Cascade Genetic Testing Research Articles

The challenges of cascade genetic testing in hereditary cancer syndromes: A few ethical considerations.

Progress in the discovery and understanding of cancer susceptibility genes and ever-cheaper genomic technologies are generating precious opportunities to optimize the identification of individuals with a hereditary cancer predisposition.Any such effort will have a more significant impact if it prioritizes those most at risk of developing cancer. This premise is central to cascade genetic testing, in which healthcare professionals encourage cancer patients carrying a predisposing gene variant to discuss the implications of their test results with their at-risk relatives so that, ideally, all the at-risk individuals in that family have the option to seek genetic counseling and testing in turn. Among the relatives found to have the gene variant, those who have developed cancer can then access targeted treatment and follow-up, those who are asymptomatic can benefit from enhanced preventive measures, while those who test negative can avoid unnecessary, costly, and time-consuming screening.Despite its life-saving potential, cascade genetic testing in hereditary cancer syndromes is often reported to have disappointing uptake rates, particularly among historically disadvantaged and underrepresented communities, for reasons that include barriers in intrafamilial genetic risk communication and low health and genetic literacy.This paper will discuss the challenges of cascade genetic testing in hereditary cancer syndromes, addressing some of the ethical questions arising from its current model, from strategies aimed at improving its uptake, as well as from alternative approaches to identifying asymptomatic individuals who may carry a cancer- associated pathogenic variant.

Abstract 4128590: Identical Twins, Non-Identical Results: Genetic Testing for Cardiomyopathy

Case: A 58-year-old male (Twin A) with no medical history presented with syncope while playing paddle ball. TTE showed LVEF 15-20%. Cardiac MRI (CMR) identified transmural late gadolinium enhancement (LGE) in the inferolateral wall of the LV, but angiography showed non-obstructive CAD. Four years later, his monozygotic twin (Twin B), also with no medical history, suffered cardiac arrest while playing paddle ball. TTE showed LVEF 5-10%. CMR revealed inferolateral LGE (Figure 1) with angiography showing non-obstructive CAD. Genetic testing was performed by different companies. Twin A was found to be heterozygous for myosin light chain kinase 3 ( MYLK3 ) p.R380H (c.1139C>A), a variant of uncertain significance (VUS). While rare (gnomAD allele frequency 2.7e -4 ), MYLK3 p.R380H is not conserved across species, exchanges amino acids with similar biochemical properties, and is predicted to be benign by in silico pathogenicity tools. Notably, MYLK3 was not sequenced in Twin B, who was instead found to be heterozygous for desmoplakin ( DSP ) p.R1002W (c.3004C>T). DSP p.R1002W is highly conserved, exchanges amino acids with dissimilar properties, and is very rare (gnomAD allele frequency 2.8e -5 ). In silico testing yielded conflicting results with some tools predicting it to be damaging to protein function. Interestingly, the variant was present in both twins but was classified differently by each company: likely benign for Twin A (and therefore not reported) and VUS for Twin B. First degree relatives are advised to undergo clinical screening and cascade genetic testing for DSP p.R1002W. Discussion: The presentation described is consistent with arrhythmogenic cardiomyopathy (ACM) and the family history strongly supports a genetic etiology. DSP is a causal gene for ACM with unique clinical features that are strikingly similar to those observed herein. The differences in genes tested and variant adjudication between companies has left diagnostic uncertainty; hence, definitive pathogenicity cannot be attributed to either variant without cosegregation analysis, which is ongoing. In summary, this case illustrates the challenges of variant interpretation, and the impact that this can have on genetic counseling and family screening.

P092 Targeted cascade genetic testing in prostate cancer probands for heritable germline variants

P092 Targeted cascade genetic testing in prostate cancer probands for heritable germline variants

The usefulness of QT interval measurement as a screening tool for cascade testing in asymptomatic patients at risk of long QT syndrome

Abstract Background Long QT syndrome (LQTS), an inherited arrhythmic syndrome, remains a public health concern with up to 3000 unexpected deaths in the US annually. A simple 12-lead ECG is the most easily accessible tool for initial screening. Purpose To describe the diagnostic utility of the standard QT correction techniques in 12-Lead ECGs, in a screening population of first-degree relatives of persons with LQTS of known genotype. Methods In this single centre study, data were included on consecutive patients undergoing cascade clinical and genetic testing for LQTS, who had a first degree relative with genotype-positive LQTS, from the years 2019 to 2022. Patient demographics, baseline ECG and genetic results were obtained. The QT interval was manually calculated between three independent readers using the tangent method and corrected using the 4 most commonly used formulae: Bazett (BQTc), Fridericia (FreQTc), Framingham (FraQTc) and Hodges (HQTc). The Mean QT was calculated by taking the average of four consecutive QT measurements in lead II or V5. The QT dispersion (QTd), was also calculated by using the formula: QTd = QT max – QT min. Results Data was available on 97 patients from 14 families. The mean age at screening was 44 years, and 51.5% were males. Two-thirds of patients were asymptomatic (n = 74, 76.3%). Fifteen patients had syncopal events. 72.2% (n = 70) of patients had a family history of arrhythmic death. After clinical screening and genotyping, 46.4% (n = 45) patients were gene positive for either KCNQ1 (75.5%) or KCNH2 (24.5%). Patients with prior syncope were more likely to be gene positive (72.7% vs 39.2%, p = 0.005). The 12-Lead ECG derived QTc result is listed in Table 1, with all correction modalities showing a higher corrected QT in the genotype-positive group (p <0.001). The diagnostic performance of BQTc was similar to that of the newer formulae (FreQTc, FraQTc and HQTc) when correcting for heart rate within the range of 60 – 100bpm as listed in Table 2. At a cut-off value of 440ms, BQTc formula had a sensitivity of 51% and a specificity of 84% for predicting genotype pathogenicity as listed in Table 3. The QT dispersion was higher in patients with KCNH2 compared to those with KCNQ1 (122msec, SD 30.5 vs 74.2 msec, SD 30.4, p value <0.001). Patients with KCNH2 were more likely to require an ICD (83.3% vs 16.7%, p <0.001). The mean Schwartz score in gene positive patient was 2.6 compared to 1.9 (p <0.003). Conclusion Formula correction of QT interval to heart rate had good overall diagnostic performance. Both FreQT and FraQT had high AUROC across different heart rates, though there was no statistically significant difference seen between correction formulae. The ECG remains a good preliminary screening tool method for identifying patients with increased risk LQTS in this population. Larger studies are needed to power for comparisons between QT correction methods.

Attitudes and engagement about cascade genetic testing among women diagnosed with cancer.

313 Background: Cascade testing in families with hereditary cancer syndromes is challenging because patients are responsible for engaging their relatives about test results and clinical support is limited. There are concerns that patient engagement with family members may not be well tailored to the clinical relevance of their test results, with particular concern about variants of uncertain significance (VUS). Methods: We selected patients from the Georgia California Genetic Linkage Initiative, which identified all patients diagnosed with cancer 2013-19 in the 2 states who linked to a germline genetic test. We surveyed 2100 women diagnosed with breast, ovarian or uterine cancer in 2018-19 in Georgia and California who reported a pathogenic variant (PV) that increases the risk of cancer on testing about 4 years after diagnosis and a comparable sample of 1250 women who reported a VUS-only result. The expected response rate from the cohorts is 55% (N=1900). We present preliminary results on patient attitudes about engagement with family and clinicians and behaviors related to their test results. Results: The 2 cohorts were comparable in age (mean 54 vs 58 for VUS, p<.001) and education (college graduate or more 52% vs 53% for VUS p=.235). The Table shows that for patients who reported a PV, belief in the utility of testing in family members was high. A substantial proportion reported that a genetic counselor encouraged them to talk to relatives and talked directly with relatives about testing. PV carriers informed most first-degree relatives about their test results. Patients who reported VUS only were less likely to endorse the utility of testing in relatives; less likely to report that a genetic counselor encouraged family engagement or engaged family directly about testing; and were less likely to have informed relatives about their test results. PV carriers with breast cancer were more likely than VUS-only carriers to receive bilateral mastectomy after diagnosis: PV high risk 88%, PV lower risk 55%, PV other 48%, VUS only 45% p<.001. Conclusions: Compared to patients with VUS-only test results, women with PVs on germline genetic testing after diagnosis of cancer had more positive attitudes about the utility of testing of family members, greater engagement with clinicians and family members about test results and greater uptake of prevention procedures. These findings suggest that engagement with family about genetic testing after cancer diagnosis matches the clinical relevance of the results. Patient attitudes and report of engagement about genetic test results. % Item PV N=596 VUS only N=166 Genetic test results are useful to my family 90 64 Wanted family members to get tested 84 46 Genetic counselor encouraged me to talk about results with family 73 46 Genetic counselor talked directly with family members about testing 56 38 % of first-degree relatives who were informed of patient test results, mean 88 65 p<.001 for all comparisons.

Childhood glaucoma: Implications for genetic counselling.

Childhood glaucoma is a heterogeneous group of ocular disorders defined by an age of onset from birth to 18 years. These vision-threatening disorders require early diagnosis, timely treatment, and lifelong management to maintain vision and minimise irreversible blindness. The genetics of childhood glaucoma is complex with both phenotypic and genetic heterogeneity. The purpose of this review is to summarise the different types of childhood glaucoma and their genetic architecture to aid in the genetic counselling process with patients and their families. We provide an overview of associated syndromes and discuss implications for genetic counselling, including genetic testing strategies, cascade genetic testing, and reproductive options.

Genetic testing for inherited arrhythmia syndromes and cardiomyopathies: results of the European Heart Rhythm Association survey.

Indications and clinical impact of genetic testing for cardiac diseases have increased significantly over the past years. The aim of this physician-based European Heart Rhythm Association (EHRA) survey was to assess current clinical practice and access to genetic testing for cardiac diseases across European Society of Cardiology countries and to evaluate adherence to the 2022 EHRA/HRS/APHRS/LAHRS Expert Consensus Statement on genetic testing. An online questionnaire composed of 28 questions was submitted to the EHRA Research Network and European Reference Network GUARD-Heart healthcare partners and promoted via dedicated social media channels. There were 357 respondents from 69 countries, 40% working in a hospital setting with a cardiac genetic service and/or a dedicated clinic focusing on inherited cardiac diseases and 27% with an onsite genetic laboratory. No genetic testing or low annual rate (<10/year) was declared by 39% of respondents. The majority of respondents (78%) declared issues or limitations to genetic testing access in their clinical practice. The main reasons for not providing or limited access to genetic testing were no availability of dedicated unit or genetic laboratory (35%) or reimbursement issues (25%). The most frequently reported indication for genetic testing was diagnostic purpose (55%). Most respondents (92%) declared offering genetic testing preceded by genetic counselling and 42% regular multidisciplinary evaluations for patients with cardiac genetic diseases. The perceived value of genetic testing in the diagnostic, prognostic, and therapeutic assessment was variable (67, 39, and 29%, respectively) and primarily based on the specific inherited disease. The majority of respondents recommended cascade genetic testing for the first-degree family members in case of pathogenic/likely pathogenic variant in the proband. This survey highlights a significant heterogeneity of genetic testing access and provision and issues attributable to the availability of dedicated unit/genetic laboratory and reimbursement. However, adequate adherence to indications in the current recommendations for genetic testing in patients with cardiac diseases was observed.

Integrating Genetics in Glaucoma Screening.

As additional glaucoma genes are identified and classified, polygenic risk scores will be refined, facilitating early diagnosis and treatment. Ensuring genetic research is equitable to prevent glaucoma blindness worldwide is crucial. To review the progress in glaucoma genetics over the past 25 years, including the identification of genes with varying contributions to the disease and the development of polygenic risk scores. Over the last 2 and a half decades, glaucoma genetics has evolved from identifying genes with Mendelian inheritance patterns, such as myocilin and CYP1B1, to the discovery of hundreds of genes associated with the disease. Polygenic risk scores have been developed, primarily based on research in Northern European populations, and efforts to refine these scores are ongoing. However, there is a question regarding their applicability to other ethnic groups, especially those at higher risk of primary open angle glaucoma, like individuals of African ancestry. Glaucoma is highly heritable and family history can be used for cascade clinical screening programs, but these will not be feasible in all populations. Thus, cascade genetic testing using well-established genes such as myocilin may help improve glaucoma diagnosis. In addition, ongoing investigations seek to identify pathogenic genetic variants within genes like myocilin. The expanding availability of genetic testing for various diseases and early access to genetic risk information necessitates further research to determine when and how to act on specific genetic results. Polygenic risk scores involving multiple genes with subtle effects will require continuous refinement to improve clinical utility. This is crucial for effectively interpreting an individual's risk of developing glaucoma and preventing blindness.

Molecular autopsy in Chinese sudden cardiac death in the young.

Inherited cardiovascular conditions are significant causes of sudden cardiac death in the young (SCDY), making their investigation using molecular autopsy and prevention a public health priority. However, the molecular autopsy data in Chinese population is lacking. The 5-year result (2017-2021) of molecular autopsy services provided for victims of SCDY (age 1-40 years) was reviewed. The outcome of family cascade genetic screening and clinical evaluation was reviewed. A literature review of case series reporting results of molecular autopsy on SCDY in 2016-2023 was conducted. Among the 41 decedents, 11 were found to carry 13 sudden cardiac death (SCD)-causative genetic variants. Likely pathogenic (LP) variants were identified in the DSP, TPM1, TTN, and SCN5A genes. Cascade genetic testing identified four family members with LP variants. One family member with familial TPM1 variant was found to have hypertrophic cardiomyopathy upon clinical evaluation. This study provided insight into the genetic profile of molecular autopsy in a Chinese cohort of SCDY. The detection of important SCD-causative variants through molecular autopsy has facilitated family cascade screening by targeted genetic testing and clinical evaluation of at-risk family members. A literature review of the current landscape of molecular autopsy in the investigation of SCDY was conducted.

Attitudes and engagement about cascade genetic testing in a population-based cohort of women diagnosed with cancer.

10589 Background: Cascade testing in families with hereditary cancer syndromes is challenging because patients are responsible for engaging their relatives about test results and clinical support is limited. There are concerns that patient engagement with relatives may not be well matched to the clinical relevance of their test results, with particular concern about variants of uncertain significance (VUS). Methods: We selected patients from the Georgia California Genetic Linkage Initiative, which identified all patients diagnosed with cancer 2013-19 in the 2 states who linked to a germline genetic test. We surveyed 2100 women diagnosed with breast, ovarian or uterine cancer in 2018-19 in Georgia and California who reported "a pathogenic variant (PV) that increases the risk of cancer" on testing about 4 years after diagnosis. We also surveyed a comparable sample of 1300 women diagnosed during the same period who reported a VUS-only result. The expected response rate from the cohorts is 55% (N=1900). We present preliminary results on patient attitudes about cascade family testing and report of engagement with genetic counselors and relatives about test results. Results: The 2 cohorts were comparable in age (mean 54 vs 58 for VUS, p&lt;.001) and education (college graduate or more 52% vs 53% for VUS p=.971). The Table shows that for patients who reported a PV, belief in the utility of testing in relatives (test results useful for family; wanted family members tested) was high. A substantial proportion reported that a genetic counselor encouraged them to talk to relatives and talked directly with relatives about testing. PV carriers informed most first-degree relatives about their test results. Patients who reported VUS only were less likely to endorse the utility of testing in relatives; less likely to report that a genetic counselor encouraged family engagement or engaged family directly about testing; and were less likely to have informed relatives about their test results. Conclusions: Compared to patients with VUS-only test results, women with PVs on germline genetic testing after diagnosis of cancer had more positive attitudes about the utility of testing of family members and greater engagement with clinicians and family members about test results. These findings suggest that engagement with family about genetic testing after cancer diagnosis matches the clinical relevance of the results. [Table: see text]

Accurate parent-of-origin variant assignment for multiple hereditary cancer syndromes using proband-only blood sample analysis.

10516 Background: Predicting which side of the family a germline variant comes from is a critical gap in current clinical practice, vital for risk management, variant curation, and cascade genetic testing. Assignment of any autosomal variant to either parent with 99% accuracy is now possible with only a blood sample from the proband. Parent-of-Origin-Aware genomic analysis (POAga) is achieved by combining methylation and sequence data from Oxford Nanopore long-read sequencing with chromosome-length haplotypes generated from Strand-seq to infer parent of origin of any variant along the length of a chromosome, due to accurate phasing of imprinted differentially methylated regions that occur on each autosome. We sought to validate POAga in common, high penetrant hereditary cancer conditions such as hereditary breast and ovarian cancer (HBOC) and Lynch syndrome, rarer syndromes with parent-of-origin-effects and other genes predisposing to breast cancer and gastrointestinal malignancies that are associated with genes across multiple chromosomes. Methods: Blood samples from carriers of pathogenic variants in ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, PMS2, EPCAM, PALB2, SDHD and SDHAF2, with known parental segregation, are currently being ascertained to determine the analytic validity of POAga in real world samples of differing age, sex, ethnicity, and cancer status. Samples are undergoing whole genome analysis by long and short read sequencing. Parent-of-origin of the pathogenic or likely pathogenic variant or variant of uncertain significance is predicted according to previously described methods (Akbari V, Hanlon VCT, et al. Cell Genom. 2022 Dec 21;3(1):100233.) under an REB approved protocol. Results: To date, analysis is complete for 100 individuals with a total of 107 rare or pathogenic germline variants with known or presumed parental segregation. Germline variants are in SDHD (n = 18), BRCA2 (n = 17), BRCA1 (n = 14), MLH1 (n = 10), PALB2 (n = 9), PMS2 (n = 8), MSH2 (n = 9), MSH6 (n = 7), ATM (n = 5), CDH1 (n = 5), SDHAF2 (n = 1), DICER1 (n = 1), MUTYH (n = 1), RET (n = 1), and EPCAM (n = 1). Of variants able to be assigned a parent-of-origin (n = 104 of 107, 97%), there was complete concordance between the predicted parent-of-origin and known clinical segregation (n = 104, 100%). Conclusions: Results to date support the ability of POAga to accurately infer parent-of-origin of rare or pathogenic variants with known parental segregation using only a blood sample from carriers of diverse hereditary cancer syndromes. Ongoing validation of POAga will continue to test its feasibility in real-world samples and inform its path towards clinically translation. Parent-of-Origin-Aware genomic analysis is a powerful technology that could improve our understanding of hereditary cancer syndromes and transform our ability to conduct genetic cancer risk assessments for patients and families.

Barricades to aiding cascading: Patient-reported barriers to uptake in the context of clinician-facilitated cascade testing for hereditary cancer syndromes.

e13533 Background: Cascade testing extends genetic testing to relatives of individuals with known pathogenic variants. Cascade testing can prompt lifesaving cancer surveillance, however, up to two thirds of at-risk relatives do not complete recommended genetic testing. Previous studies suggest that a clinician-mediated approach of direct relative contact can increase testing rates. As part of an ongoing clinician-facilitated cascade testing intervention, we investigated the barriers to completion of cascade testing. Methods: All patients with a known cancer-associated germline mutation presenting to a gynecologic oncology clinic from 11/2023-2/2024 were offered clinician-facilitated cascade testing, an intervention whereby the genetics team was granted permission to contact designated at-risk relatives by telephone, review the familial mutation, and assist with accessing genetic testing. Patients that declined were asked about their decision and responses were analyzed using the socio-ecological model. Results: Ninety patients were offered clinician-facilitated cascade genetic testing and 50 (55%) declined. Of the patients that declined: median age was 45 (range 23-84), 41 (82%) self-identified as non-Hispanic, 38 (76%) as White, 23 (46%) were of Ashkenazi Jewish heritage, 23 (46%) had a personal history of cancer. There were no significant differences in any of the above variables when comparing those that declined and accepted the intervention. Twenty-nine (58%) patients declined because all family members were already tested. The most common barriers were “limited access to care” (5, 10%) at the healthcare community level, and “perceived readiness of relatives” (5, 10%) at the interpersonal relationship level. While these were the most common, most barriers were at the individual level including “perceived lack of responsibility” (3, 6%), “limited knowledge” (2, 4%), and “emotional burden” (2, 4%) (Table). Stated barriers were not associated with any demographical group. Conclusions: Although clinician-facilitated cascade testing has been shown to increase rates of relative testing uptake, several barriers persist at all levels of the socio-ecological model. While facilitated interventions should be individualized, our findings suggest that future interventions should focus efforts at all socio-ecological levels. Clinical trial information: NCT04613440 . [Table: see text]

Genetic counseling and subsequent cascade genetic testing for women with a family history of pathogenic BRCA1 mutation: A cost-effectiveness model.

10621 Background: BRCA1 pathogenic mutations significantly increase the lifetime risk for breast and ovarian cancer, but risk reducing interventions such as bilateral salpingo-oophorectomy (RRBSO) and mastectomy (RRM) can improve outcomes. For women with a known family history of pathogenetic mutation, genetic counseling and testing is recommended. We sought to determine the cost-effectiveness (CE) of referral to genetic counseling with subsequent cascade testing. Methods: A decision analytic model was created using TreeAgePro 2023 software to evaluate the strategies of routine genetics consultation with Ambry panel testing versus no referral. It was assumed that known BRCA1 carriers would undergo annual breast cancer screening with mammogram and MRI at 25yo, RRBSO at 35yo, and RRM at 40yo. Non-carriers underwent routine annual mammogram at 40yo. Additionally, women who did not undergo genetic testing initially do so at the time of diagnosis of first cancer (breast of ovary) and subsequently underwent all recommended risk reducing strategies if found to have a pathogenic BRCA1 mutation. Outcomes included cost, quality adjusted life years (QALYs), ovarian and breast cancer cases and deaths. Univariate and multi-variate analyses were used to investigate the impact of the strategies. Results: In a Monte Carlo Microsimulation cohort of 10,000 women with a first degree relative with a pathogenic BRCA1 mutation, referral to genetic counseling with testing was the dominate strategy. This strategy resulted in a similar mean cost ($185,543 vs $185,171), but with 2,322 additional QALYs and incremental CE ratio (ICER) of 1,605 per QALY. This dominant strategy also resulted in 73 fewer ovarian cancer cases and 545 fewer breast cancer cases. Sensitivity analysis for the age of RRM was remarkable for an annual reduction in breast cancer cases by 97 cases and an annual cost savings of 375,658 for year prior to age 40 that mastectomy was performed. Conclusions: Routine genetic counseling and screening for all patients with a known family history of pathogenic BRCA1 mutation reduces breast and ovarian cancer diagnoses by prompting risk-reducing procedures without significant increase in cost when compared to diagnosis-based testing. Routine access to genetic counseling in a high-risk population would help inform earlier counseling and further decrease cancer risk, particularly as earlier RRM may improve outcomes. This is further supported by the low cost to implement. Improvement in identification and early referral could be targeted. [Table: see text]

Lynch syndrome in Mexican-Mestizo families: Genotype, phenotypes, and challenges in cascade testing among relatives at risk

Lynch syndrome (LS) is the most frequent cancer predisposition syndrome affecting the colon and rectum. A pathogenic variant (PV) disrupting one of the mismatch repair (MMR) genes is responsible for the disease. The spectrum of tumors in LS is heterogeneous and includes cancer of the colon and rectum (CRC), endometrium, ovaries, stomach, small bowel, urinary tract, bladder, pancreas, and skin. Knowledge of the phenotypic variation of patients with LS, the type and frequency of PVs, and cascade testing studies in the Latin American population is limited. The present study aims to recognize the PVs in MMR genes, describe the phenotype in Mexican-Mestizo patients and their relatives, and identify the acceptance rate of cascade testing of relatives at risk. We included 40 carriers of a MMR gene PV and 142 relatives that developed a LS-related neoplasm. Patients’ clinical data, number, and type of malignancies were obtained from their medical records. Amsterdam I-II, Bethesda criteria, and PREMM5® predictive model score were estimated. Available immunohistochemistry (IHC) reports were analyzed. Relatives at risk were determined from index cases pedigrees. The distribution of MMR gene mutations among 40 probands was: MLH1 (67.5 %), MSH2 (22.5 %), MSH6 (7.5 %), and PMS2 (2.5 %). Out of the 182 LS cases, 58 % exhibited the LS phenotype before age 50. The most common tumor was CRC, followed by endometrial cancer in women and gastric cancer in males. We found a 90.0 % concordance between the IHC and germline PV. The most frequent PV in our sample was MLH1 c.676C > T, occurring in 1/6 index cases. All probands disclosed their molecular test result to their family. Out of the 451 asymptomatic relatives at risk, 28.2 % underwent germline testing. Our results highlight the importance of conducting germline genetic studies in LS since it allows the establishment of appropriate cancer screening, risk-reducing measures, and genetic cascade testing among relatives at risk. Interestingly, we observed a significantly higher prevalence of the c.676C > T variant in MLH1, probably a singular characteristic of the Mexican-Mestizo population. New strategies to facilitate accurate communication between index cases and relatives should be implemented to improve the cascade testing acceptance rate.

Healthcare Professionals' Learning Needs and Perspectives on Essential Information in Genetic Cancer Care: A Systematic Review.

The increased demand for genetic testing and counseling necessitates healthcare professionals (HCPs) to improve their genetic competency through training programs. This systematic review identified HCPs' learning needs and their perspectives on essential information for families with hereditary cancer. This review covered studies published from 2013 to 2024 across five databases. Data were analyzed using a content analysis. Thirteen studies involving 332 HCPs were analyzed. Most studies focused on the learning needs of physicians caring for families affected by Hereditary Breast and Ovarian Cancer in North America and Europe. HCPs required training emphasizing practical counseling skills over the basics of genetics. Learning needs varied by profession: physicians needed training in assessing cancer risk and supporting decision-making in risk management; nurses required information on resources and the genetic care system; genetic counselors sought guidance on family communication and planning. Essential information identified for families included risk-reducing strategies, personalized cancer risk assessment, family implications, psychological issues, (cascade) genetic testing, and social concerns. The findings have implications for the development of training programs for HCPs, emphasizing the need for tailored training based on professions. Future research should explore the needs of HCPs caring for families with diverse hereditary cancers and cultural backgrounds.

Familial communication and cascade testing following elective genomic testing.

Familial communication of results and cascade genetic testing (CGT) can extend the benefits of genetic screening beyond the patient to their at-risk relatives. While an increasing number of health systems are offering genetic screening as an elective clinical service, data are limited about how often results are shared and how often results lead to CGT. From 2018 to 2022, the Sanford Health system offered the Sanford Chip, an elective genomic test that included screening for medically actionable predispositions for disease recommended by the American College of Medical Genetics and Genomics for secondary findings disclosure, to its adult primary care patients. We analyzed patient-reported data about familial sharing of results and CGT among patients who received Sanford Chip results at least 1 year previously. Among the patients identified with medically actionable predispositions, 94.6% (53/56) reported disclosing their result to at least one family member, compared with 46.7% (423/906) of patients with uninformative findings (p < 0.001). Of the patients with actionable predispositions, 52.2% (12/23) with a monogenic disease risk and 12.1% (4/33) with a carrier status reported that their relatives underwent CGT. Results suggest that while the identification of monogenic risk during elective genomic testing motivates CGT in many at-risk relatives, there remain untested at-risk relatives who may benefit from future CGT. Findings identify an area that may benefit from increased genetic counseling and the development of tools and resources to encourage CGT for family members.

Cascade genetic testing: an underutilized pathway to equitable cancer care?

The Precision Medicine Initiative was launched upon the potential of genomic information to tailor medical care. Cascade genetic testing represents a powerful application of precision medicine and involves the process of familial diffusion or the "cascade" of genomic risk information. When an individual (proband) is found to carry a cancer-associated germline pathogenic mutation, the information should be cascaded or shared with at-risk relatives. First degree relatives have a 50% likelihood of carrying the same cancer-associated mutation. This process of cascade testing offers at-risk relatives the opportunity for genetic testing and, for those who also carry the cancer-associated mutation, genetically targeted primary disease prevention through intensive cancer surveillance, chemoprevention and risk-reducing surgery, reducing morbidity and preventing mortality. Cascade testing has been designated by the Centers for Disease Control and Prevention as a Tier 1 genomic application for hereditary breast and ovarian cancer. In this manuscript we describe a cascade genetic testing and in particular focus on its potential to provide necessary care to medically underserved and vulnerable populations.

BRCA1/2 Testing Landscape in Ovarian Cancer: A Nationwide, Real-World Data Study.

Analyzing BRCA1/2 tumor pathogenic variants (TPVs) in epithelial tubal/ovarian cancers (EOCs) has become an essential part of the diagnostic workflow in many centers to guide treatment options and genetic cascade testing. However, there is no standardization of testing procedures, including techniques, gene assays, or sequencers used, and data on the execution of tumor tests remains scarce. Therefore, we evaluated characteristics of BRCA1/2 tumor testing in advanced-stage EOC with real-world national data. Pathology reports of patients diagnosed with EOC in 2019 in the Netherlands were obtained from the Dutch Pathology Registry (PALGA), and data regarding histological subtype and BRCA1/2 tumor tests were extracted. A total of 999 patients with advanced-stage EOC were included. Tumor tests were performed for 502 patients (50.2%) and BRCA1/2 TPVs were detected in 14.7%. Of all tests, 48.6% used hybrid capture techniques and 26.5% used PCR-based techniques. More than half of the tests (55.0%) analyzed other genes in addition to BRCA1/2. Overall, this study highlights the heterogeneity in the execution of BRCA1/2 tumor tests. Despite a lack of evidence of quality differences, we emphasize that adequate reporting and internal and external quality monitors are essential for the high-quality implementation and execution of reliable BRCA1/2 tumor testing, which is crucial for identifying all patients with BRCA1/2 TPVs.

Psychosocial barriers and facilitators for cascade genetic testing in hereditary breast and ovarian cancer: a scoping review.

Despite increased awareness and availability of genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome for over 20years, there is still significant underuse of cascade genetic testing among at-risk relatives. This scoping review synthesized evidence regarding psychosocial barriers and facilitators of family communication and/or uptake of cascade genetic testing in relatives from HBOC families. Search terms included 'hereditary breast and ovarian cancer' and 'cascade genetic testing' for studies published from 2012-2022. Through searching common databases, and manual search of references, 480 studies were identified after excluding duplications. Each article was reviewed by two researchers independently and 20 studies were included in the final analysis. CASP, RoBANS 2.0, RoB 2.0, and MMAT were used to assess the quality of included studies. A convergent data synthesis method was used to integrate evidence from quantitative and narrative data into categories and subcategories.Evidence points to 3 categories and 12 subcategories of psychosocial barriers and facilitators for cascade testing: (1) facilitators (belief in health protection and prevention; family closeness; decisional empowerment; family support, sense of responsibility; self-efficacy; supportive health professionals); (2) bidirectional concepts (information; perception of genetic/cancer consequences; negative emotions and attitude); and (3) barriers (negative reactions from family and negative family dynamics). Healthcare providers need to systematically evaluate these psychosocial factors, strengthen facilitators and alleviate barriers to promote informed decision-making for communication of genetic test results and uptake of genetic testing. Bidirectional factors merit special consideration and tailored approaches, as they can potentially have a positive or negative influence on family communication and uptake of genetic testing.

National Experiences from 30 Years of Provider-Mediated Cascade Testing in Lynch Syndrome Families-The Danish Model.

Cascade genetic testing and surveillance reduce morbidity and mortality in Lynch syndrome. However, barriers to conveying information about genetic disorders within families result in low uptake of genetic testing. Provider-mediated interventions may increase uptake but raise legal and ethical concerns. We describe 30 years of national experience with cascade genetic testing combining family- and provider-mediated contact in Lynch syndrome families in the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Register. We aimed to estimate the added value of information letters to family members in Lynch syndrome families (provider-mediated contact) compared to family members not receiving such letters and thus relying on family-mediated contact. National clinical practice for cascade genetic testing, encompassing infrastructure, legislation, acceptance, and management of the information letters, is also discussed. Cascade genetic testing resulted in 7.3 additional tests per family. Uptake of genetic testing was 54.4% after family-mediated and 64.9% after provider-mediated contact, corresponding to an odds ratio of 1.8 (p < 0.001). The uptake of genetic testing was highest in the first year after diagnosis of Lynch syndrome in the family, with 72.5% tested after provider-mediated contact. In conclusion, the Danish model combining family- and provider-mediated contact can increase the effect of cascade genetic testing.