Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases and 3205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare-variant burden and ontologic analysis identified two sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, whereas heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma, and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas.

Recommendations for BRCA1 and BRCA2 mutation carriers to disseminate information to at-risk relatives pose significant challenges. This study aimed to quantify family dissemination, to explain the differences between fully informed families (all relatives informed verbally or in writing) and partially informed families (at least one relative uninformed), and to identify dissemination barriers. BRCA1 and BRCA2 mutation carriers identified from four Australian hospitals (n=671) were invited to participate in the study. Distress was measured at consent using the Kessler psychological distress scale (K10). A structured telephone interview was used to assess the informed status of relatives, geographical location of relatives, and dissemination barriers. Family dissemination was quantified, and fully versus partially informed family differences were examined. Dissemination barriers were thematically coded and counted. A total of 165 families participated. Information had been disseminated to 81.1% of relatives. At least one relative had not been informed in 52.7% of families, 4.3% were first-degree relatives, 27.0% were second-degree relatives, and 62.0% were cousins. Partially informed families were significantly larger than fully informed families, had fewer relatives living in close proximity, and exhibited higher levels of distress. The most commonly recorded barrier to dissemination was loss of contact. Larger, geographically diverse families have greater difficulty disseminating BRCA mutation risk information to all relatives. Understanding these challenges can inform future initiatives for communication, follow-up and support.

Context Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors. Objective To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with those described in the current literature. Design/Methods Three case studies, including clinical presentation, germline, and tumor genetic analysis and family history. Setting Two tertiary University Hospitals in Sydney, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia. Outcome Phenotype of the 3 cases and their kindred; molecular analysis and tumor p27^kip1 immunohistochemistry. Results Family A: The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B: The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushing’s syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G > A, p.Trp60*; c.475G > A, p.Asp159Asn) and 1 previously reported (c.374_375delCT, p.Ser125*). Conclusions Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4.

Background: Despite considerable encouragement for healthcare professionals to use or be clear about the theory used in their improvement programmes, the uptake of these approaches to design interventions or report their content is lacking. Recommendations suggest healthcare practitioners work with social and/or behavioural scientists to gain expertise in programme theory, ideally before, but even during or after the work is done. We aim to demonstrate the extent to which intuitive intervention strategies designed by healthcare professionals to overcome patient barriers to communicating genetic cancer risk information to family members align with a theoretical framework of behaviour change.Methods: As part of a pre-post intervention study, a team of genetic counsellors aimed to understand, and design interventions to overcome, the major barriers a group of familial cancer patients face around communicating hereditary cancer risk information to their relatives. A behavioural change specialist worked with the team to review and recode barriers and interventions according to the Theoretical Domains Framework (TDF) and 93 behaviour change techniques (BCTs). Resulting BCTs were cross-referenced against the Theory and Techniques Tool to examine whether evidence-based mechanistic links have been established to date.Results: Five themes emerged from the genetic counsellor coded barriers, which when recoded according to the TDF represented seven domains of behaviour change. Forty-five experiential and intuitive interventions were used to tackle key barriers. These were represented by 21 BCTs, which were found to be used on 131 occasions. The full mapping exercise is presented, resulting in a suite of intervention strategies explicitly linked to a theoretical framework. Structured, written reflections were provided retrospectively by the core clinical team.Conclusions: Although the ideal is to use theory prospectively, or even whilst a project is underway, making links between theory and interventions explicit, even retrospectively, can contribute towards standardising intervention strategies, furthering understanding of intervention effects, and enhancing the opportunities for accurate replicability and generalisability across other settings. Demonstrating to healthcare professionals how their intuition aligns with theory may highlight the additional benefits that theory has to offer and serve to promote its use in improvement.

Precision medicine is changing cancer care and placing new demands on oncology professionals. Precision medicine trials for high-risk childhood cancer exemplify these complexities. We assessed clinicians’ (n = 39) and scientists’ (n = 15) experiences in the first year of the PRecISion Medicine for Children with Cancer (PRISM) trial for children and adolescents with high-risk cancers, through an in-depth semi-structured interview. We thematically analysed participants’ responses regarding their professional challenges, and measured oncologists’ knowledge of genetics and confidence with somatic and germline molecular test results. Both groups described positive early experiences with PRISM but were cognisant of managing parents’ expectations. Key challenges for clinicians included understanding and communicating genomic results, balancing biopsy risks, and drug access. Most oncologists rated ‘good’ knowledge of genetics, but a minority were ‘very confident’ in interpreting (25%), explaining (34.4%) and making treatment recommendations (18.8%) based on somatic genetic test results. Challenges for scientists included greater emotional impact of their work and balancing translational outputs with academic productivity. Continued tracking of these challenges across the course of the trial, while assessing the perspectives of a wider range of stakeholders, is critical to drive the ongoing development of a workforce equipped to manage the demands of paediatric precision medicine.

Objective: Women diagnosed with breast cancer or ductal carcinoma in situ and those with a genetic susceptibility to developing this disease face the challenging decision of whether or not to undergo breast reconstruction following mastectomy. As part of a large randomized controlled trial, this qualitative study examined women's experiences of using the Breast RECONstruction Decision Aid (BRECONDA) and health professionals' feedback regarding the impact of this resource on patients' knowledge and decision making about breast reconstruction.Method: Semistructured interviews were conducted with women who accessed the BRECONDA intervention (N = 36) and with their healthcare providers (N = 6). All interviews were transcribed verbatim and subjected to thematic analysis by 3 independent coders.Results: Participants reported an overall positive impression, with all interviewees endorsing this decision aid as a useful resource for women considering reconstructive surgery. Thematic analysis of patient interviews revealed 4 themes: overall impressions and aesthetics; personal relevance and utility; introducing BRECONDA; and advantages and suggested improvements. Analysis of health professionals' interviews also revealed 4 themes: need for BRECONDA, impact of BRECONDA, potential difficulties that may arise in using the decision aid, and recommending BRECONDA to patients. Patients indicated that they derived benefit from this resource at all stages of their decision‐making process, with the greatest perceived benefit being for those early in their breast reconstruction journey.Conclusion: These findings support the use of BRECONDA as an adjunct to clinical consultation and other information sources.