scholarly journals Germline Testing Data Validate Inferences of Mutational Status for Variants Detected From Tumor-Only Sequencing

2021 ◽  
pp. 1749-1757
Author(s):  
Nahed Jalloul ◽  
Israel Gomy ◽  
Samantha Stokes ◽  
Alexander Gusev ◽  
Bruce E. Johnson ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Sequencing Data ◽  
Cancer Susceptibility Genes ◽  
Statistical Measures ◽  
Mutational Status ◽  
Testing Data ◽  
Somatic Status ◽  
Germline Testing

PURPOSE Pathogenic germline variants (PGVs) in cancer susceptibility genes are usually identified through germline testing of DNA from blood or saliva: their detection can affect treatment options and potential risk-reduction strategies for patient relatives. PGV can also be identified in tumor sequencing assays, which, when performed without patient-matched normal specimens, render determination of variants' germline or somatic origin critical. METHODS Tumor-only sequencing data from 1,608 patients were retrospectively analyzed to infer germline versus somatic status of variants using an information-theoretic, gene-independent approach. Loss of heterozygosity was also determined. Predicted mutational models were compared with clinical germline testing results. Statistical measures were computed to evaluate performance. RESULTS Tumor-only sequencing detected 3,988 variants across 70 cancer susceptibility genes for which germline testing data were available. We imputed germline versus somatic status for > 75% of all detected variants, with a sensitivity of 65%, specificity of 88%, and overall accuracy of 86% for pathogenic variants. False omission rate was 3%, signifying minimal error in misclassifying true PGV. A higher portion of PGV in known hereditary tumor suppressors were found to be retained with loss of heterozygosity in the tumor specimens (72%) compared with variants of uncertain significance (58%). CONCLUSION Analyzing tumor-only data in the context of specimens' tumor cell content allows precise, systematic exclusion of somatic variants and suggests a balance between type 1 and 2 errors for identification of patients with candidate PGV for standard germline testing. Although technical or systematic errors in measuring variant allele frequency could result in incorrect inference, misestimation of specimen purity could result in inferring somatic variants as germline in somatically mutated tumor suppressor genes. A user-friendly bioinformatics application facilitates objective analysis of tumor-only data in clinical settings.

scholarly journals Germline testing data validate inferences of mutational status for variants detected from tumor-only sequencing

2021 ◽  
Author(s):  
Nahed Jalloul ◽  
Israel Gomy ◽  
Samantha Stokes ◽  
Alexander Gusev ◽  
Bruce E. Johnson ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Sequencing Data ◽  
Germline Variants ◽  
Information Theoretic ◽  
Cancer Susceptibility Genes ◽  
Mutational Status ◽  
Testing Data ◽  
Uncertain Significance ◽  
Somatic Status ◽  
Germline Testing

Structured AbstractBackgroundPathogenic germline variants (PGV) in cancer susceptibility genes are usually identified in cancer patients through germline testing of DNA from blood or saliva: their detection can impact patient treatment options and potential risk reduction strategies for relatives. PGV can also be identified, in tumor sequencing assays, often performed without matched normal specimens. It is then critical to determine whether detected variants are somatic or germline. Here, we evaluate the clinical utility of computational inference of mutational status in tumor-only sequencing compared to germline testing results.Patients and MethodsTumor-only sequencing data from 1,608 patients were retrospectively analyzed to infer germline-versus-somatic status of variants using an information-theoretic, gene-independent approach. Loss of heterozygosity (LOH) was also determined. The predicted mutational models were compared to clinical germline testing results. Statistical measures were computed to evaluate performance.ResultsTumor-only sequencing detected 3,988 variants across 70 cancer susceptibility genes for which germline testing data were available. Our analysis imputed germline-versus-somatic status for >75% of all detected variants, with a sensitivity of 65%, specificity of 88%, and overall accuracy of 86% for pathogenic variants. False omission rate was 3%, signifying minimal error in misclassifying true PGV. A higher portion of PGV in known hereditary tumor suppressors were found to be retained with LOH in the tumor specimens (72%) compared to variants of uncertain significance (58%).ConclusionsTumor-only sequencing provides sufficient power to distinguish germline and somatic variants and infer LOH. Although accurate detection of PGV from tumor-only data is possible, analyzing sequencing data in the context of specimens’ tumor cell content allows systematic exclusion of somatic variants, and suggests a balance between type 1 and 2 errors for identification of patients with candidate PGV for standard germline testing. Our approach, implemented in a user-friendly bioinformatics application, facilities objective analysis of tumor-only data in clinical settings.HighlightsMost pathogenic germline variants in cancer predisposition genes can be identified by analyzing tumor-only sequencing data.Information-theoretic gene-independent analysis of common sequencing data accurately infers germline vs. somatic status.A reasonable statistical balance can be established between sensitivity and specificity demonstrating clinical utility.Pathogenic germline variants are more often detected with loss of heterozygosity vs. germline variants of uncertain significance.

Characterization of findings on prostate cancer tumor sequencing that should prompt consideration for germline testing.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5022-5022
Author(s):  
Hong Truong ◽  
Kelsey Breen ◽  
Yelena Kemel ◽  
Andrew Thomas Lenis ◽  
Peter Reisz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Germline Mutation ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Susceptibility Genes ◽  
Study Cohort ◽  
Targeted Next Generation Sequencing ◽  
Cancer Susceptibility Genes ◽  
Tumor Sequencing ◽  
Germline Testing

5022 Background: 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% (range: 0% in MLH1 to 83% in CHEK2). The number of total mutations, germline mutations, and germline probability of genes found in > 0.5% of the study cohort are summarized in Table. All these genes 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 and germline testing.[Table: see text]

Germline alterations in cancer susceptibility genes in women with high-risk bladder cancer: Implications for germline testing and clinical management.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 418-418
Author(s):  
Hong Truong ◽  
Rania Sheikh ◽  
Aliya Khurram ◽  
Yelena Kemel ◽  
Andrew Thomas Lenis ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Susceptibility Genes ◽  
Stage At Diagnosis ◽  
Germline Variants ◽  
Cancer Susceptibility Genes ◽  
High Penetrance ◽  
Germline Testing

418 Background: Gender differences exist in bladder cancer incidence, stage at diagnosis, and outcomes. Women have lower incidence of bladder cancer but are diagnosed with more advanced disease at presentation. They also have less favorable outcomes even after adjusting for tumor stage and treatment modality. The biologic mechanisms underlying gender disparities in bladder cancer remain unknown. Methods: We leveraged a prospective matched tumor-normal genomic profiling initiative to determine the prevalence and spectrum of pathogenic/likely pathogenic (P/LP) germline variants in women with bladder cancer. Germline DNA was tested for mutations in ≥77 cancer susceptibility genes using next-generation sequencing in 686 patients with bladder cancer. Mutation frequency and clinical characteristics were assessed by gender. Results: A total of 184 (27%) women and 502 (73%) men with bladder cancer underwent germline testing; median age of diagnosis was 66 ± 11.3 and 65 ± 11.3 years, respectively. Twenty-two women (12%) had bladder cancer diagnosis at age ≤ 50 years. Both groups had similar rate of tobacco exposure (57% vs 63%, p = 0.1), family history of bladder cancer (10% vs 10%, p = 0.5), and disease stage at diagnosis (non-muscle invasive bladder cancer [NMIBC] 54% vs 54%, MIBC 38% vs 39%, and metastatic disease 8% vs 6%, p = 0.7). Women had more non-urothelial carcinoma histology than men (adenocarcinoma 5% vs. 1%; squamous cell carcinoma 1% vs 0.2%, p = 0.001). More P/LP germline variants were found in women than men (38 [21%] vs. 70 [14%], p = 0.04). Twenty-eight women (15%) had P/LP variants in DNA-damage repair (DDR) genes; 23 (13%) carried moderate/high penetrance germline mutations, the most common were BRCA1/ 2, CHEK2, NBN, ATM, and MITF. Current clinical guideline for referral for genetic testing failed to identify 12 (52%) women with moderate/high penetrance germline mutations. Nine women (5%) carried germline mutations associated with increased risk of ovarian/endometrial cancers ( BRCA1/ 2 [5], ATM [2], MLH1 [1], TP53 [1]). Conclusions: Deleterious germline alterations are commonly present in women with high-risk bladder cancer. The presence of germline variants in some genes, such as BRCA1/2, can guide cancer screening and risk-reducing surgeries for patients and their families. Women with high-risk bladder cancer should be evaluated for suitability of germline testing, especially those who desire preservation of uterus and ovaries at the time of radical cystectomy, to rule out the presence of P/LP variants that increase risk of future gynecologic malignancies.

Universal germline testing among patients with colorectal cancer: clinical actionability and optimised panel

2021 ◽  
pp. jmedgenet-2020-107230
Author(s):  
Wu Jiang ◽  
Lin Li ◽  
Chuan-Feng Ke ◽  
Wei Wang ◽  
Bin-Yi Xiao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Hereditary Cancer Syndromes ◽  
Cancer Susceptibility Genes ◽  
Additional Testing ◽  
Cancer Syndromes ◽  
Germline Testing ◽  
Testing Set

PurposeUniversal germline testing in patients with colorectal cancer (CRC) with a multigene panel can detect various hereditary cancer syndromes. This study was performed to understand how to choose a testing panel and whether the result would affect clinical management.MethodsWe prospectively enrolled 486 eligible patients with CRC, including all patients with CRC diagnosed under age 70 years and patients with CRC diagnosed over 70 years with hereditary risk features between November 2017 and January 2018. All participants received germline testing for various hereditary cancer syndromes.ResultsThe prevalence of germline pathogenic variants (PVs) in cancer susceptibility genes was 7.8% (38/486), including 25 PVs in genes with high-risk CRC susceptibility (the minimal testing set) and 13 PVs in genes with moderate-risk CRC susceptibility or increased cancer risk other than CRC (the additional testing set). All the clinically relevant PVs were found in patients diagnosed under age 70 years. Among them, 11 patients would not have been diagnosed if testing reserved to present guidelines. Most (36/38) of the patients with PVs benefited from enhanced surveillance and tailored treatment. PVs in genes from the minimal testing set were found in all age groups, while patients carried PVs in genes from the additional testing set were older than 40 years.ConclusionUniversal germline testing for cancer susceptibility genes should be recommended among all patients with CRC diagnosed under age 70 years. A broad panel including genes from the additional testing set might be considered for patients with CRC older than 40 years to clarify inheritance risks.Trial registration numberNCT03365986.

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