Yield of targeted genotyping for the recurring pathogenic variants in cancer susceptibility genes in a healthy, multiethnic Israeli population

Cancer ◽  
2021 ◽  
Author(s):  
Rinat Bernstein‐Molho ◽  
Lee Galmor ◽  
Yael Laitman ◽  
Shlomo Segev ◽  
Eitan Friedman
Keyword(s):  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Israeli Population

scholarly journals Prevalence of Pathogenic Variants in Cancer Susceptibility Genes Among Women With Postmenopausal Breast Cancer

JAMA ◽  
2020 ◽  
Vol 323 (10) ◽  
pp. 995 ◽  
Author(s):  
Allison W. Kurian ◽  
Ryan Bernhisel ◽  
Katie Larson ◽  
Jennifer L. Caswell-Jin ◽  
Aladdin H. Shadyab ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Postmenopausal Breast Cancer ◽  
Susceptibility Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13113-e13113
Author(s):  
Howard John Lim ◽  
Kasmintan A Schrader ◽  
Sean Young ◽  
Jessica Nelson ◽  
Alexandra Fok ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Genomic Research ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

e13113 Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.

scholarly journals A novel high-throughput assay using mixed genomic DNA for fast screening germline pathogenic variants in breast cancer susceptibility genes

2021 ◽  
Author(s):  
Qiting Wan ◽  
Li Hu ◽  
Lu Yao ◽  
Jiuan Chen ◽  
Jie Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Throughput ◽  
Genomic Dna ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Breast Cancer Susceptibility Genes ◽  
High Throughput Assay

The demand for genetic testing for breast cancer susceptibility genes is increasing for both breast cancer patients and healthy individuals. Here we established a novel high-throughput assay to detect germline pathogenic variants in breast cancer susceptibility genes. In general, up 10 to 50 individual genomic DNA samples were mixed together to create a mixed DNA sample and the mixed DNA sample was subjected to a next-generation multigene panel. Germline pathogenic variants in breast cancer susceptibility genes could be found in the mixed DNA sample; next, site-specific Sanger sequencing was performed to identify individuals who carried he pathogenic variant in the mixed samples. We found that the recall and precision rates were 89.9% and 92.9% when twenty individual genomic samples were mixed. Therefore, our new assay can increase an approximately 20-fold of efficacy to identify the pathogenic variants in breast cancer susceptibility genes in individuals when compared with current assay.

scholarly journals Li-Fraumeni syndrome: not a straightforward diagnosis anymore—the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Felipe Batalini ◽  
Ellie G. Peacock ◽  
Lindsey Stobie ◽  
Alison Robertson ◽  
Judy Garber ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Cancer Susceptibility ◽  
Somatic Mosaicism ◽  
Susceptibility Genes ◽  
Breast Cancer Patients ◽  
Li Fraumeni Syndrome ◽  
Clonal Hematopoiesis ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

Abstract The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25–35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management. The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment. Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives. We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients.

scholarly journals Search Behavior Regarding Cancer Susceptibility Genes Using a Clinical Decision Support Tool for Gene-Specific Penetrance: Content Analysis

JMIR Cancer ◽  
10.2196/28527 ◽  
2021 ◽  
Vol 7 (3) ◽  
pp. e28527
Author(s):  
Kanhua Yin ◽  
Jingan Zhou ◽  
Preeti Singh ◽  
Jin Wang ◽  
Danielle Braun ◽  
...  
Keyword(s):  
Decision Support ◽  
Clinical Decision Support ◽  
Cancer Susceptibility ◽  
Decision Support Tool ◽  
Clinical Decision ◽  
Susceptibility Genes ◽  
Support Tool ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

Background Genetic testing for germline cancer susceptibility genes is widely available. The Ask2Me.org (All Syndromes Known to Man Evaluator) tool is a clinical decision support tool that provides evidence-based risk predictions for individuals with pathogenic variants in cancer susceptibility genes. Objective The aim of this study was to understand the search behavior of the Ask2Me.org tool users, identify the patterns of queries entered, and discuss how to further improve the tool. Methods We analyzed the Ask2Me.org user-generated queries collected between December 12, 2018, and October 8, 2019. The gene frequencies of the user-generated queries were compared with previously published panel testing data to assess the correspondence between usage and prevalence of pathogenic variants. The frequencies of prior cancer in the user-generated queries were compared with the most recent US population–based cancer incidence. Results A total of 10,085 search queries were evaluated. The average age submitted in the queries was 48.8 (SD 16.5) years, and 84.1% (8478/10,085) of the submitted queries were for females. BRCA2 (1671/10,085, 16.6%), BRCA1 (1627/10,085, 16.1%), CHEK2 (994/10,085, 9.9%), ATM (662/10,085, 6.6%), and APC (492/10,085, 4.9%) were the top 5 genes searched by users. There was a strong linear correlation between genes queried by users and the frequency of pathogenic variants reported in published panel testing data (r=0.95, r2=0.90, P<.001). Over half of the queries (5343/10,085, 53.0%) included a prior personal history of cancer. The frequencies of prior cancers in the queries on females were strongly correlated with US cancer incidences (r=0.97, r2=0.95, P<.001), while the same correlation was weaker among the queries on males (r=0.69, r2=0.47, P=.02). Conclusions The patients entered in the Ask2Me.org tool are a representative cohort of patients with pathogenic variants in cancer susceptibility genes in the United States. While a majority of the queries were on breast cancer susceptibility genes, users also queried susceptibility genes with lower prevalence, which may represent a transformation from single gene testing to multigene panel testing. Owing to these changing tides, more efforts are needed to improve evidence-based clinical decision support tools to better aid clinicians and their practice.

Breast cancer treatment according to pathogenic variants in cancer susceptibility genes in a population-based cohort.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 560-560 ◽  
Author(s):  
Allison W. Kurian ◽  
Kevin C. Ward ◽  
Paul Abrahamse ◽  
Ann S Hamilton ◽  
Dennis Deapen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Genetic Test ◽  
Cancer Susceptibility ◽  
Population Based ◽  
Susceptibility Genes ◽  
Breast Cancer Treatment ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
To Receive

560 Background: Increasing use of germline genetic testing may have unintended consequences on breast cancer treatment. We do not know whether treatment deviates from guidelines for women with pathogenic variants (PV) in cancer susceptibility genes. Methods: SEER data for all women aged ≥20 years, diagnosed with breast cancer in 2014-15 and reported to Georgia and California registries (N = 77,588) by December 1, 2016 were linked to germline genetic testing results from 4 laboratories that did nearly all clinical testing. We examined first course of therapy (before recurrence or progression) of stage < IV patients who linked to a genetic test: bilateral mastectomy (BLM) in candidates for surgery (unilateral, stages 0-III); post-lumpectomy radiation in those with an indication (all but age ≥70, stage I, hormone receptor (HR)-positive and HER2-negative); and chemotherapy in those without a definitive indication (stage I-II, HR-positive, HER2-negative and 21-gene recurrence score < 30). We report the percent treated based on multivariable modeling, adjusted for age, race, stage, grade, insurance and socioeconomic status. Results: The table shows that 9% of patients who linked to a genetic test result had a PV (N = 1,283). Compared to women with negative results,women with BRCA1/2 PVs were more likely to receive BLM, more likely to receive chemotherapy without definitive indication, and less likely to receive indicated radiation in their first course of therapy. Lower-magnitude effects were seen with other PVs but not variants of uncertain significance (VUS). Conclusions: In a population-based setting, women with PVs in BRCA1/2 or other cancer susceptibility genes may have a higher risk of receiving locoregional and systemic treatment that does not follow guidelines. [Table: see text]

scholarly journals Development and Validation of a Clinical Polygenic Risk Score to Predict Breast Cancer Risk

2020 ◽  
pp. 585-592 ◽  
Author(s):  
Elisha Hughes ◽  
Placede Tshiaba ◽  
Shannon Gallagher ◽  
Susanne Wagner ◽  
Thaddeus Judkins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Cancer History ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Breast Cancer Susceptibility Genes

PURPOSE Women with a family history of breast cancer are frequently referred for hereditary cancer genetic testing, yet < 10% are found to have pathogenic variants in known breast cancer susceptibility genes. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms [SNPs]) with individually modest breast cancer risk that, in aggregate, account for considerable breast cancer susceptibility. Here, we describe the development and empirical validation of an SNP-based polygenic breast cancer risk score. METHODS A panel of 94 SNPs was examined for association with breast cancer in women of European ancestry undergoing hereditary cancer genetic testing and negative for pathogenic variants in breast cancer susceptibility genes. Candidate polygenic risk scores (PRSs) as predictors of personal breast cancer history were developed through multivariable logistic regression models adjusted for age, cancer history, and ancestry. An optimized PRS was validated in 2 independent cohorts (n = 13,174; n = 141,160). RESULTS Within the training cohort (n = 24,259), 4,291 women (18%) had a personal history of breast cancer and 8,725 women (36%) reported breast cancer in a first-degree relative. The optimized PRS included 86 variants and was highly predictive of breast cancer status in both validation cohorts ( P = 6.4 × 10−66; P < 10−325). The odds ratio (OR) per unit standard deviation was consistent between validations (OR, 1.45 [95% CI, 1.39 to 1.52]; OR 1.47 [95% CI, 1.45 to 1.49]). In a direct comparison, the 86-SNP PRS outperformed a previously described PRS of 77 SNPs. CONCLUSION The validation and implementation of a PRS for women without pathogenic variants in known breast cancer susceptibility genes offers potential for risk stratification to guide surveillance recommendations.

scholarly journals Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

2021 ◽  
pp. 1588-1602
Author(s):  
Monica D. Levine ◽  
Rachel Pearlman ◽  
Heather Hampel ◽  
Casey Cosgrove ◽  
David Cohn ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Type Ii ◽  
Newly Diagnosed ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Multigene Panel Testing ◽  
Multigene Panel

PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

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