Cascade Testing Research Articles

A Review of Breast Cancer Risk Factors in Adolescents and Young Adults.

Simple SummaryCancer diagnosed in patients between the ages of 15 and 39 deserves special consideration. Diagnoses within this cohort of adolescents and young adults include childhood cancers which present at an older age than expected, or an early presentation of cancers that are typically observed in older adults, such as breast cancer. Cancers within this age group are associated with worse disease-free and overall survival rates, and the incidence of these cases are rising. Knowing an individual’s susceptibility to disease can change their clinical management and allow for the risk-testing of relatives. This review discusses the risk factors that contribute to breast cancer in this unique cohort of patients, including inherited genetic risk factors, as well as environmental and lifestyle factors. We also describe risk models that allow clinicians to quantify a patient’s lifetime risk of developing disease.Cancer in adolescents and young adults (AYAs) deserves special consideration for several reasons. AYA cancers encompass paediatric malignancies that present at an older age than expected, or early-onset of cancers that are typically observed in adults. However, disease diagnosed in the AYA population is distinct to those same cancers which are diagnosed in a paediatric or older adult setting. Worse disease-free and overall survival outcomes are observed in the AYA setting, and the incidence of AYA cancers is increasing. Knowledge of an individual’s underlying cancer predisposition can influence their clinical care and may facilitate early tumour surveillance strategies and cascade testing of at-risk relatives. This information can further influence reproductive decision making. In this review we discuss the risk factors contributing to AYA breast cancer, such as heritable predisposition, environmental, and lifestyle factors. We also describe a number of risk models which incorporate genetic factors that aid clinicians in quantifying an individual’s lifetime risk of disease.

Pathogenic Germline Variants in Cancer Susceptibility Genes in Children and Young Adults With Rhabdomyosarcoma.

Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort. We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (ATM, CDKN1C) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with FOXO1 fusion-negative RMS patients versus the patients with FOXO1 fusion-positive RMS. We identified pathogenic germline variants in CSGs previously (TP53, NF1, DICER1, mismatch repair genes), rarely (BRCA2, CBL, CHEK2, SMARCA4), or never (FGFR4) reported in RMS. Numerous genes (TP53, BRCA2, mismatch repair) were on the ACMG Secondary Findings 2.0 list. In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines.

Multigene Panel Testing in Individuals With Hepatocellular Carcinoma Identifies Pathogenic Germline Variants.

A prospective study at a tertiary medical center enrolled 217 patients with a personal history of HCC. Multigene panel testing was performed for 134 cancer predisposition genes in all patients. The rate of P/LP variants was compared with population rates. A separate retrospective cohort included 219 patients with HCC who underwent testing at a commercial laboratory. In the prospective cohort, P/LP germline variants were identified in 25 of 217 patients with HCC (11.5%). Four patients (1.8%) had P/LP variants in the highly penetrant cancer genes BRCA2 (n = 2), MSH6 (n = 1), and PMS2 (n = 1). In addition, multiple patients had P/LP variants in FANCA (n = 5) and BRIP1 (n = 4), which were significantly enriched in HCC compared with the general population. Detection of P/LP variants led to changes in clinical management in regard to therapy selection, screening recommendations, and cascade testing of relatives. In a separate retrospective analysis of 219 patients with HCC, 30 (13.7%) were positive for P/LP variants including 13 (5.9%) with highly penetrant genes APC (n = 2), BRCA1 (n = 1), BRCA2 (n = 6), MSH2 (n = 2), or TP53 (n = 2). P/LP germline variants in cancer predisposition genes were detected in 11%-14% of patients with HCC. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.

The High-Speed Cascade Wind Tunnel at the Bundeswehr University Munich after a Major Revision and Upgrade

Since its first operation in 1956 at DFL Braunschweig and after its movement to Munich, the High-Speed Cascade Wind Tunnel (HGK) at Bundeswehr University Munich is intensively used for fundamental and application-oriented research on aero-thermodynamics of turbomachinery bladings. Numerous systematic airfoil design studies were performed over the last decades. Thanks to the HGK facility, which enables thorough and detailed cascade testing at turbomachinery-relevant conditions, many of those airfoils for different purposes finally made it into turbomachinery applications. Nowadays, the HGK still provides very useful contributions to the understanding of the complicated flow in compressor and turbine bladings, and thereby extends the knowledge on relevant physical phenomena. As a consequence of the intense usage, this unique test facility was subject to a major revision and upgrade. The performed changes are presented within this paper including an overview on new capabilities in terms of the extended operating range, the data acquisition system, and the recently available measurement equipment.

Cost-effectiveness of DNA testing for Lynch syndrome for colorectal cancer patients in Switzerland

Abstract Purpose To estimate the cost-effectiveness of genetic testing for Lynch syndrome among newly diagnosed patients with colorectal cancer and targeted testing for their relatives in Switzerland. Methods We integrated decision tree and Markov model to calculate incremental costs per quality adjusted life-year saved for universal genetic testing for Lynch syndrome relative to using preliminary tumor tests (immunohistochemistry or microsatellite instability) followed by DNA sequencing test for patients with colorectal cancer. Results The incremental cost-effectiveness ratio (ICER) of the proposed strategy using universal genetic testing for Lynch syndrome with systematic CASCADE testing of their relatives is CHF 65,058 per QALY saved, which is cost-effective in Swiss settings where cost-effectiveness threshold is CHF 100,000 per QALY saved. The gained utility is 361,358 QALYs saved. Sensitivity analysis demonstrated cost-effectiveness of the proposed strategies in most of the scenarios. Conclusions The overall effectiveness of the universal genetic testing is greatly dependent on willingness of patients and relatives to be tested and compliance with the increased surveillance. Therefore, close cooperation across different stakeholders such as family doctors, oncologists, genetic clinicians, and laboratories is crucial to encourage and educate patients about the importance of the LS screening. Key messages Universal genetic testing for Lynch syndrome for all patients with colorectal caner is cost-effective in Swiss settings. Close cooperation across all stakeholders such as family doctors, oncologists, genetic clinicians, and laboratories is crucial to encourage and educate patients about the importance of the LS testing.

Do research participants share genomic screening results with family members?

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network-3 (eMERGE-3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE-3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first-degree relatives. Across the sites, 279 participants completed a 1-month and/or 6-month post-results survey. By 6months, only 34% of the 156 respondents shared their results with all first-degree relatives and 4% did not share with any. Over a third (39%) first-degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first-degree relatives compared with 11% of participants who received their results from a non-genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.

Estimated Cost-effectiveness of Genetic Testing in Siblings of Newborns With Cancer Susceptibility Gene Variants

Newborn population-based genetic screening may reduce pediatric cancer deaths and could be cost-effective.1 Testing siblings of newborns with variants (ie, cascade testing) could further improve population health.2 Economic studies of cascade testing have focused on adults, although evidence suggests that cost-effectiveness improves for some cancer syndromes when surveillance is initiated in younger individuals.3 Our objective was to estimate the benefits and costs of cascade testing of siblings of newborns with cancer susceptibility gene variants.

American Gastroenterological Association Institute and College of American Pathologists Quality Measure Development for Detection of Mismatch Repair Deficiency and Lynch Syndrome Management

American Gastroenterological Association Institute and College of American Pathologists Quality Measure Development for Detection of Mismatch Repair Deficiency and Lynch Syndrome Management

ASO Author Reflections: Germline Testing for All Patients With Breast Cancer: Has the Time Finally Come?

For the young breast cancer population in India, the burden of hereditary breast cancer is not well defined. Moreover, genetic testing criteria (National Comprehensive Cancer Network and Mainstreaming Cancer Genetics (MCG) plus) have never been validated for the Indian population. Therefore, this study tested 236 consecutive breast cancer patients for germline pathogenic mutations using next-generation sequencing and reflex Multiplex Ligation Probe Amplification (MLPA). The findings showed a high prevalence of pathogenic/likely pathogenic (P/LP) mutations (18.64%), with 34% mutations in non BRCA genes. The sensitivity of the testing criteria was inadequate (88.6% for NCCN and 86.36% for MCG plus criteria), reiterating the need to expand the criteria. The uptake of cascade testing was low (10% of eligible previvors), highlighting this as an area of unmet need. Multicentric studies to validate these data and provide further insight into the hereditary cancer burden in India are the need of the hour.

Population genomic screening of all young adults in Australia to detect familial hypercholesterolemia: a cost-effectiveness analysis

Abstract Background Heterozygous familial hypercholesterolemia (FH) is a highly-penetrant, autosomal dominant monogenic disorder that causes elevated plasma low-density cholesterol (LDL-C) levels and risk of premature coronary heart disease (CHD). To date, the cost-effectiveness of the emerging strategy of genomic screening of adult populations for FH has not been investigated. Purpose To assess the impact and cost-effectiveness of offering population genomic screening to all young adults in Australia to detect heterozygous familial hypercholesterolemia (FH). Methods We designed a decision analysis model to compare the current standard of care for heterozygous FH diagnosis in Australia (opportunistic cholesterol screening and genetic cascade testing) with population genomic screening of adults aged 18–40 years to detect pathogenic variants in the LDLR/APOB/PCSK9 genes. The model captured morbidity/mortality due to coronary heart disease (CHD) over a lifetime horizon, from a healthcare perspective. Risk of CHD, treatment effects, prevalence, and healthcare costs were estimated from published studies. Outcomes included quality adjusted life years (QALYs), costs and incremental cost-effectiveness ratio (ICER), discounted 5% annually. Sensitivity analyses were undertaken to explore the impact of key input parameters on the robustness of the model. The model structure was designed to be transferable to countries with different healthcare systems. Results Over the lifetime of the population (4,167,768 men; 4,129,961 women), the model estimated a gain of 62,722 years of life lived and 73,959 QALYs due to CHD prevention. Population genomic screening for FH would be cost-effective from a healthcare perspective if the cost per test was ≤AU$300 (∼US$233) which would yield an ICER AU$28,000 cost-saving. Conclusion Based on our model, offering population genomic screening to all young adults to detect FH could be cost-effective in the Australian healthcare system, at testing costs that are currently feasible. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This work was supported by the Australian National Heart Foundation and Monash University Faculty of Medicine, Nursing and Health Sciences Results from scenario analysesResults from Monte Carlo simulations

Novel Models of Genetic Education and Testing for Pancreatic Cancer Interception: Preliminary Results from the GENERATE Study.

Up to 10% of patients with pancreatic ductal adenocarcinoma (PDAC) carry underlying germline pathogenic variants in cancer susceptibility genes. The GENetic Education Risk Assessment and TEsting (GENERATE) study aimed to evaluate novel methods of genetic education and testing in relatives of patients with PDAC. Eligible individuals had a family history of PDAC and a relative with a germline pathogenic variant in APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, or TP53 genes. Participants were recruited at six academic cancer centers and through social media campaigns and patient advocacy efforts. Enrollment occurred via the study website (https://GENERATEstudy.org) and all participation, including collecting a saliva sample for genetic testing, could be done from home. Participants were randomized to one of two remote methods that delivered genetic education about the risks of inherited PDAC and strategies for surveillance. The primary outcome of the study was uptake of genetic testing. From 5/8/2019 to 5/6/2020, 49 participants were randomized to each of the intervention arms. Overall, 90 of 98 (92%) of randomized participants completed genetic testing. The most frequently detected pathogenic variants included those in BRCA2 (N = 15, 17%), ATM (N = 11, 12%), and CDKN2A (N = 4, 4%). Participation in the study remained steady throughout the onset of the Coronavirus disease (COVID-19) pandemic. Preliminary data from the GENERATE study indicate success of remote alternatives to traditional cascade testing, with genetic testing rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for PDAC interception approaches. PREVENTION RELEVANCE: Preliminary data from the GENERATE study indicate success of remote alternatives for pancreatic cancer genetic testing and education, with genetic testing uptake rates over 90% and a high rate of identification of germline pathogenic variant carriers who would be ideal candidates for pancreatic cancer interception.

Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes

Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied. Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results. The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator. In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations. In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.

Effectiveness of cascade testing strategies in relatives for familial hypercholesterolemia: A systematic review and meta-analysis

Background and aimsCascade testing in relatives of index cases is the most cost-effective approach to identifying people with familial hypercholesterolemia (FH); however, it is currently unclear which strategy to contact relatives would be the most effective. A systematic review was performed to quantify the effectiveness of different strategies in cascade testing of FH. MethodsComprehensive searches of three electronic databases and grey literature sources were done (from inception to May 2020). Screening, data extraction and assessments of methodological quality were made independently by two reviewers. Meta-analyses of proportions were performed using random effects models. Effect measures are reported as percentages with 95% confidence intervals. Results24 non-comparative studies were included, of which 11 used a direct, 8 used an indirect, and 5 used a combination of both direct and indirect cascade strategies. The median number of new relatives with FH per known index case was approximately 1. The combination strategy resulted in the largest yields of relatives tested for FH out of those contacted (40%, 95% CI 37%–42%, 1 study) and relatives responding to testing out of those contacted (54%, 1 study); however, the direct strategy had the largest yield of index cases participating in cascade testing out of those with FH confirmed (94%, 8 studies) compared to other strategies (p ≤ 0.01 for all comparisons). ConclusionsEvidence is limited; however, a combination strategy, which allows the index case to decide on method of contacting relatives, appears to lead to better yields compared to using the direct or indirect strategy.

Profile of Pathogenic Mutations and Evaluation of Germline Genetic Testing Criteria in Consecutive Breast Cancer Patients Treated at a North Indian Tertiary Care Center.

BackgroundThe burden of hereditary breast cancer in India is not well defined. Moreover, genetic testing criteria (National Comprehensive Cancer Network [NCCN] and Mainstreaming Cancer Genetics [MCG] Plus) have never been validated in the Indian population.MethodsAll new female breast cancer patients from 1st March 2019 to 28th February 2020 were screened. Those providing informed consent and without previous genetic testing were recruited. Multigene panel testing (107 genes) by next-generation sequencing was performed for all patients. The frequency of pathogenic/likely pathogenic (P/LP) mutations between patients qualifying and not qualifying the testing criteria was compared and their sensitivity was computed.ResultsOverall, 275 breast cancer patients were screened and 236 patients were included (median age 45 years); 30 patients did not consent and 9 patients previously underwent genetic testing. Thirty-four (14%) women had a positive family history and 35% had triple-negative breast cancer. P/LP mutations were found in 44/236 (18.64%) women; mutations in BRCA1 (22/47, 46.8%) and BRCA2 (9/47, 19.1%) were the most common, with 34% of mutations present in non-BRCA genes. Patients qualifying the testing criteria had a higher risk of having a P/LP mutation (NCCN: 23.6% vs. 7.04%, p = 0.03; MCG plus: 24.8% vs. 7.2%, p = 0.01). The sensitivity of the NCCN criteria was 88.6% (75.4–96.2) and 86.36% (72.65–94.83) for MCG plus. More than 95% sensitivity was achieved if all women up to 60 years of age were tested. Cascade testing was performed in 31 previous (16/44 families), with 23 testing positive.ConclusionsThe frequency of P/LP mutations in India is high, with significant contribution of non-BRCA genes. Testing criteria need modification to expand access to testing.Supplementary InformationThe online version contains supplementary material available at 10.1245/s10434-021-10870-w.

S3539 The Importance of Taking a Family History: Diagnosis of Lynch Syndrome After Direct Access Colonoscopy

Introduction: Lynch Syndrome (LS) is a familial cancer-predisposition syndrome caused by mutations in DNA mismatch repair genes. LS accounts for 3-8% of all new cases of colorectal cancer (CRC), and it increases the lifetime risk of multiple associated cancers. LS is common, occurring in approximately 1 in 200-300 individuals, but remains underdiagnosed. Estimates indicate that less than 1% of individuals with LS are aware of their diagnosis. This represents a missed opportunity for cancer screening and prevention. Case Description/Methods: A 50-year-old healthy woman presented to endoscopy for direct access screening colonoscopy. Family history included in her electronic medical record noted two malignancies in first degree relatives (thyroid and uterine). Colonoscopy revealed 13 tubular adenomas (3- 12mm). Office follow up to discuss genetic testing was delayed due to COVID-19. 10 months later the patient presented for follow up, and family history revealed ureteral and CRC in her father, CRC in her paternal uncle, and uterine cancer in her paternal aunt and paternal grandmother. Germline genetic testing was discussed and sent. While awaiting results, she was found to have atypical endometrial cells on routine pap smear. Colposcopy revealed complex endometrial hyperplasia (CAH) with atypia, bordering on grade 1 endometrioid carcinoma. The following week, genetic results showed a mutation in MSH6. One week later, surveillance colonoscopy revealed 4 sub-cm tubular adenomas. She then underwent total hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node biopsy. Pathology showed CAH but no definitive features of endometrioid carcinoma. The patient recovered from her surgery uneventfully, is now in a screening/surveillance program, and cascade testing has begun for her first-degree relatives, including her two adult children. Discussion: This case highlights the importance of obtaining cancer family history during patient contact, so that this underdiagnosed condition can be identified and patients can benefit from appropriate cancer screening..

P62.11 Germline Genetic Testing in Patients with Lung Cancer in a Mexican Center

Germline variants explain a minority of Lung Cancer (LC) cases. Accumulating evidence have shown a role of genes of the Fanconi pathway, such as BRCA2, CHEK2 and PALB2, in LC. Suggested features of LC patients (pts) carrying germline mutations are young pts, pts with double primary tumor, and cancer family history (CFH). Nowadays, guidelines for genetic testing (GT) in LC have not been published. GT could provide benefits such as target therapy and cascade testing for relatives. Herein, we describe the result of germline GT with a Multigene (MPG) panel in LC pts.

Improving our model of cascade testing for hereditary cancer risk by leveraging patient peer support: a concept report

Consensus and evidence suggest that cascade testing is critical to achieve the promise of cancer genetic testing. However, barriers to cascade testing include effective family communication of genetic risk information and family members’ ability to cope with genetic risk. These barriers are further complicated by the developmental needs of unaffected family members during critical windows for family communication and adaptation. Peer support could address these barriers. We provide two illustrative examples of ongoing BRCA1/2-related clinical trials that apply a peer support model to improve family communication and functioning. Peer support can augment currently available genetic services to facilitate adjustment to and effective use of cancer genetic risk information. Importantly, this scalable approach can address the presence of cancer risk within families across multiple developmental stages. This applies a family-centered perspective that accommodates all potentially at-risk relatives. This peer support model can be further applied to emerging topics in clinical genetics to expand reach and impact.

Oncology clinic-based germline genetic testing for exocrine pancreatic cancer enables timely return of results and unveils low uptake of cascade testing

BackgroundTraditional medical genetics models are unable to meet the growing demand for germline genetic testing (GT) in patients with exocrine pancreatic cancer (PC). This study investigates the impact of an...

1850P Communication patterns and cascade testing among pathogenic variant carriers

Cascade testing (CT) for hereditary cancer predisposition syndromes in families of pathogenic variant (PV) carrier enables precisely targeted surveillance and risk-reducing strategies. Genetic test results communication within families is key to enhance CT. The frequency and factors associated with carriers’ disclosure of test results to family members and CT were studied at 2 cancer centers in Mexico.

PD44-01 WHEN SHOULD PROSTATE CANCER TUMOR SEQUENCING PROMPT CONSIDERATION FOR GERMLINE TESTING?

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II (PD44)1 Sep 2021PD44-01 WHEN SHOULD PROSTATE CANCER TUMOR SEQUENCING PROMPT CONSIDERATION FOR GERMLINE TESTING? Hong Truong, Kelsey Breen, Yelena Kemel, Andrew Lenis, Peter Reisz, Nicole Benfante, Behfar Ehdaie, Karim Touijer, Vincent Laudone, James Eastham, Vijai Joseph, Ozge Birsoy, Diana Mandelker, Zsofia Stadler, Kenneth Offit, Michael Morris, Wassim Abida, Mark Robson, and Maria Carlo Hong TruongHong Truong More articles by this author , Kelsey BreenKelsey Breen More articles by this author , Yelena KemelYelena Kemel More articles by this author , Andrew LenisAndrew Lenis More articles by this author , Peter ReiszPeter Reisz More articles by this author , Nicole BenfanteNicole Benfante More articles by this author , Behfar EhdaieBehfar Ehdaie More articles by this author , Karim TouijerKarim Touijer More articles by this author , Vincent LaudoneVincent Laudone More articles by this author , James EasthamJames Eastham More articles by this author , Vijai JosephVijai Joseph More articles by this author , Ozge BirsoyOzge Birsoy More articles by this author , Diana MandelkerDiana Mandelker More articles by this author , Zsofia StadlerZsofia Stadler More articles by this author , Kenneth OffitKenneth Offit More articles by this author , Michael MorrisMichael Morris More articles by this author , Wassim AbidaWassim Abida More articles by this author , Mark RobsonMark Robson More articles by this author , and Maria CarloMaria Carlo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002058.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Tumor sequencing is increasingly used for therapeutic selection in men with advanced prostate cancer (PC). If tumor-only sequencing is performed without matched germline, identified mutations could be of somatic or germline origin. Germline mutations could confer additional risk for other cancers to the patient and at-risk family members. The objective of this study is to determine the overall and gene-specific probability of pathogenic/likely pathogenic germline mutations based on tumor-only sequencing. METHODS: We investigated mutations found in a cohort of men with PC who underwent targeted next generation sequencing of PC tumor and matched peripheral blood using the MSK-IMPACT assay between 01/2015 and 01/2020. A germline probability for each gene was determined by dividing the number of germline mutations by the total number of somatic and germline mutations. Cancer susceptibility genes commonly sequenced on tumor-based tests for PC were assessed, including ATM, BRCA1/2, BRIP1, CHEK2, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2 (henceforth referred to as PC genes). RESULTS: A total of 1883 men with PC were included, with median age of diagnosis of 62.0±8.8 years. 84% had high risk PC, 52% had metastasis, 38% had family history of PC. A total of 364 (19%) men had at least one mutation (either somatic or germline) in PC genes. Overall, 189 (10%) men had at least one germline mutation that would not have been reported as germline without matched normal. The average germline probability of PC genes was 40%. The number of total mutations, germline mutations, and germline probability of each gene were summarized in Figure 1. Genes with highest germline probability were CHEK2 (83%), PALB2 (69%), HOXB13 (60%), BRCA1 (55%), and BRCA2 (47%). All listed genes in Figure 1 are moderate/high penetrance autosomal dominant genes with established guidelines for cascade testing, enhanced cancer screening, or potential risk-reducing surgery. CONCLUSIONS: In this study, an average of 40% of mutations found in cancer susceptibility genes on PC tumor sequencing were germline mutations. Men undergoing tumor-only sequencing should be counseled on the possibility of uncovering a germline mutation. In addition to BRCA1/2, mutations in certain genes, such as CHEK2 and PALB2, have a high probability of being germline and should prompt referral for genetic counseling. Source of Funding: NIH T32 Ruth L. Kirschstein National Research Service Award 2020 - 2022 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e736-e736 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hong Truong More articles by this author Kelsey Breen More articles by this author Yelena Kemel More articles by this author Andrew Lenis More articles by this author Peter Reisz More articles by this author Nicole Benfante More articles by this author Behfar Ehdaie More articles by this author Karim Touijer More articles by this author Vincent Laudone More articles by this author James Eastham More articles by this author Vijai Joseph More articles by this author Ozge Birsoy More articles by this author Diana Mandelker More articles by this author Zsofia Stadler More articles by this author Kenneth Offit More articles by this author Michael Morris More articles by this author Wassim Abida More articles by this author Mark Robson More articles by this author Maria Carlo More articles by this author Expand All Advertisement Loading ...