited access to dermatology due to workforce shortages, distance to providers, or limitations in their mobility. Two common ways of teledermatology are differentiated: life synchronous, where patient and doctor communicate directly, or store and forward asynchronous methods, where the patient and doctor provide and assess the medical information independently. Teledermatology has been tested for its safety, feasibility and accuracy for a number of dermatological conditions, including the early detection of skin cancer and is usually safe, feasible and accurate. Studies reported somewhat better results for synchronous than asynchronous methods, possibly because of loss of information if no direct patient doctor contact is feasible. However asynchronous methods are easier to organize, require less sophisticated technology and are more widely accessible, and are more convenient for both patients and doctors. No study to date focused solely on teledermatology of actinic keratosis, but such lesions are typically found during teledermatology examinations for other main target lesions. In studies where such results were reported, actinic keratoses seemed to be readily identifiable for teledermatologists and adequate management and treatment can be suggested within remote consultations.

Keeping kids sun safe: exploring parents' beliefs about their young child's sun-protective behaviours

Objectives Melanoma of the skin is the third most commonly diagnosed cancer in Australia. Given the high incidence of sunburn in children and the level of sun protection provided by parents is often infrequent and/or insufficient, this research employed qualitative methodology to examine parents' beliefs about their young child's sun safe behaviour. Methods Parents (N = 21; n = 14 mothers, n = 7 fathers) of children aged 2–5 years participated in focus groups to identify commonly held beliefs about their decision to sun protect their child. Data were analysed using thematic content analysis. Results Parents generally had knowledge of the broad sun safe recommendations; however, the specific details of the recommendations were not always known. Parents reported adopting a range of sun-protective measures for their child, which depended on the time of year. A range of advantages (e.g. reducing the risk of skin cancer, developing good habits early and parental peace of mind), disadvantages (e.g. false sense of safety and preventing vitamin D absorption), barriers (e.g. child refusal) and facilitators (e.g. routine and accessibility) to performing sun safe practices were identified. Normative pressures and expectations also affected parents' motivation to be sun safe for their child. Conclusions These identified beliefs can be used to inform interventions to improve sun safe behaviours in young children who reside in a region that has the highest skin cancer incidence in the world.