Australian children's physical activity and screen time while in grandparental care.

OBJECTIVE: The objective of this study was to explore Australian children's engagement in physical activity and screen time while being cared for by their grandparents. METHOD: Grandparents (N = 1,190) providing ≥3 hours of weekly care to a grandchild aged 3-14 years completed an online survey assessing their grandchildren's movement behaviours while in their care. Descriptive statistics were computed for frequency of engagement in unstructured and structured physical activities, minutes spent playing outdoors, and minutes spent engaged in screen time. Regression analyses were conducted to assess socio-demographic predictors of movement behaviours. RESULTS: Playing in the yard was the most common form of physical activity in which grandchildren reportedly participated (77% 'usually' or 'always'), followed by playing with toys/equipment (62%). Few (14-36%) frequently engaged in active transport. Children spent an average of 181 minutes per week engaged in screen-based activities. CONCLUSIONS: There is an opportunity to improve children's movement behaviours while in grandparental care. Communicating to grandparents their importance in supporting an active lifestyle is warranted. IMPLICATIONS FOR PUBLIC HEALTH: Findings highlight the importance of creating environments that facilitate play-based, outdoor activities. Ensuring children have access to play equipment while in the care of grandparents and improving access to and quality of neighbourhood parks may assist with activity promotion.

Parents on the Concept of Physical Literacy: What Do They Know, What Do They Do, and What Do They Want?

Physical literacy development in early childhood, viewed by many as the foundation for lifelong physical activity engagement, is significantly influenced by parents. Our aim was to explore parents' understanding of physical literacy and gain insight into their perspectives on physical literacy promotion. We recruited 18 parents of children between 5 and 8 years old in Australia. Using semistructured interviews and thematic analysis, we identified several key issues regarding parents' understanding and implementation of physical literacy. Parents expressed interest in improving their implementation of physical literacy practices and had (often unintentionally) provided support for physical literacy subcomponents in the past. However, they described difficulties prioritizing physical literacy above other parental demands and expressed conflicting perceptions regarding where the responsibility should lie for developing their child's physical literacy (e.g., at home or at school). To ensure that the physical literacy "message" reaches parents, we encourage physical literacy promoters to consider the target (e.g., responsibility, priorities, and awareness) of their promotional strategies. Further investigation into the influence of sociocultural and economic factors on parents' understanding and application of physical literacy is warranted.

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC. Patients and methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss. Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10-7), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10-6) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

The Right Advice, from the Right Person, in the Right Way: Non-Engaged Consumer Families' Preferences for Lifestyle Intervention Design Relating to Severe Obesity in Childhood.

Family-based lifestyle interventions for children/adolescents with severe levels of obesity are numerous, but evidence indicates programs fail to elicit short- or longer-term weight loss outcomes. Families with lived experience can provide valuable insight as we strive to improve outcomes from programs. Our aim was to explore elements that families desired in a program designed to treat severe levels of obesity in young people. We recruited a cross-sectional sample of 13 families (parents and young people) who had been referred but had not engaged with the state-wide Perth Children's Hospital, Healthy Weight Service (Perth, Australia), between 2016 and 2018. Utilizing semi-structured interviews and reflexive qualitative thematic analysis, we identified two broad themes, (1) bridging the gap between what to do and how to do it, and (2) peers doing it with you. The first theme reflected parents' and young people's feelings that programs ought to teach specialist-designed practical strategies utilizing non-generic information tailored to address the needs of the family, in a collaboratively supportive way, and encourage young people to learn for themselves. The second theme reflected the importance of social connection facilitated by peer support, and intervention programs should be offered in a group format to foster inclusion. Families indicated a willingness to engage in tertiary intervention programs but desired support from specialized health professionals/programs to be tailored to their needs, sensitive to their experiences and challenges and provide useful practical strategies that support the knowledge-to-action process.

The Stride program: Feasibility and pre-to-post program change of an exercise service for university students experiencing mental distress.

Rates of mental illness are disproportionately high for young adult and higher education (e.g., university student) populations. As such, universities and tertiary institutions often devote significant efforts to services and programs that support and treat mental illness and/or mental distress. However, within that portfolio of treatment approaches, structured exercise has been relatively underutilised and greater research attention is needed to develop this evidence base. The Stride program is a structured 12-week exercise service for students experiencing mental distress. We aimed to explore the feasibility of the program and assess pre- and post-program change, through assessments of student health, lifestyle, and wellbeing outcomes. Drawing from feasibility and effectiveness-implementation hybrid design literatures, we conducted a non-randomised feasibility trial of the Stride program. Participants were recruited from the Stride program (N = 114, Mage = 24.21 years). Feasibility results indicated the program was perceived as acceptable and that participants reported positive perceptions of program components, personnel, and sessions. Participants' pre-to-post program change in depressive symptomatology, physical activity levels, mental health-related quality of life, and various behavioural outcomes were found to be desirable. Our results provide support for the feasibility of the Stride program, and more broadly for the delivery and potential effectiveness of structured exercise programs to support university students experiencing mental distress.

'It's been a lifelong thing for me': parents' experiences of facilitating a healthy lifestyle for their children with severe obesity.

OBJECTIVE: For parents and guardians, assisting children/adolescents with severe obesity to lose weight is often a key objective but a complex and difficult challenge. Our aim in this study was to explore parents' (and guardians') perspectives on the challenges they have faced in assisting their children/adolescents with severe obesity to lead a healthy lifestyle. METHODS: Thirteen parents/guardians were interviewed from a pool of families who had been referred but did not engage between 2016 and 2018 (N = 103), with the Perth Children's Hospital Healthy Weight Service, a clinical obesity program for children/adolescents (parent age M = 43.2 years, children age M = 10.3 years). Using semi-structured interviews and thematic analysis, we identified 3 broad themes. RESULTS: Parental weight-related factors reflected parents' own lifelong obesity narrative and its effect on their own and their families' ability to live a healthy lifestyle. Perceived inevitability of obesity in their child reflected parents' feelings that the obesity weight status of their children/adolescent was a persistent and overwhelming problem that felt 'out of control'. Lastly, parents reported challenges getting medical help stemming from co-morbid medical diagnosis in their child/adolescent, and difficulties with medical professionals. CONCLUSION: This study demonstrates that parents face challenges in supporting healthy lifestyle for children/adolescents with severe obesity due to parents own internal weight biases and their negative experiences within the healthcare system when seeking help.

The Influence of Grandparents on Children's Dietary Health: A Narrative Review.

PURPOSE OF REVIEW: To examine and synthesise recent evidence on the role of grandparents in shaping children's dietary health. RECENT FINDINGS: The influence of grandparents on children's dietary health was evident across studies. Grandparents frequently provide their grandchildren with meals and snacks, and engage in many of the same feeding practices used by parents. Although grandparents report providing their grandchildren with healthy foods, the provision of treat foods high in sugar or fat was a common finding. This provision led to family conflict, with the indulgent behaviours of grandparents seen by parents as a barrier to healthy eating. Grandparents are exerting significant influence on child dietary health. Efforts are needed to ensure these care providers are considered key stakeholders in the promotion of healthy eating and are targeted in policies and programs addressing children's diets. Research that determines how to best support grandparents to foster healthy behaviours in children is critical.

Structured exercise programs for higher education students experiencing mental health challenges: background, significance, and implementation.

The incidence of mental illness is greatest among young adults, and those enrolled in higher education may be particularly vulnerable compared to the general young adult population. Many higher education institutions employ student support staff tasked with implementing strategies to improve student wellbeing and mental illness. However, these strategies tend to be focused on clinical therapies and pharmacological interventions with limited lifestyle approaches. Exercise is an effective method for addressing mental illness and promoting wellbeing, yet widespread provision of structured exercise services to support treatment options for students with mental health challenges has not been fully realized. In an effort to guide exercise strategies for student mental health, we synthesize considerations for developing and delivering exercise programs in higher education settings. We draw directly from the evidence base on existing exercise programs in higher education; and the broader behavior change, exercise adherence, health psychology, implementation science, and exercise prescription literatures. Our broad considerations cover issues regarding program engagement and behavior change, exercise 'dose' and prescription, integration with other on-campus services, and robust research and evaluation. These considerations may provide impetus for widespread program development and implementation, as well as informing research focused on protecting and improving student mental health.

Support needs and experiences of young people living in families with mental illness.

INTRODUCTION: Children and adolescents living in families affected by mental illness are at elevated risk of developing mental health problems. A range of interventions have been designed to help these young people; however, the effectiveness of these programs is, in some cases, mixed. Our aim was to understand in detail the support needs and experiences of a group of Australian children and adolescents living in families with mental illness. METHODS: Our study is a qualitative in nature. In 2020-2021, we interviewed 25 Australian young people (Mage = 13.60, SD = 2.26, 20 females and 5 males) living with family members affected by mental illness to understand their (the young people's) experiences, and to identify the types of support that these young people considered important or effective. We conducted reflexive thematic analyses of interview data, underpinned by interpretivist assumptions. RESULTS: We identified seven themes within two higher-order categories reflecting our aims to understand (1) lived experiences within families affected by mental illness (i.e., increased responsibilities, missing out, and stigmatization), and (2) support experiences, needs, and preferences (i.e., respite, shared experiences with like-minded others, education, and flexibility). CONCLUSIONS: Our findings hold substantial practical value by informing services, interventions, and conversations that better support young people living in families affected by mental illness.

MAN v FAT Soccer: Feasibility Study and Preliminary Efficacy of a Sport-Based Weight-Loss Intervention for Overweight and Obese Men in Australia.

MAN v FAT Soccer is a sport-based weight-loss program for overweight and obese men that originated in the United Kingdom (i.e., as MAN v FAT Football) and appears to successfully engage men with weight loss. We sought to explore whether the program would work in an Australian context by (a) establishing a foundation for the implementation of the program on a larger scale and (b) determining how large-scale implementation is most feasible. We conducted a nonrandomized, single intervention group feasibility trial of MAN v FAT Soccer in Australia with 418 male participants with a body mass index greater than 27.50 kg/m2. Results indicate that the program is acceptable, with participants reporting positive perceptions of the various components of the program and a high proportion reporting intentions to recommend the program to others (95.9%). Furthermore, preliminary effectiveness results indicate positive changes in weight (4.6% reduction) and physical activity (88.5% increase) and improvements in psychological outcomes such as depression (17.6% decrease), stress (19.0% decrease), and body appreciation (19.1% increase). Our findings provide general support for the feasibility of MAN v FAT Soccer and the notion that leveraging competition and masculinity may help drive men's health behavior change.

Perceptions of a family-based lifestyle intervention for children with overweight and obesity: a qualitative study on sustainability, self-regulation, and program optimization.

BACKGROUND: Family-based lifestyle interventions (FBLIs) are an important method for treating childhood weight problems. Despite being recognized as an effective intervention method, the optimal structure of these interventions for children's overweight and obesity has yet to be determined. Our aim was to better understand participants' (a) implementation of behaviour strategies and long-term outcomes, (b) perceptions regarding the optimal structure of FBLIs, and (c) insights into psychological concepts that may explain the success of these programs. METHODS: Purposive sampling was used to recruit participants. We conducted focus groups as well as one-to-one interviews with parents (n = 53) and children (n = 50; aged 7-13, M = 9.4 yr, SD = 3.1) three months following their involvement in a 10-week, multi-component, FBLI involving education and activities relating to healthy nutrition, physical activity, and behavior modification. Using an interpretivist approach, a qualitative study design was employed to examine participant experiences. RESULTS: We identified three higher-order categories: (a) participants' program experiences and perceptions (b) lifestyle changes post-program, and (c) recommendations for optimizing family-based programs. Themes identified within these categories included (a) support and structure & content, (b) diet and physical activity, and (c) in-program recommendations and post-program recommendations. CONCLUSIONS: We identified several challenges that can impair lasting behavior change (e.g., physical activity participation) following involvement in a FBLI. On optimizing these programs, participants emphasized fun, interactive content, interpersonal support, appropriate educational content, and behavior change techniques. Concepts rooted in motivational theory could help address calls for greater theoretical and mechanistic insight in FBLIs. Findings may support research advancement and assist health professionals to more consistently realize the potential of these interventions.

Understanding parent perspectives on engagement with online youth-focused mental health programs.

OBJECTIVE: Online youth-focused health programs often include parent modules-that equip parents with skills to assist their child in improving their health-alongside youth-specific content. BRAVE Self-Help, an evidence-based program designed for children and teenagers with early signs of anxiety, is a popular Australian program that includes six parent modules. Despite its popularity and proven efficacy, BRAVE Self-Help shares the same challenge as many online self-help programs-that of low participant engagement. Using parents registered in BRAVE Self-Help as 'information rich' participants, we explored (a) factors that influenced parent engagement in online health programs, and (b) their recommendations for enhancing parent engagement. DESIGN AND OUTCOME MEASURE: We conducted semi-structured interviews with 14 parents registered in BRAVE Self-Help. Data were analysed through reflexive thematic analysis. RESULTS: Social-, family- and program-related factors drove parents' program engagement and recommendations. Social sub-themes related to the benefits of professional and community support in promoting more engagement. Family sub-themes included difficulties with program engagement due to competing priorities, perceptions that condition severity influenced engagement, and feelings that previously-acquired health knowledge reduced motivation to engage. Program sub-themes included perceived usefulness and ease-of-use. CONCLUSION: Program designers could target support systems, include flexible delivery options, and use iterative design processes to enhance parent engagement.

Molecular characterization of fast-growing melanomas.

BACKGROUND: The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM) and the potential to stratify patients at high risk of death has not been comprehensively studied. OBJECTIVE: To investigate the epidemiologic, clinical, and mutational profile of primary cutaneous melanomas with a thickness ≥ 1 mm, stratified by rate of growth. METHODS: Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin-embedded primary melanoma samples. Comparison of FGMM (rate of growth > 0.5 mm/month) and nonFGMM (rate of growth ≤ 0.5 mm/month). RESULTS: Two hundred patients were enrolled, among wom 70 had FGMM. The relapse-free survival was lower in the FGMM group (P = .014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than nonFGMM (P = .033). Ulceration (P = .032), thickness (P = .006), lower sun exposure (P = .049), and fibroblast growth factor receptor 2 (FGFR2) mutations (P = .037) were significantly associated with fast growth. LIMITATIONS: Single-center study, cohort size, potential memory bias, number of investigated genes. CONCLUSION: Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness, and FGFR2 mutations are associated with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM, which are probably good candidates for adjuvant therapies.

Ultraviolet light-induced collagen degradation inhibits melanoma invasion.

Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.

Female Immunity Protects from Cutaneous Squamous Cell Carcinoma.

PURPOSE: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation. EXPERIMENTAL DESIGN: We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing. RESULTS: We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. CONCLUSIONS: This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.

Overweight and obese men's experiences in a sport-based weight loss intervention for men.

In Western countries, such as Australia and the UK, a significantly greater proportion of men (relative to women) are overweight and obese, yet relatively few weight loss interventions have been developed that sufficiently target men. This lack of male-focused programming may be in part because 'traditional' weight loss programs are unappealing for what is considered a 'hard-to-reach' population. One program that appears to have such appeal for men is the MAN v FAT Football (MVFF) program, based out of the United Kingdom, which is designed for men with a body mass index of (or greater than) 27.5. MVFF encourages men's participation in a community-based weight loss program that incentivizes weight loss through participation in a football league, and since 2016 MVFF has supported the weight loss efforts of several thousand men. Using MVFF as an exemplar, our aim was to derive insight into how men experience a male-only competitive, sport-based weight loss program. We recruited twenty-seven players (Mage = 41.13, SD = 9.93), and ten coaches (Mage = 31.8, SD = 11.55) from program locations throughout the United Kingdom. Using semi-structured interviews and thematic analysis, we identified several appraisal aspects of the program that players and coaches considered important, including the appeal of sport, competition on a level playing field, being part of a team, camaraderie, accountability, men sharing issues with other men, gender-sensitized environment, likeminded and similar men, and perceptions that traditional weight loss programs are tailored towards women. Player experiences (i.e., competence and enjoyment) and functional supports in the program (e.g., player handbook, weight loss coach) were reported to drive outcomes of effective weight loss and program retention. Interventions aiming to target men may be more successful working with rather than against formulations of identity such as masculinities, and this can be achieved by tailoring program content (e.g., messaging), settings (e.g., among men sharing similar characteristics such as body-type or goals), and mode of delivery (e.g., through organized sports, and leveraging competition to drive healthy behaviours).

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

PURPOSE: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. EXPERIMENTAL DESIGN: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. RESULTS: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. CONCLUSIONS: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.

Not All Promotion Is Good Promotion: The Pitfalls of Overexaggerated Claims and Controlling Language in Exercise Messaging.

Across 2 studies, the authors explored reactance effects to overexaggerated claims and controlling language in exercise messaging. In Study 1, participants received either a message exaggerating the benefits of an upcoming exercise session or no message. They subsequently undertook a mundane exercise session led by an instructor, which was either need supportive or "realistically controlling." Relative to no-message participants, those who had read the message reported less positive evaluations of the session. These results were observed despite participants in the message condition holding more positive presession expectations, and the effect was apparent even for those who received need-supportive instruction. In Study 2, participants read an advertisement that was written in either autonomy-supportive language or controlling language. Despite reporting comparable expectations, participants who received a controlling-language message reported significantly greater anger and freedom threat-factors commonly linked to contrast effects. These studies highlight the operation of message-driven contrast effects in exercise.

MC1R CpG island regulates MC1R expression and is methylated in a subset of melanoma tumours.

Melanocortin 1 receptor (MC1R) is a G protein-coupled receptor expressed in melanocytes where it plays an important role in skin pigmentation and in the UV response, and has implications in melanoma development. Here we show that methylation of a CpG island (CGI) within the MC1R gene can control expression of MC1R in melanoma. This CGI overlaps with a potential enhancer region, and is unmethylated in normal melanocytes but highly methylated in other skin cells, suggesting a melanocyte specific function. Analysis showed that MC1R was the only gene significantly differentially expressed by methylation of this region. Within several data sets, this region is methylated in a subset of melanoma tumours (55%-74% of tumours) and results in reduced MC1R expression and significantly longer overall survival.

Does the primary site really matter? Profiling mucinous ovarian cancers of uncertain primary origin (MO-CUP) to personalise treatment and inform the design of clinical trials.

OBJECTIVE: Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin 'MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials. METHODS: We analyzed a large de-identified, multi-platform tumor profiling dataset of MO-CUPs enriched for advanced stage and recurrent cases submitted to Caris Life Sciences. Available data included a 45-gene next-generation sequencing (NGS) panel, gene amplification of HER2 and cMET and 18 immunohistochemical (IHC) markers of drug sensitivity/resistance. RESULTS: Mucinous tumors from 333 patients were analyzed, including 38 borderline tumors and 295 invasive cancers. The most common mutations in a subset (n = 128) of invasive cancers were KRAS (60%), TP53 (38%), PIK3CA (13%) and PTEN (9%). Borderline tumors had higher rates of BRAF mutations, and PGP and TOP2A overexpression than invasive cases. KRAS mutant invasive cancers had lower expression of thymidylate synthase (p = 0.01) and higher expression of TUBB3 (p = 0.01) than KRAS wildtype tumors. CONCLUSIONS: To our knowledge, this is the largest series profiling mucinous ovarian cancers and almost certainly includes cases of ovarian and non-ovarian origin. Given the difficulty recruiting patients to histotype-specific trials in rare subsets of ovarian cancer, it may be more important to focus on identifying potential treatment targets and to personalise treatment and design clinical trials in MO-CUPS agnostic of primary site to overcome these issues.