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Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

In this article, we problematize the concept of "culture" in genetic counseling. With globalization and increased mobility of both genetic professionals and clients, there is an increased acknowledgement of the impact of "culture" on a counseling process. There is, however, little agreement on what "culture" is. The essentialist understanding that has long been dominant in the medical literature views culture as a set of shared beliefs, attitudes and practices among a group of people. Such an approach does not account for the individual differences and the dynamic nature of genetic counseling encounters. Following Zayts and Schnurr (2017), we use the distinction between two orders of culture: culture1 that refers to the static, generalized understanding of culture that is external to the specific context, and culture2 , an analytic concept that denotes dynamic enactments of culture, emerging in the interaction. We use empirical data from genetic counseling sessions to illustrate these different facets of culture and to consider how and why speakers draw on them. The clinical implications of the study include highlighting the importance of cultural awareness among counselors, including cultural self-awareness, and demonstrating how authentic interactional data could be used to enhance cultural training in genetic counseling.

Over 100,000 individuals living in Ireland carry a mutated gene for an inherited cardiac condition (ICC), most of which demonstrate an autosomal dominant pattern of inheritance. First-degree relatives of individuals with these mutations are at a 50 % risk of being a carrier: disclosing genetic information to family members can be complex. This study explored how families living in Ireland communicate genetic information about ICCs and looked at the challenges of communicating information, factors that may affect communication and what influence this had on family relationships. Face to face interviews were conducted with nine participants using an approved topic guide and results analysed using thematic analysis. The participants disclosed that responsibility to future generations, gender, proximity and lack of contact all played a role in family communication. The media was cited as a source of information about genetic information and knowledge of genetic information tended to have a positive effect on families. Results from this study indicate that individuals are willing to inform family members, particularly when there are children and grandchildren at risk, and different strategies are utilised. Furthermore, understanding of genetics is partially regulated not only by their families, but by the way society handles information. Therefore, genetic health professionals should take into account the familial influence on individuals and their decision to attend genetic services, and also that of the media.

Decreasing costs of genetic testing and advances in treatment for women with cancer with germline BRCA1/BRCA2 mutations have heralded more inclusive genetic testing programs. The Genetic Testing in Epithelial Ovarian Cancer (GTEOC) Study, investigates the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (universal genetic testing or UGT). Study participants and staff were interviewed to: (i) assess the impact of UGT (ii) integrate patients' and staff perspectives in the development of new UGT programs. Semi-structured interviews were conducted with twelve GTEOC Study participants and five members of staff involved in recruiting them. The transcripts were transcribed verbatim and analyzed using Interpretative Phenomenological Analysis. There are two super-ordinate themes: motivations and influences around offers of genetic testing and impacts of genetic testing in ovarian cancer patients. A major finding is that genetic testing is contextualized within the broader experiences of the women; the impact of UGT was minimized in comparison with the ovarian cancer diagnosis. Women who consent to UGT are motivated by altruism and by their relatives' influence, whilst those who decline are often considered overwhelmed or fearful. Those without a genetic mutation are usually reassured by this result, whilst those with a genetic mutation must negotiate new uncertainties and responsibilities towards their families. Our findings suggest that UGT in this context is generally acceptable to women. However, the period shortly after diagnosis is a sensitive time and some women are emotionally overburdened. UGT is considered a 'family affair' and staff must acknowledge this.

Background: Over recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs. Objective: To explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC). Methods: Between 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Eligibility was irrespective of patient age and family history of cancer. The psychosocial arm of the study used self-report, psychometrically validated questionnaires (Depression Anxiety and Stress Scale (DASS-21); Impact of Event Scale (IES)) and cost analysis was performed. Results: 232 women were recruited and 18 mutations were detected (12 in BRCA1, 6 in BRCA2), giving a mutation yield of 8%, which increased to 12% in unselected women aged, published_or_final_version

The motivations of those who give consent to bio-banking research have received a great deal of attention in recent years. Previous work draws upon the notion of altruism, though the self and/or family have been proposed as significant factors. Drawing on 11 interviews with staff responsible for seeking consent to cancer bio-banking and 13 observations of staff asking people to consent in routine clinical encounters, we investigate how potential participants are oriented to, and constructed as oriented to, self and other related concerns (Author 2007). We adopt a rhetorical discourse analytic approach to the data and our perspective can be labelled as ‘ethics-in-interaction’. Using analytic concepts such as repetition, extreme case formulation, typical case formulation and contrast structure, our observations are three-fold. Firstly, we demonstrate that orientation to ‘general others’ in altruistic accounts and to ‘self’ in minimising burden are foregrounded in constructions of motivation to participate in cancer bio-banking across the data corpus. Secondly, we identify complex relational accounts which involve the self as being more prominent in the consent encounter data where the staff have a nursing background whereas ‘general others’ feature more when the staff have a scientific background. Finally, we suggest implications based on the disparities between how participants are oriented in interviews and consent encounters which may have relevance for developing staff’s reflective practice.

Testing cancers for mismatch repair (MMR) gene defects assists selection of families for genetic testing for cancer predisposing Lynch syndrome. Performing MMR tumour testing without consent is debated, though little empirical work has been undertaken. We address this by examining the significance of testing for those who have consented without prior genetic counselling, particularly their ‘accounts’ of testing via displays of knowledge and responsibility. Semi-structured interviews were conducted with participants recruited from a UK genetics service. Participants had difficulties in formulating the benefits of testing when consent was facilitated by a relative or by mail. Discourse analysis revealed that in the absence of specific or accurate understandings of tumour testing, participants displayed responsibility towards themselves and others by generalising and diminishing the implications of testing. Within the framework of ‘genetic responsibility’, MMR tumour testing seems less important in participants’ accounts compared to more definitive genetic testing. If facilitating genetic knowledge and responsibility are goals of genetic testing then developing appropriate consent procedures for MMR tumour testing is an important consideration. Further research is required to differentiate whether genetic counselling is a precondition for enacting genetic responsibility or whether intrinsic differences between types of testing make the concept less relevant.

Informed consent is the ethical and legal bedrock of much clinical practice and research involving humans. A paradigm of consent focusing on individual autonomy and self-determination is dominant and underpins much of the empirical work undertaken. Alongside a focus on seeking to ‘improve’ consent within this framework are alternative perspectives, considering consent in the context of human interaction and communication. Such perspectives highlight the roles and relationships of all involved parties and the complexity of the unfolding discourse. They call for a redefinition of what a successful consent encounter is and for a review of understandings of professional practice and persuasion. Though these issues are touched on by other sociological work, discursive studies highlight the achievement of consent as a proceeding interaction and the involvement and influences of all involved, with implications for professional practice. Key Concepts: Informed consent has become central to much clinical practice and research involving humans. There are limitations to addressing the challenges of achieving informed consent in practice from within its own frame of reference. Sociological work has emphasised the significance of social contexts and processes in how consent proceeds. Discursive and interactional approaches give further emphasis to the performative and contextual nature of consent interactions, highlighting the roles of all interlocutors. Professionals involved in seeking consent could use insights from discursive work in selecting communicative strategies that best go on to enable their patients and research participants. Keywords: informed consent; consent; discourse; interaction; medical ethics; autonomy; professional practice; persuasion

Accounts of participation in genetic research are dynamic and innately social. Participation is viewed not as an individualised act but as morally significant and involving relational responsibilities. Previous work has investigated individuals’ motivations for research participation in terms of such relational complexities. Here we explore the significance of relational responsibility in the context of participation in a familial cancer study where many family members are eligible for recruitment. We consider accounts of family (non)participation, (im)morality and (ir)responsibility. By looking at accounts we can explore the ways in which people use explanations to construct social reality. Accounts are more than disclosing internal attitudes, rather they provide claims of moral worth and participation in the social world. The accounts are taken from eight in depth interviews with participants from the kConFab Study, investigating familial breast cancer. Interviewees gave the juxtaposed accounts described elsewhere, with motivations for research participation framed in terms of self, family and society. In addition to accounts relating to themselves, all interviewees accounted for family members’ (non) participation. Accounts of self and relatives’ participation in the research were brief, with strongly altruistic framing and participation described as meeting expectations. Four participants knew of family members who had chosen not to participate. Accounts about this were longer and involved more elaborate moral character work. As research participation was framed as beneficial to the family and others, with minimal burden to the participant, excusing and justifying non-participation was required in order to explain it. This was done through descriptions of illness, disability, relatives’ feelings of guilt and logistics. In one instance a sister’s non-participation was not justified or excused but explained it in terms of her ‘selfishness’. Reports of non-participation by relatives involved negative feelings towards them, ranging from frustration to anger. Stronger emotional responses were described when the relative was perceived as having particular responsibilities towards the interviewee or their offspring, as a parent or sibling. The familial tensions described in the accounts are part of a broader narrative of pre-existing difficulties in family dynamics. The genetic research context became another field in which these difficulties became evident or entrenched. Our findings inform our understanding of how genetic research may be experienced within a family. With participation framed as acting responsibly towards others there may be relational ramifications if individuals decline to do so. This has implications for how consent is viewed and how studies may choose to recruit participants.