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We aimed to describe the clinical characteristics of families with heritable TP53-related cancer (hTP53rc) syndrome in Sweden with class 4 and 5 germline TP53 variants (gTP53), and to evaluate the genotype-phenotype correlation. These results were also used to evaluate our previously published phenotype prediction model based on TP53 missense variants and their impact on protein conformation. 90 families with hTP53rc were initially identified in Sweden. After variant reclassification using the TP53-specific ACMG criteria, 83 families remained (176 carriers) to harbour a pathogenic (class 5) or likely pathogenic (class 4) variant in TP53. Of these, 112 carriers (64%) had a previous history of cancer, and 35 (31%) had developed more than one primary tumour. 16% of the families met the stricter criteria for Classic Li-Fraumeni syndrome, 45% the updated Chompret criteria, 35% for hereditary breast cancer (HBC), and the remaining 5% were classified as “Others”. We identified 42 different gTP53 variants of which 22 were missense. The most frequently observed variant was the missense c.542 G > A, p.R181H identified in 14/29 (48%) of HBC families. Fifteen of the 20 informative missense variants (75%) were phenotypically predicted correctly using our previously published in silico prediction model. The TP53 p.R181H was identified as a common Swedish variant predominantly associated with an HBC phenotype. Apart from this variant, there were no significant genotype-phenotype correlations. Therefore, due to phenotypic overlap it is still too early to stratify surveillance programme for different TP53-carriers.

Key features: 

• The Northern Sweden Health and Disease Study (NSHDS) was initiated in the mid-1980s. The NSHDS is a population-based prospective longitudinal cohort comprising >140 000 participants in the two northernmost regions in Sweden, Norrbotten and Västerbotten, with >240 000 blood samples and 1.5 million person-years of follow-up.
• The NSHDS includes three sub-cohorts: the Västerbotten Intervention Programme (VIP), the expanded Northern Sweden Monitoring of Trends and Determinants of Cardiovascular Disease (MONICA) Study, and the Mammography Screening Project (MSP). The VIP is both a community-based cardiometabolic intervention programme encouraging healthy lifestyle (targeting individuals 40, 50, and 60 years of age), and a corresponding research cohort. The MONICA is an observational study focusing on cardiovascular disease and its associated risk factors, recruiting individuals aged 25–74 years. The MSP recruited women attending mammography during 1995–2006. The NSHDS median participation age is 50 years (53% women).
• Most participants contribute data on health, lifestyle, anthropometric measures, blood pressure, blood lipids, and glucose tolerance, along with research blood samples that are fractionated, frozen within an hour of collection, and stored at –80°C. Linkage to registries, clinical cohorts, and biological tissue archives facilitates studies of well-characterized participants (often combined with intervention studies).
• Collaborations are encouraged. Additional information can be found at: info.brs@umu.se; https://www.umu.se/en/biobank

Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.

Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.

Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).

Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.

Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.

Objectives: Hereditary cancer risks can be effectively managed if at-risk relatives enroll in surveillance and preventive care. Family-mediated risk disclosure has internationally been shown to be incomplete, selective and leave over a third of eligible at-risk individuals without access to genetic counseling. We explored patients handling of cancer risk information in practice. 

Methods: We conducted twelve semi-structured interviews with patients who had completed their genetic counseling and been asked to disclose risk information to relatives. Questions were designed to investigate lived experiences of communicating hereditary risk and focused on disclosure strategies, intrafamilial interactions and emotional responses. 

Results: Qualitative content analysis yielded five categories. These span personal fears, shared responsibilities, feeling of empowerment, innovative solutions and unmet needs. Patients put high value on collaboration with their genetic healthcare professionals but also solicited better overview of the counseling process and more personalized, case-tailored information. 

Conclusions: Our results add novel insights about the practical strategies employed by genetic counselees and their motivations behind disclosing hereditary risk information to relatives. 

Practice implications: A patient-centered cancer genetics care would clarify roles and responsibilities around risk disclosure, inform counselees about the process upfront and tailor information to offer case-specific data with the family’s inheritance pattern explained.

In a multicentre randomised controlled trial (DIRECT), we evaluate whether an intervention of providing direct letters from healthcare professionals to at-risk relatives (ARRs) affects the proportion of ARRs contacting a cancer genetics clinic, compared with patient-mediated disclosure alone (control). With the aim to explore how the patients included in the trial perceived and performed risk communication with their ARRs we analysed 17 semi-structured interviews with reflexive thematic analysis. All patients described that they disclosed risk information to all close relatives themselves. No integrity-related issues were reported by patients offered the intervention, and all of them accepted direct letters to all their ARRs. Patients’ approaches to informing distant relatives were unpredictable and varied from contacting all distant ARRs, sharing the burden with the family, utilising the offer of sending direct letters, vaguely relying on others to inform, or postponing disclosure. Most patients limited their responsibility to the disclosure, although others wanted relatives to get genetic counselling or felt a need to provide additional information to the ARRs before ending their mission. We also identified confusion about the implication of test results, who needed risk information, and who was responsible for informing ARRs. These misunderstandings possibly also affected risk disclosure. This study revealed that despite accepting the direct letters to be sent to all relatives, the patients also contributed to risk disclosure in other ways. It was only in some situations to distant relatives that the healthcare-assisted letter was the only means of communication to the ARRs.

Direct contact may be an option for supporting disclosure in families with hereditary cancer risk. In this qualitative interview study, we explored how healthy at-risk relatives experience receiving a letter with information about hereditary cancer directly from healthcare rather than via a relative. The study is part of an ongoing multicentre randomised clinical trial in Sweden that evaluates the effectiveness of direct letters from cancer genetics clinics to at-risk relatives. After conducting semi-structured interviews with 14 relatives who had received a letter and contacted the clinic, we analysed the data using thematic analysis. The relatives had different levels of prior knowledge about the hereditary cancer assessment. Many had been notified by family that a letter was coming but some had not. Overall, these participants believed healthcare-mediated disclosure could complement family-mediated disclosure. They expressed that the letter and the message raised concerns and a need for counselling, and they wanted healthcare to be accessible and informed when making contact. The participants found the message easier to cope with when they had been notified by a family member beforehand, with a general attitude that notifying relatives was the appropriate step to take. They thought healthcare should help patients with the disclosure process but also guard the right of at-risk relatives to be informed. The findings support a direct approach from healthcare as a possible complement to an established model of family-mediated risk disclosure, but implementation must be made within existing frameworks of good practice for genetic counselling.

Objectives: Hereditary cancer has implications not only for patients but also for their at-risk relatives (ARRs). In current clinical practice, risk disclosure to ARRs involves collaboration between patients and healthcare providers (HCPs). However, the specific responsibilities of each party are intertwined and at times unclear. In this study, we explored public attitudes regarding moral and legal responsibilities to disclose familial risk information to uninformed ARRs.

Design: In an online cross-sectional survey, participants were prompted with a hypothetical scenario where a gender-neutral patient learnt about their familial risk of colorectal cancer. The patient was advised to regularly undergo colonoscopy screening, and this recommendation was extended to both their siblings and cousins. While the patient informed their siblings, they had not spoken to their cousins in 20 years and did not want to contact them. The survey assessed respondents’ views on the patient’s and HCPs’ ethical responsibility and legal obligation to inform the cousins (ARRs).

Participants: A random selection of 1800 Swedish citizens 18–74 years of age were invited. Out of those, 914 (51%) completed the questionnaire.

Results: In total, 75% believed that HCPs had a moral responsibility to inform ARRs, while 59% ascribed this moral responsibility to the patient. When asked about the ultimate responsibility for risk disclosure to ARRs, 71% placed this responsibility with HCPs. Additionally, 66% believed that HCPs should have a legal obligation to inform ARRs, while only 21% thought the patient should have such an obligation. When prompted about a scenario in which the patient actively opposed risk disclosure, a majority believed that HCPs should still inform the ARRs.

Conclusion: Our study indicates that the Swedish public ascribes moral responsibility for informing ARRs to both the patient and HCPs. However, contrary to current practice, they believe HCPs hold the ultimate responsibility. The majority of respondents support disclosure even without patient consent.

Background: The results of germline genetic testing for hereditary cancer are of importance not only to the patients under investigation but also to their genetic at-risk relatives. Standard care is to encourage the proband (first family member under investigation) to pass on this risk information to the relatives. Previous research suggests that with family-mediated disclosure, only about a third of at-risk relatives contact health care to receive genetic counselling. In some studies, complementing family-mediated risk disclosure with healthcare-assisted risk disclosure almost doubles the uptake of genetic counselling in at-risk relatives. In this study, we evaluate healthcare-assisted direct letters to relatives at risk of hereditary cancer syndromes in a randomized controlled trial.

Methods: Probands are recruited from Swedish outpatient cancer genetics clinics to this two-arm randomized controlled trial. The study recruits probands with either a pathogenic variant in a cancer susceptibility gene (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2) or probands with familial breast and colorectal cancer based on clinical and pedigree criteria. In both arms, probands receive standard care, i.e., are encouraged and supported to pass on information to relatives. In the intervention arm, the proband is also offered to have direct letters sent to the at-risk relatives. The primary outcome measure is the proportion of at-risk relatives contacting a Swedish cancer genetics clinic within 12 months of the proband receiving the test results.

Discussion: This paper describes the protocol of a randomized controlled clinical trial evaluating a healthcare-assisted approach to risk disclosure by offering the probands to send direct letters to their at-risk relatives. The results of this study should be informative in the future development of risk disclosure practices in cancer genetics clinics.

Trial registration: ClinicalTrials.gov. Identifier NCT04197856 (pre-trial registration on December 13, 2019). Also registered at the website “RCC Cancerstudier i Sverige” as study #86719.

BACKGROUND: Genetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.

METHODS: Women with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.

RESULTS: In 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.

CONCLUSIONS: This study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.