Clinical application of comprehensive next generation sequencing in the management of metastatic cancer in adults.

101 Background: Next generation sequencing (NGS) platforms are frequently utilized in the care of patients (pts) with metastatic cancer to identify tumor genomic alterations that may serve as therapeutic targets. Biomarker driven clinical trials, such as NCI-Molecular Analysis for Therapy Choice (MATCH) and Targeted Agent and Profiling Utilization Registry (TAPUR) have augmented clinicians’ ability use this strategy in clinical practice. Methods: From 2011-2015 over 500 adult pts with metastatic solid tumors of diverse lineage underwent biopsy for whole exome and transcriptome sequencing of tumor and matched normal sample through the Michigan Oncology Sequencing Center (Mi-Oncoseq). Genomic alterations identified were reviewed at Precision Medicine Tumor Board and tiered according to their clinical relevance. Alterations were also classified as being identifiable or not identifiable by a commercially available NGS assay such as Oncomine Focus or FoundationOne. Results: Genomic alterations identified by Mi-Oncoseq provided rationale for enrollment in a clinical trial in 72% (n = 360) of cases. The percentage of pts who did receive therapy informed by NGS results increased over time (5% in 2012 versus 11% in 2015). 11% of pts (n = 55) had a pathogenic germline variant (PGV) conferring increased cancer risk identified, none of which were known prior to study entry. Numerous pts had clinically relevant molecular alterations identified by Mi-Oncoseq that would not have been identifiable utilizing targeted NGS assays, including PGVs and activating/deleterious gene fusions. Conclusions: Comprehensive NGS, including DNA and RNA sequencing, readily identifies potentially actionable alterations in the vast majority of pts beyond what is observed with use of targeted NGS platforms. Observed modest increase in utilization of NGS results to direct subsequent therapy over time is due to clinician employment of this strategy earlier in the therapeutic algorithm, increased availability of biomarker driven clinical trials and changes in physician referral patterns. Comprehensive NGS identified many unanticipated PGVs of clinical importance for pts and their families. Clinical trial information: HUM00067928.

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Clinical Trial Accrual Targeting Genomic Alterations After Next-Generation Sequencing at a Non-National Cancer Institute–Designated Cancer Program

Journal of Oncology Practice ◽

10.1200/jop.2015.008433 ◽

2016 ◽

Vol 12 (4) ◽

pp. e396-e404 ◽

Cited By ~ 8

Author(s):

Kalyan C. Mantripragada ◽

Adam J. Olszewski ◽

Andrew Schumacher ◽

Kimberly Perez ◽

Ariel Birnbaum ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Next Generation Sequencing ◽

National Cancer Institute ◽

Next Generation ◽

Genomic Alterations ◽

Cancer Centers ◽

Cancer Program ◽

Clinical Trial Accrual ◽

Generation Sequencing

Purpose: Successful clinical trial accrual targeting uncommon genomic alterations will require broad national participation from both National Cancer Institute (NCI)–designated comprehensive cancer centers and community cancer programs. This report describes the initial experience with clinical trial accrual after next-generation sequencing (NGS) from three affiliated non–NCI-designated cancer programs. Materials and Methods: Clinical trial participation was reviewed after enrollment of the first 200 patients undergoing comprehensive genomic profiling by NGS as part of an institutional intuitional review board–approved protocol at three affiliated hospitals in Rhode Island and was compared with published experience from NCI-designated cancer centers. Results: Patient characteristics included a median age of 64 years, a median of two lines of prior therapy, and a predominance of GI carcinomas (58%). One hundred sixty-four of 200 patients (82%) had adequate tumor for NGS, 95% had genomic alterations identified, and 100% had variants of unknown significance. Fifteen of 164 patients (9.2%) enrolled in genotype-directed clinical trials, and three patients (1.8%) received commercially available targeted agents off clinical trials. The reasons for nonreceipt of NGS-directed therapy were no locally available matching trial (48.6%), ineligibility (33.6%) because of comorbidities or interim clinical deterioration, physician's choice of a different therapy (6.8%), or stable disease (11%). Conclusion: This experience demonstrates that a program enrolling patients in specific targeted agent clinical trials after NGS can be implemented successfully outside of the NCI-designated cancer program network, with comparable accrual rates. This is important because targetable genes have rare mutation rates and clinical trial accrual after NGS is low.

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PATH-03. CLINICAL UTILITY OF NEXT GENERATION SEQUENCING IN IDH-WILDTYPE GLIOBLASTOMA: THE DANA-FARBER CANCER INSTITUTE EXPERIENCE

Neuro-Oncology ◽

10.1093/neuonc/noaa215.685 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii164-ii164

Author(s):

Mary Jane Lim-Fat ◽

Gilbert Youssef ◽

Mehdi Touat ◽

Bryan Iorgulescu ◽

Eleanor Woodward ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Next Generation Sequencing ◽

Immune Checkpoint Blockade ◽

Next Generation ◽

Single Nucleotide Variants ◽

Dana Farber Cancer Institute ◽

Clinical Records ◽

Ngs Data ◽

Generation Sequencing

Abstract BACKGROUND Comprehensive next generation sequencing (NGS) is available through many academic institutions and commercial entities, and is incorporated in practice guidelines for glioblastoma (GBM). We retrospective evaluated the practice patterns and utility of incorporating NGS data into routine care of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with histologically confirmed GBM with OncoPanel testing, a targeted exome NGS platform of 447 cancer-associated genes at Dana Farber Cancer Institute (DFCI), from 2013-2019. We selected and retrospectively reviewed clinical records of all IDH-wildtype GBM patients treated at DFCI. RESULTS We identified 557 GBM IDH-wildtype patients, of which 227 were male (40.7%). OncoPanel testing revealed 833 single nucleotide variants and indels in 44 therapeutically relevant genes (Tier 1 or 2 mutations) including PIK3CA (n=51), BRAF (n=9), FGFR1 (n=8), MSH2 (n=4), MSH6 (n=2) and MLH1 (n=1). Copy number analysis revealed 509 alterations in 18 therapeutically relevant genes including EGFR amplification (n= 186), PDGFRA amplification (N=39) and CDKN2A/2B homozygous loss (N=223). Median overall survival was 17.5 months for the whole cohort. Seventy-four therapeutic clinical trials accrued 144 patients in the upfront setting (25.9%) and 203 patients (36.4%) at recurrence. Altogether, NGS data for 107 patients (19.2%) were utilized for clinical trial enrollment or targeted therapy indications. High mutational burden (>17mutations/Mb) was identified in 11/464 samples (2.4%); of whom 3/11 received immune checkpoint blockade. Four patients received compassionate use therapy targeting EGFRvIII (rindopepimut, n=2), CKD4/6 (abemaciclib, n=1) and BRAFV600E (dabrafenib/trametinib, n=1). CONCLUSION While NGS has greatly improved diagnosis and molecular classification, we highlight that NGS remains underutilized in selecting therapy in GBM, even in a setting where clinical trials and off-label therapies are relatively accessible. Continued efforts to develop better targeted therapies and efficient clinical trial design are required to maximize the potential benefits of genomically-stratified data.

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Therapeutic impact and timing of gastrointestinal malignancy genomic profiling: A single-institution experience.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.584 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 584-584

Author(s):

Kristin Lynn Koenig ◽

Jarred Burkart ◽

Sameh Mikhail ◽

Christina Sing-Ying Wu ◽

Anne M. Noonan ◽

...

Keyword(s):

Clinical Trials ◽

Next Generation Sequencing ◽

Targeted Therapies ◽

Clinical Care ◽

Comprehensive Cancer Center ◽

Genomic Profiling ◽

Next Generation ◽

Wild Type ◽

Genomic Alterations ◽

Generation Sequencing

584 Background: Tumor genomic profiling has become critical in the identification of targeted therapeutic options for patients (pts) with advanced malignancies. Mutational frequencies and their therapeutic importance vary among tumor types. This analysis was undertaken to characterize the landscape of genomic alterations in gastrointestinal (GI) malignancies found in a large academic institutional practice, and to determine the frequency of alteration-specific targeted therapy selection based on genomic profiling. Methods: Adult pts with GI malignancies presenting to the Ohio State University Comprehensive Cancer Center oncology clinics were offered next generation sequencing through FoundationOne testing as part of routine clinical care. Institutional review board approval was obtained to retrospectively analyze results from FoundationOne testing performed between 2012 and 2015. Results: 265 pts with GI malignancies underwent successful genomic profiling. 1205 genomic alterations were found, with an average of 4.5 per tumor (range 0-20); 365 (30%) of these were potentially actionable and most often found in colorectal or gastroesophageal tumors. 14 pts (5.3%) had actionable alterations in MET, CDKN2A/B, FGFR2, KRAS, BRAF, or NF2 that led to enrollment in genotype-directed clinical trials or off label use of targeted therapies beyond standard of care. Pt performance status at the time of genomic alteration identification was a significant factor in precluding genotype-directed therapy. One variant of unknown significance involving FGFR2 identified at initial testing subsequently became actionable and led to pt enrollment on a clinical trial. One pt with rectal cancer was found to have a KRAS wild-type and BRAF mutant primary but KRAS mutant and BRAF wild-type liver metastasis. Conclusions: Genomic profiling of GI malignancies through next generation sequencing is feasible and can lead to genotype-directed therapy selection; however, it should be considered early in the pt’s course to optimize use of targeted therapies through clinical trials. Consideration should be given to serial tumor testing to identify emerging genomic alterations for optimal therapy selection.

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No-cost next generation sequencing of advanced cancer patients within the Strata Precision Oncology Network supports clinical trial enrollment.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3073 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3073-3073

Author(s):

Marc Ryan Matrana ◽

Scott A. Tomlins ◽

Kat Kwiatkowski ◽

Khalis Mitchell ◽

Jennifer Marie Suga ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Next Generation Sequencing ◽

Clinical Samples ◽

Precision Oncology ◽

Cancer Type ◽

Next Generation ◽

Match Trial ◽

The Impact ◽

Generation Sequencing

3073 Background: Widespread integration of systematized next generation sequencing (NGS)-based precision oncology is hindered by numerous barriers. Hence, we developed the Strata trial (NCT03061305), a screening protocol to determine the impact of scaled precision oncology. Methods: We implemented no-cost NGS on formalin fixed paraffin embedded (FFPE) clinical samples for all patients with advanced tumors, a common portfolio of partnered therapeutic clinical trials, and robust infrastructure development across the Strata Precision Oncology Network. Results: Across the network of 17 centers, specimens from 8673/9222 (94%) patients were successfully tested in the Strata CLIA/CAP/NCI-MATCH accredited laboratory using comprehensive amplicon-based DNA and RNA NGS. Patients were tested with one of three StrataNGS test versions; the most recent panel assesses all classes of actionable alterations (mutations, copy number alterations, gene fusions, microsatellite instability, tumor mutation burden and PD-L1 expression). Median surface area of received FFPE tumor samples was 25mm2 (interquartile range 9-95mm2), and the median turnaround time from sample receipt to report was 6 business days. 2577 (27.9%) patients had highly actionable alterations, defined as alterations associated with within-cancer type FDA approved or NCCN guideline recommended therapies (1072 patients), NCI-MATCH trial arms (1467 patients), Strata-partnered therapeutic trials (327 patients), or specific alteration-matched FDA approved therapies in patients with cancers of unknown primary (71 patients). Of the 1467 patients matched to an NCI-MATCH trial arm, 15 enrolled. Of the 327 patients matched to one of nine Strata-partnered clinical trials, 77 (24%) were screen failures, while 250 (76%) have either enrolled or are being actively followed for enrollment upon progression. Conclusions: Through streamlined consent methods, electronic medical record queries, and high throughput laboratory testing at no cost to patients, we demonstrate that scaled precision oncology is feasible across a diverse network of healthcare systems when paired with access to relevant clinical trials. Clinical trial information: NCT03061305.

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Utility of Combined DNA and RNA Next Generation Sequencing in Leukemias for Identification of Prognostic and Therapeutically Relevant Genomic Alterations in Clinical Practice

Blood ◽

10.1182/blood.v124.21.1039.1039 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1039-1039

Author(s):

Catherine C. Coombs ◽

Aaron D. Viny ◽

Jie He ◽

Rachel Kobos ◽

Doron Lipson ◽

...

Keyword(s):

Clinical Trials ◽

Clinical Practice ◽

Next Generation Sequencing ◽

Acute Leukemia ◽

Consecutive Series ◽

Genomic Profiling ◽

Next Generation ◽

Genomic Alterations ◽

Dna And Rna ◽

Generation Sequencing

Abstract Genome and exome sequencing have provided important insights into the biology of hematologic malignancies, and have led to the identification of prognostically relevant mutations and therapeutically targetable genomic alterations. However, the utility of genomic profiling in routine clinical practice remains an area of active investigation, and there is a need for evidence-based approaches to application of these data. Although most adults with acute leukemia relapse after initial therapy, only 25% of acute leukemia patients are enrolled onto clinical trials. Reasons for limited enrollment are multifold, but include a limited understanding by clinicians of genomic alterations, and lack of access to broad-based analytically validated clinical genomic profiling, both hampering the ability of clinicians to enroll patients on genotype-specific, mechanism-based clinical trials. As such, the development of high throughput, state-of-the-art genomic profiling assays for clinical practice, such as FoundationOneHeme, provide an unprecedented opportunity. Here we analyzed a consecutive series of 62 leukemia patients at Memorial Sloan Kettering Cancer Center for whom FoundationOneHeme was performed to determine the incidence and applicability of genomic findings on clinical care. The clinical sample cohort included 17 patients with myelodysplastic syndromes (MDS), 14 patients with acute myeloid leukemia (AML), 14 patients with acute lymphoblastic leukemia (ALL), 6 patients with myeloproliferative neoplasms (MPN), 5 patients with chronic lymphocytic leukemia (CLL), 4 patients with aplastic anemia (AA), and 2 patients with chronic myeloid leukemias (CML). DNA and RNA were successfully extracted from 58/62 samples (94%). Adaptor ligated sequencing libraries were captured by solution hybridization using a custom bait-set targeting 405 cancer-related genes and 31 frequently rearranged genes by DNA-seq, and 265 frequently-rearranged genes by RNA-seq. Samples were sequenced to high depth (Illumina HiSeq) in a CLIA-certified CAP-accredited laboratory (Foundation Medicine), averaging 590x for DNA and >20M total pairs for RNA, to enable the sensitive and specific detection of short variants (substitutions and indels), CNAs and gene fusions. A genomic alteration was characterized as “therapeutic” if it has been shown to determine response or resistance to an available therapy, or mechanism-based trial and “prognostic” if it has been shown to be predictive of outcome by individual disease states. Of the 58 patients with informative genomic data, 84% had at least one pathogenic variant identified. A total of 154 such alterations were identified (2.7 alterations per sample), including 81 base substitutions, 39 indels, 6 splice mutations, 10 CNAs and 18 fusions/rearrangements. 69% of patients had variants identified that were classified as clinically significant. 53% of patients had potential therapeutically relevant genomic alterations, and 43% of patients had prognostically relevant alterations identified. 36% of patients had both therapeutic and prognostic alterations identified. The most common alterations identified in our cohort were TP53 (n= 8), NRAS (n= 6), KMT2A, KRAS, RUNX1 (n= 5), CDKN2A, CDKN2B, SF3B1, TET2 (n= 4). In sum, 54 prognostic and 47 therapeutic genomic alterations were identified. 7 MDS cases, 4 AA cases, 2 AML cases, 2 ALL cases, 1 CML case, and 1 CLL case did not have a pathogenic or actionable allele, demonstrating that almost all patients in our cohort had mutations with biologic and clinical relevance. We also noted a set of variants of unknown significance, including 37 deletions and 26 insertions, which are under investigation in regard to prognostic and therapeutic significance. However, given that at least one genomic variant was identified in the majority of patients, our data demonstrate the utility of this approach in the identification of somatic genomic alterations for prognostic and therapeutic value, and to identify clonal markers which can be used to track molecular response during anti-leukemic therapy. In summary, we analyzed the mutational profiles of leukemia patients using an analytic and clinically validated assay, which allowed us to identify both prognostic and therapeutically relevant mutations in the majority of patients, confirming the utility of comprehensive next-generation sequencing in clinical practice. Disclosures He: Foundation Medicine: Employment. Lipson:Foundation Medicine, Inc.: Employment. Otto:Foundation Medicine, Inc.: Employment. Miller:Foundation Medicine, Inc: Employment. van den Brink:Foundation Medicine, Inc.: Consultancy. Armstrong:Foundation Medicine, Inc.: Consultancy. Stephens:Foundation Medicine: Employment, Equity Ownership. Levine:Foundation Medicine, Inc.: Consultancy.

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Pilot study of clinical targeted next generation sequencing for prostate cancer: Consequences for treatment and genetic counseling.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.251 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 251-251

Author(s):

Heather H. Cheng ◽

Nola Klemfuss ◽

Robert B. Montgomery ◽

Celestia S. Higano ◽

Michael Thomas Schweizer ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Next Generation Sequencing ◽

Pilot Study ◽

Germline Mutations ◽

Next Generation ◽

Targeted Next Generation Sequencing ◽

Targeted Ngs ◽

High Penetrance ◽

Generation Sequencing

251 Background: Targeted next generation sequencing (NGS) panels for identification of actionable mutations are increasingly used in oncology for therapeutic decision-making, but have yet to be widely used for prostate cancer.To determine the utility of applying a targeted next generation sequencing to prostate cancer management, we conducted a pilot study using the clinical molecular diagnostic assay, UW-OncoPlex, on primary and metastatic tumors from patients with prostate cancer. Methods: Patients receiving treatment for prostate cancer by a medical oncologist were eligible. After providing informed consent, tumor DNA was extracted from formalin-fixed, paraffin-embedded (FFPE)primary tumors and/or metastatic biopsies. Extracted DNA was analyzed using UW-OncoPlex, a targeted NGS panel designed to assess genomic alterations in 234 cancer-associated genes (PMID: 24189654). Results were discussed at a monthly multidisciplinary precision tumor board prior to communicating results to patients. Results: Forty patients consented to the study and 31 (78%) had reportable results. Findings included frequently observed prostate cancer genomic aberrations, including: TMPRSS2-ERG fusions and copy-number alterations of PTEN, TP53, FOXA1, AR, and SPOP. We also observed potentially actionable alterations in BRAF, MAP2K1 (MEK1), PIK3R1, MET, FGFR1, and FGFR3, which inform future treatment and clinical trial considerations. Notably, 8/31 (25%) patients had suspected high penetrance germline mutations, including in BRCA2 (N = 3), TP53 (N = 2), ATM (N = 1), and CHEK2 (N = 2). These 8 individuals were referred to medical genetics and 7 of 8 mutations were confirmed to be germline. One patient was found to have a hypermutated phenotype associated with bi-allelic MSH6 mutation and microsatellite instability. Conclusions: Targeted NGS panel testing may be useful in informing future treatment approaches and clinical trial selection for patients with prostate cancer. In addition, we observed a high proportion of cases with suspected high-penetrance germline mutations and immediate actionability through referral to medical genetics.

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An observational study profiling biospecimens from 10,000 metastatic prostate cancer (mPCa) patients to screen for molecular alterations.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.tps402 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. TPS402-TPS402

Author(s):

Won Kim ◽

Kat Kwiatkowski ◽

Justin Brown ◽

Dan R Rhodes ◽

Scott A Tomlins ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Clinical Trials ◽

Next Generation Sequencing ◽

Observational Study ◽

Large Scale ◽

Screening Program ◽

Next Generation ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

TPS402 Background: Despite recent success in development and use of targeted agents in patients with solid tumors, there is a paucity of such therapies approved for use in prostate cancer. This observational study provides next-generation sequencing (NGS) to men with mPCa to evaluate the proportion of patients available for targeted therapy clinical trials in mPCa and to assess the feasibility of using a large-scale NGS screening program to match patients for eligibility criteria in clinical trials. Methods: Using a virtual clinical trial model to maximize patient access and enrollment, this study is providing next-generation sequencing (NGS) to 10,000 men with mPCa. Patients with histologically-documented mPCa and surplus formalin-fixed paraffin-embedded tumor tissue are eligible for enrollment. Leftover archival tissue is submitted for NGS to Strata Oncology, a clinical laboratory improvement amendments (CLIA)-certified lab. The StrataNGS assay sequences DNA and RNA, and simultaneously detects a range of actionable genomic alterations including gene mutations, small insertions and deletions, copy number changes, and gene fusions in 87 cancer-related genes. Microsatellite instability status is determined via the number of length variant alleles observed in NGS sequencing data at several microsatellite loci. Test reports presented to the clinician include all positive and negative variants detected, and information about potential matching therapeutic protocols. Clinical trial information: NCT03061305.

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Using sequential next-generation sequencing assays to identify germline cancer predisposition variants.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.1581 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 1581-1581 ◽

Cited By ~ 1

Author(s):

Ira Lignugaris Kraft ◽

Amy M. Trottier ◽

George F. Steinhardt ◽

Nifang Niu ◽

Pankhuri Wanjari ◽

...

Keyword(s):

Next Generation Sequencing ◽

Clinical Care ◽

Clinical Samples ◽

Clinical Test ◽

Next Generation ◽

Worst Case ◽

Germline Variants ◽

Targeted Ngs ◽

Generation Sequencing ◽

Over Time

1581 Background: Next-generation sequencing (NGS) increasingly guides clinical care in hematological malignancies by identifying DNA mutations that change dynamically over time. Clinical samples contain variable numbers of malignant and non-malignant cells. So, careful interpretation is required to determine if a particular variant is somatic, germline, or clonal hematopoietic in origin. Methods: The University of Chicago uses a targeted NGS assay of ~1200 genes, reporting 150 as a clinical test. We aimed to identify individuals with hereditary predisposition by detecting persistent variants on sequential assays regardless of disease state. Results: 943 NGS assays from July 2017 – Feb. 2020 on 711 patients [ages 1 mo – 95 yrs, median 65 yrs] were included. 2,320 variants in 33 genes were identified with 144 patients having the same variant identified on more than one assay. Single nucleotide variants (SNVs) with variant allele frequency (VAF) ≥ 0.3 were prioritized. The first candidate gene identified with potential germline SNVs was CSF3R. 28 unique SNVs in CSF3R were found, 14 were confirmed as germline, 6 somatic, and 8 were unconfirmed due to lack of available tissue. At least 2 confirmed germline CSF3R variants were likely deleterious based on functional testing. Sequential SNVs were quantified using the coefficient of variation, characterizing each by change in VAF over time. Using a worst-case-scenario analysis, in which unconfirmed variants were not counted as germline, a computer algorithm was designed to identify potential germline variants (specificity 0.89, PPV 0.75). Via an iterative method, the algorithm compares new assays to a pool of previously reported tests, flagging patients with potential germline mutations so that biopsies may be studied in the lab, records reviewed, and referrals placed to genetic counselors. To date, 61 patients with 89 likely germline variants have been identified. Known hereditary hematological malignancy genes, such as ATM, ASXL1, CHEK2, DDX41, TSC1, and RUNX1, had the most variants identified. Limitations include the challenge in distinguishing variants that do not change over time, reliance on a targeted NGS panel, and normalizing VAF data prior to analysis. Conclusions: These data highlight the utility of NGS of bone marrow and peripheral blood samples to identify patients suspected of having germline DNA variants. In addition to identifying known predisposition syndromes, one may discover new inherited cancer syndromes and help guide clinical practice in real time.

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