Test-takers' perspectives on consumer genetic testing for hereditary cancer risk.

Purpose: With few exceptions, research on consumer genetic testing for hereditary cancer risk has focused on tests with limited predictive value and clinical utility. Our study advances the existing literature by exploring the experiences and behaviors of individuals who have taken modern consumer genetic tests for cancer susceptibility that, unlike earlier tests, screen for medically significant variants. Methods: We interviewed 30 individuals who had undergone consumer genetic testing for hereditary cancer risk between 2014 and 2019. We explored participants' pre-test sentiments (7 items), experiences receiving results (5 items), behavioral and health-related changes (6 items), and attitudes and beliefs (3 items). Data were analyzed for thematic content. Results: Most participants reported a personal (n = 6) and/or family history (n = 24) of cancer, which influenced their choice to pursue testing. Before testing, most participants did not consult with a physician (n = 25) or receive genetic counseling (n = 23). Nevertheless, the majority felt that they understood test-related information (n = 20) and their results (n = 20), though a considerable number reported experiencing negative emotions related to their results. Most also shared their results with family members (n = 27). Overall, participants' attitudes towards consumer genetic testing for cancer risk were predominantly positive (n = 23). Conclusion: This study offers new insights into how individuals use and perceive modern consumer genetic tests for hereditary cancer risk, focusing on their perceptions of the risks, benefits, and limitations of these services. Understanding test-takers' perspectives can potentially inform improvements aimed at ensuring that tests meet users' needs and deliver clinically valuable genetic risk assessments.

Clinical management of TP53 mosaic variants found on germline genetic testing.

BACKGROUND: Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management. PATIENTS AND METHODS: Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing. RESULTS: Twenty-one of 125 unrelated probands (17 %) were found to harbor a TP53 PV with VAF<30 % or a designation of "mosaic". A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (n = 8) or without (n = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative. CONCLUSIONS: Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.

The ENGAGE study: a 3-arm randomized hybrid type 1 effectiveness and implementation study of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic services in childhood cancer survivors.

BACKGROUND: Germline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and screening guidelines for genetic carriers. Access to genetic services is limited in many places, which leaves many genetic carriers unidentified and at risk for late diagnosis of cancers and poor outcomes. This poses a problem for childhood cancer survivors, as this is a population with an increased risk for subsequent malignant neoplasms (SMN) due to cancer therapy or inherited cancer predisposition. The ENGaging and Activating cancer survivors in Genetic services (ENGAGE) study evaluates the effectiveness of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic testing in childhood cancer survivors compared to usual care options for genetic testing. METHODS: The ENGAGE study is a 3-arm randomized hybrid type 1 effectiveness and implementation study within the Childhood Cancer Survivor Study population which tests a clinical intervention while gathering information on its delivery during the effectiveness trial and its potential for future implementation among 360 participants. Participants are randomized into three arms. Those randomized to Arm A receive genetic services via videoconferencing, those in Arm B receive these services by phone, and those randomized to Arm C will receive usual care services. DISCUSSION: With many barriers to accessing genetic services, innovative delivery models are needed to address this gap and increase uptake of genetic services. The ENGAGE study evaluates the effectiveness of an adapted model of remote delivery of genetic services to increase the uptake of recommended genetic testing in childhood cancer survivors. This study assesses the uptake in remote genetic services and identify barriers to uptake to inform future recommendations and a theoretically-informed process evaluation which can inform modifications to enhance dissemination beyond this study population and to realize the benefits of precision medicine. TRIAL REGISTRATION: This protocol was registered at clinicaltrials.gov (NCT04455698) on July 2, 2020.

Childhood physical activity and pubertal timing: findings from the LEGACY girls study.

BACKGROUND: There is limited research on whether physical activity (PA) in early childhood is associated with the timing of pubertal events in girls. METHODS: We used data collected over 2011-16 from the LEGACY Girls Study (n = 984; primarily aged 6-13 years at study enrolment), a multicentre North American cohort enriched for girls with a breast cancer family history (BCFH), to evaluate if PA is associated with age at thelarche, pubarche and menarche. Maternal-reported questionnaire data measured puberty outcomes, PA in early childhood (ages 3-5 years) and total metabolic equivalents of organized PA in middle childhood (ages 7-9 years). We used interval-censored Weibull parametric survival regression models with age as the time scale and adjusted for sociodemographic factors, and we tested for effect modification by BCFH. We used inverse odds weighting to test for mediation by body mass index-for-age z-score (BMIZ) measured at study enrolment. RESULTS: Being highly active vs inactive in early childhood was associated with later thelarche in girls with a BCFH [adjusted hazard ratio (aHR) = 0.39, 95% CI = 0.26-0.59), but not in girls without a BCFH. In all girls, irrespective of BCFH, being in the highest vs lowest quartile of organized PA in middle childhood was associated with later menarche (aHR = 0.70, 95% CI = 0.50-0.97). These associations remained after accounting for potential mediation by BMIZ. CONCLUSION: This study provides new data that PA in early childhood may be associated with later thelarche in girls with a BCFH, also further supporting an overall association between PA in middle childhood and later menarche.

User and Usability Testing of a Web-Based Genetics Education Tool for Parkinson Disease: Mixed Methods Study.

BACKGROUND: Genetic testing is essential to identify research participants for clinical trials enrolling people with Parkinson disease (PD) carrying a variant in the glucocerebrosidase (GBA) or leucine-rich repeat kinase 2 (LRRK2) genes. The limited availability of professionals trained in neurogenetics or genetic counseling is a major barrier to increased testing. Telehealth solutions to increase access to genetics education can help address issues around counselor availability and offer options to patients and family members. OBJECTIVE: As an alternative to pretest genetic counseling, we developed a web-based genetics education tool focused on GBA and LRRK2 testing for PD called the Interactive Multimedia Approach to Genetic Counseling to Inform and Educate in Parkinson's Disease (IMAGINE-PD) and conducted user testing and usability testing. The objective was to conduct user and usability testing to obtain stakeholder feedback to improve IMAGINE-PD. METHODS: Genetic counselors and PD and neurogenetics subject matter experts developed content for IMAGINE-PD specifically focused on GBA and LRRK2 genetic testing. Structured interviews were conducted with 11 movement disorder specialists and 13 patients with PD to evaluate the content of IMAGINE-PD in user testing and with 12 patients with PD to evaluate the usability of a high-fidelity prototype according to the US Department of Health and Human Services Research-Based Web Design & Usability Guidelines. Qualitative data analysis informed changes to create a final version of IMAGINE-PD. RESULTS: Qualitative data were reviewed by 3 evaluators. Themes were identified from feedback data of movement disorder specialists and patients with PD in user testing in 3 areas: content such as the topics covered, function such as website navigation, and appearance such as pictures and colors. Similarly, qualitative analysis of usability testing feedback identified additional themes in these 3 areas. Key points of feedback were determined by consensus among reviewers considering the importance of the comment and the frequency of similar comments. Refinements were made to IMAGINE-PD based on consensus recommendations by evaluators within each theme at both user testing and usability testing phases to create a final version of IMAGINE-PD. CONCLUSIONS: User testing for content review and usability testing have informed refinements to IMAGINE-PD to develop this focused, genetics education tool for GBA and LRRK2 testing. Comparison of this stakeholder-informed intervention to standard telegenetic counseling approaches is ongoing.