Outcomes of the "BRCA Quality Improvement Dissemination Program": An initiative to improve patient receipt of cancer genetics services at five health systems.

OBJECTIVE: A quality improvement initiative (QII) was conducted with five community-based health systems' oncology care centers (sites A-E). The QII aimed to increase referrals, genetic counseling (GC), and germline genetic testing (GT) for patients with ovarian cancer (OC) and triple-negative breast cancer (TNBC). METHODS: QII activities occurred at sites over several years, all concluding by December 2020. Medical records of patients with OC and TNBC were reviewed, and rates of referral, GC, and GT of patients diagnosed during the 2 years before the QII were compared to those diagnosed during the QII. Outcomes were analyzed using descriptive statistics, two-sample t-test, chi-squared/Fisher's exact test, and logistic regression. RESULTS: For patients with OC, improvement was observed in the rate of referral (from 70% to 79%), GC (from 44% to 61%), GT (from 54% to 62%) and decreased time from diagnosis to GC and GT. For patients with TNBC, increased rates of referral (from 90% to 92%), GC (from 68% to 72%) and GT (81% to 86%) were observed. Effective interventions streamlined GC scheduling and standardized referral processes. CONCLUSION: A multi-year QII increased patient referral and uptake of recommended genetics services across five unique community-based oncology care settings.

RNA sequencing uncovers clinically actionable germline intronic MSH2 variants in previously unresolved Lynch syndrome families.

Despite advances in genetic testing for Lynch syndrome, nearly one quarter of mismatch repair-deficient (MMRd) colorectal and endometrial cancers remain unexplained. When added to germline DNA testing, RNA sequencing can increase diagnostic yield, improve variant classification and reduce variants of uncertain significance. Here, we describe two cases where RNA sequencing uncovered likely pathogenic MSH2 variants in families with MMRd tumours that were initially unexplained following comprehensive genetic testing for Lynch syndrome.

Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.

Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.

Creation and Implementation of an Environmental Scan to Assess Cancer Genetics Services at Three Oncology Care Settings.

An environmental scan (ES) is an efficient mixed-methods approach to collect and interpret relevant data for strategic planning and project design. To date, the ES has not been used nor evaluated in the clinical cancer genetics setting. We created and implemented an ES to inform the design of a quality improvement (QI) project to increase the rates of adherence to national guidelines for cancer genetic counseling and genetic testing at three unique oncology care settings (OCS). The ES collected qualitative and quantitative data from reviews of internal processes, past QI efforts, the literature, and each OCS. The ES used a data collection form and semi-structured interviews to aid in data collection. The ES was completed within 6 months, and sufficient data were captured to identify opportunities and threats to the QI project's success, as well as potential barriers to, and facilitators of guideline-based cancer genetics services at each OCS. Previously unreported barriers were identified, including inefficient genetic counseling appointment scheduling processes and the inability to track referrals, genetics appointments, and genetic test results within electronic medical record systems. The ES was a valuable process for QI project planning at three OCS and may be used to evaluate genetics services in other settings.

Two decades of Huntington disease testing: patient's demographics and reproductive choices.

Predictive testing for Huntington disease (HD) has been available in the United States (US) since 1987, and the Indiana University Predictive Testing Program has been providing this testing since 1990. To date there has been no published description of those who present for such testing in the US. Here we describe demographics of 141 individuals and reproductive decision making of a subset of 16 of those individuals who underwent predictive HD testing between 1990 and 2010 at one site in the US. This study is a retrospective chart review of the "Personal History Questionnaire" participants completed prior to testing. As seen in other studies, most participants were female (64.5 %), in their mid-30s (mean = 34), and had at least one child prior to testing (54 %). Multiple demographic datum points are described, and the reproductive decision making of these at-risk individuals was analyzed using Fisher's Exact Tests. Of those women who had children before learning of their risk to inherit HD, those who attended church more frequently, had three or more children total, or whose mother was affected with HD were more likely to be comfortable with their choice to have children. We conclude that these demographic factors influence the reproductive decision-making of individuals at risk for HD. Psychologists, clinical geneticists, and genetic counselors may be able to use this information to help counsel at-risk patients regarding current or past reproductive decision making.