A Breast Radiology Department-operated, Proactive Same-day Program Identifies Pathogenic Breast Cancer Mutations in Unaffected Women.

RATIONALE AND OBJECTIVES: Pathogenic mutations in some genes elevate women's breast cancer risk, necessitating risk-reduction strategies. Unfortunately, women are underscreened for cancer risk, and when identified as potentially high risk, women seldom pursue genetic counseling or testing. To improve cancer risk management, this project determined the feasibility of radiology-operated, proactive, same-day risk assessment and genetic testing programs to diagnose high-risk women undergoing breast imaging. MATERIALS AND METHODS: The Comprehensive Assessment, Risk & Education Program launched on June 5, 2019. Data was tracked through July 22, 2020. Women undergoing breast imaging completed questionnaires that calculated Tyrer-Cuzick risk and assessed genetic testing eligibility using National Comprehensive Cancer Network criteria. To encourage eligible women's genetic testing adherence, pretest counseling and saliva sample collection occurred that same day in the imaging center. Samples were tested by a 34-multigene panel. Genetic counselors called women with positive results. Women with negative results or variants of uncertain significance were mailed notifications. Summary statistics were calculated. RESULTS: A total of 3345 women completed questionnaires. 1080 (32.3%) met genetic testing criteria. 468/1080 (43.3%) submitted genetic samples, and 416/1080 (38.5%) completed testing. Of 416 completed tests, 269 (64.7%) tested negative, 109 (26.2%) had variants of uncertain significance, and 38 (9.1%) diagnosed pathogenic mutations. 13/38 (34.2%) women with pathogenic mutations implemented risk-reduction strategies at our institution. CONCLUSION: Breast imaging centers can operate same-day cancer risk assessment and genetic testing programs, identifying high-risk women that conventional risk assessment methods may not have diagnosed. These proactive programs add value to radiology departments' cancer care beyond traditional imaging services.

Precise and Programmable Detection of Mutations Using Ultraspecific Riboregulators.

The ability to identify single-nucleotide mutations is critical for probing cell biology and for precise detection of disease. However, the small differences in hybridization energy provided by single-base changes makes identification of these mutations challenging in living cells and complex reaction environments. Here, we report a class of de novo-designed prokaryotic riboregulators that provide ultraspecific RNA detection capabilities in vivo and in cell-free transcription-translation reactions. These single-nucleotide-specific programmable riboregulators (SNIPRs) provide over 100-fold differences in gene expression in response to target RNAs differing by a single nucleotide in E. coli and resolve single epitranscriptomic marks in vitro. By exploiting the programmable SNIPR design, we implement an automated design algorithm to develop riboregulators for a range of mutations associated with cancer, drug resistance, and genetic disorders. Integrating SNIPRs with portable paper-based cell-free reactions enables convenient isothermal detection of cancer-associated mutations from clinical samples and identification of Zika strains through unambiguous colorimetric reactions.

Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue.

PURPOSE: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. PATIENTS AND METHODS: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. RESULTS: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. CONCLUSION: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

Evolving Decisions: Perspectives of Active and Athletic Individuals with Inherited Heart Disease Who Exercise Against Recommendations.

Individuals with hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS) are advised to avoid certain forms of exercise to reduce their risk of sudden death. Cardiovascular genetic counselors facilitate both adaptation to, and decision-making about, these exercise recommendations. This study describes decision-making and experiences of active adults who exercise above physicians' recommendations. Purposive sampling was used to select adults with HCM and LQTS who self-identified as exercising above recommendations. Semi-structured interviews explored participants' decision-making and the psychological impact of exercise recommendations. Fifteen individuals were interviewed (HCM: 10; LQTS: 5; mean age: 40). Transcripts were coded and analyzed for underlying themes. Despite exercising above recommendations, nearly all participants made some modifications to their prior exercise regimen. Often these decisions changed over time, underscoring the importance of shared decision-making conversations beyond the initial evaluation. The importance of exercise was frequently cited as a reason for continued exercise, as were perceptions of sudden death risk as low, acceptable, or modifiable. Many participants reported that family and friends supported their exercise decisions, with a minority having family or friends that expressed significant reservations. Genetic counselors, cardiologists, and nurses can use these data to inform their counseling regarding exercise recommendations.

Exercise restrictions trigger psychological difficulty in active and athletic adults with hypertrophic cardiomyopathy.

OBJECTIVE: We examined the extent and nature of the psychological difficulty experienced by athletic adults with hypertrophic cardiomyopathy (HCM), correlates of that difficulty and coping mechanisms. METHODS: A survey assessed athletic history and psychological impact of exercise restrictions. LASSO penalised linear regression identified factors associated with psychological difficulty. Semistructured interviews provided deeper insight into the nature and origins of psychological difficulty. RESULTS: 54 individuals (33% female, mean age 55.9) completed the survey. The majority were recreational athletes at the time of restriction (67%). There was a drop in athleticism after diagnosis, including time spent exercising (p=0.04) and identification as an athlete (p=0.0005). Most respondents (54%) found it stressful and/or difficult to adjust to exercise restrictions. Greater psychological morbidity was associated with history of elite or competitive athletics, athletic identity and decrease in time spent exercising. 16 individuals (44% female, mean age 52.4) were interviewed. Long-term effects included weight gain and uncertainty about exercising safely. The role of exercise in interviewees' lives contracted significantly after restriction, from multiple functions (eg, social, stress relief, fitness) to solely health maintenance. Interviewees reported a unique form of social support: having family and friends participate with them in lower intensity exercise. Lack of understanding from family or friends and avoiding exercise completely were detrimental to coping. CONCLUSIONS: Athletic adults with HCM experience multifaceted, lasting difficulty adjusting to exercise recommendations. These data can guide clinicians in identifying patients at highest risk for distress and in helping to bolster coping and adaptation.