Healthcare professionals are key stakeholders in the clinical delivery of genome sequencingbased services. Paired tumornormal tn wholegenome sequencing wgs or tn wholeexome sequencing wes have emerged as ideal methods for the discovery of somatic mutations. An exploratory ethnographic study of issues and concerns with whole genome sequencing. How to apply key study design principles to next generation sequencing ngs can be unclear and is sometimes overlooked by researchers who are new to this technology. These attributes support sequencing of complex genomes and comprehensive characterization of the widest range of structural variants.
The burgundy, shaded boxes highlight the second substudy, which is the focus of this report. However, cancer genome sequencing will eventually emerge as a routine tool to dissect the cancer genomes especially with the arrival of third generation sequencing technologies. Although previous studies based on candidate gene approaches have identified important common somatic mutations in mpm, these studies have focused on small sets of genes and have provided a limited view of the genetic alterations underlying this. Precision medicine integrating wholegenome sequencing.
Genome sequencing of human cancer tissues full text view. Objectives genome sequencing is poised to be incorporated into clinical care for diagnoses of rare diseases and some cancers in many parts of the world. Jun 28, 2018 to test the analytic implications of a study design that uses its resources solely for the sequencing of cases and collects controls from an external source, we merged genotypes from the als cases. The currently technologies used include second generation and third generation platforms. Listing a study does not mean it has been evaluated by the u. Apr 07, 2014 genome sequencing of human cancer tissues the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Table 1 examples of clinically relevant actionable mutations. The generation of such data will, thanks to technical advances, soon become commonplace. These studies will provide us with a detailed and comprehensive perspective on how individual cancers. The yellow boxes highlight that singlepatient studies are wellsuited for personalized.
Background little is known about knowledge of, and attitudes towards, genome sequencing gs among individuals with a personal history of cancer who decide to undergo gs. Four study design principles for genetic investigations. More than 12 % of women will be diagnosed with breast cancer in their lifetime. Yielding a series of dna fragments whose sizes can be measured by electrophoresis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genomewide diseaseassociated genes in adults with deep phenotyping has not been reported. These changes can be inherited, but most arise randomly during a. The genetics of breast cancer risk in the postgenome era. The discovery of brca1 and brca2 over 20 years ago remains the.
Choosing a path along these boxes, which are connected by arrows, represents a possible cancer. Our aim was to explore views of healthcare professionals with experience of offering genome sequencing via the 100 000 genomes project. Healthcare professionals are key stakeholders in the clinical delivery of genome sequencing based services. Webinars brp dccpsncinih national cancer institute. Traditional gene sequencing approaches in clinical oncology. Traditional dna sequencing for cancer patient management table 2 was initially focused on the detection of cancer predisposition in the patients germline. Clinical analysis of whole genome sequencing in cancer. An exploratory ethnographic study of issues and concerns. We evaluate current stateoftheart sequencing and analytic techniques and offer a dataset that will serve as a valuable resource for developing the. Tumor dna sequencing can identify unique dna changes that could help doctors determine the optimal cancer treatment for a patient. Participants will have choices about what kinds of results from whole genome sequencing they wish to learn.
Using dynamic work design to help cure cancer and other diseases. Cancer genomesequencing study design ccsb stanford. Choosing a path along these boxes, which are connected by arrows, represents a possible cancer genomesequencing study design. Preapplication webinars for participant engagement and cancer genome sequencing pecgs. However, most participants in this study can expect to undergo whole genome sequencing, which is a technique to study all of a person s genes. Our aim was to explore views of healthcare professionals with experience of offering genome. Using dynamic work design to help cure cancer and other. This qualitative study aimed to investigate baseline knowledge and attitudes among individuals previously diagnosed with a cancer of likely genetic origin who have consented to gs. Cancer patients views and understanding of genome sequencing. Study design designing a research study is not a simple task. To explore clinical value of wgs, we sequenced 254 triple negative breast cancers tnbc with associated treatment and outcome data collected between 20102015 via the populationbased sweden cancerome analysis networkbreast scanb project. Genome sequencing in solid tumors provides several potential challenges, including the fact that any tumor section used for genomic dna isolation will include normal cells such as stromal cells, blood vessels and immune cells, all of which contribute a normal genomic dna signature to that provided by the tumor cells. Development and clinical application of an integrative. A broad catalogue of genetic mutations enable data from wholegenome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically predicted.
A randomized phase ii study of the mek1mek2 inhibitor trametinib gsk1120212 compared with docetaxel in krasmutant advanced nonsmallcell lung cancer nsclc. This joint effort between the national cancer institute and the national human genome research institute began in 2006, bringing together researchers from diverse disciplines and multiple institutions. Cancer genome sequencing an overview sciencedirect topics. Recent advances have made the process of sequencing cancer genomes far less expensive and much more efficient, which has led to genome sequencing being increasingly utilized to study nearly all types of malignancies, and gastrointestinal cancers are no exception. Wholegenome sequencing can successfully identify cancer. In this study, to identify genetic variants with greater risk of diild, we carried out whole genome sequencing wgs of germline dna samples from 26 patients who developed diild, and conducted a casecontrol association study between these 26 cases. Sep 23, 2015 by sequencing a tumor to exceptionally high depth and breadth using multiple platforms, we demonstrate the inability of standard 30x50x wgs sequencing to capture both lowfrequency variants and clonal complexity. This is the first study that has used whole genome sequencing to evaluate a.
The number of true driver gene mutations is less than 200550, or less than % of all human genes based on bert vogelsteins and michael strattons estimations. T en years ago, the idea that all of the genes altered in cancer could be identified at basepair resolution would have seemed like science fiction. Four study design principles for genetic investigations using. Second generation technology platforms include solid sequencing by abi, pyrosequencing by roche and bridge amplification sequencing technology by illumina. The cancer genome atlas program national cancer institute. Implications of using whole genome sequencing to test. These systematic studies of these cancer genome data have reveled. Request pdf cancer genomesequencing study design discoveries from cancer genome sequencing have the potential to translate into advances in. As a significant number of proofofconcept studies have been published, it is important to analyze now the likely implications of these. Elsi challenges in the latter are many, particularly with reference to the data sets generated and how they will be used for patient care. Second generation technology platforms include solid sequencing by abi, pyro sequencing by roche and bridge amplification sequencing technology by illumina. Genome sequencing has established clinical utility for rare disease diagnosis.
While there may have been some validity to this view a decade or more ago, an emerging framework known as dynamic work design now plays an increasingly central role in understanding the genetic basis of a variety of diseases, ranging from cancer, to type ii. We analysed germline genomesequencing and exomesequencing data appendix pp 89 from 1022 patients with medulloblastoma, of whom 673 were in the retrospective discovery cohort and 349 were in the prospective clinical study cohort figure 1a, appendix p 3. Cancer is a genetic disease that is, it is caused by changes in dna that control the way cells function, especially how they grow and divide. Patients were either selfreferred or physicianreferred. Although previous studies based on candidate gene approaches have identified important common somatic mutations in mpm, these studies have focused on small sets of genes and have provided a limited view of the genetic alterations underlying this disease. Dec 23, 2014 whole genome sequencing can be used to identify patients risk for hereditary cancer, researchers have demonstrated. Breast cancer genome sequencing department of molecular. This is the first study that has used wholegenome sequencing to evaluate a. Applied to cancer, the availability of cancer genome sequences permits realtime decisionmaking with the potential to affect diagnosis, prognosis, and treatment, and has opened the door. Participant engagement and cancer genome sequencing pe. The first report of cancer genome sequencing appeared in 2006. New dna sequencing platforms have revolutionized human genome sequencing.
Some participants may be asked to take part in a telephone interview andor a webbased survey. Cancers free fulltext cancer genome sequencing and its. A million cancer genome warehouse uc berkeley eecs. This approach could be integrated into routine diagnostic workflows, phasing out phenotypic drugsusceptibility testing while reporting drug resistance early. The decision to test for high risk breast cancer gene mutations is traditionally based on risk scores derived from age, family and personal cancer history. Several u2c research centers to be supported under this foa. The sanger dna sequencing method uses dideoxy nucleotides to terminate dna synthesis. The classical study design for a cancer genome project is to sequence the bulk. Whole genome medical sequencing for genome discovery full. Approaches for detecting somatic mutations 4 targeted sequencing solutions for somatic mutation detection 4 exome sequencing 4 focused sequencing panels 4 custom targeted sequencing 4 wholegenome sequencing solutions 4. A subsequent follow up was published in 2007 where the same group added just over 5,000 more genes and almost 8,000 transcript species to complete the exomes of 11 breast and colorectal tumors. In this study, to identify genetic variants with greater risk of diild, we carried out whole genome sequencing wgs of germline dna samples from 26 patients who developed diild, and conducted a casecontrol association study. Pdf recent explosive advances in nextgeneration sequencing technology and.
Next generation sequencing technologies such as whole genome sequencing wgs make wider population testing more feasible. In the tree layout induced by the lifting scheme, the position of a coefficient equals that of. One u24 coordinating center to be supported under companion rfaca19046. Cancer whole genome sequencing wgs is now feasible, with thousands of matched tumornormal pairs successfully sequenced to date, revealing novel biological insights 24. Request pdf cancer genomesequencing study design discoveries from cancer genome sequencing have the potential to translate into advances in cancer prevention, diagnostics, prognostics.
With the publishing of the first complete whole genome of a human cancer and its paired normal, we have passed a key milestone in the cancer genome sequencing strategy. Although there have been tremendous advances in elucidating genetic risk factors underlying both familial and sporadic breast cancer, much of the genetic contribution to breast cancer etiology remains unknown. A proper study design in ngs studies can be achieved with awareness of factors that can influence. Whole genome sequencing an overview sciencedirect topics. Specifically, this network falls under a scientific priority designated by the blue ribbon panel brp as recommendation a establish a network for direct patient engagement. Cancers free fulltext cancer genome sequencing and. The broad clinical research sequencing platform crsp is a clinical laboratory accredited by the college of american pathogists cap, licensed by the state of massachusetts and registered with the centers for medicare and medicaid services to provide testing under the clia regulations. In this study,023 genes were sequenced in 11 breast and 11 colorectal tumors. Integrating nextgeneration sequencing into clinical oncology. Whole genome sequencing wgs brings comprehensive insights to cancer genome interpretation. Arrows indicate examples of the various types of somatic. Genomic sequencing illumina sequencing offers an unparalleled combination of read lengths, read depth, and pairedend insert size ranges. Design and cost to build and operate a million cancer genome warehouse.
Wholegenome sequencing for prediction of mycobacterium. Whole cancer genome sequencing by nextgeneration methods. The participant engagement and cancer genome sequencing pecgs network is part of the cancer moonshot. Proper study design is crucial for obtaining meaningful results and reaching correct conclusions in scientific investigations. The cancer genome sequencing project has confirmed most of the previously known cancer genes as driver mutations. Nextgeneration dna sequencing technology means that researchers can now study the complete genome of an individual patients cancer tumour much faster. By sequencing a tumor to exceptionally high depth and breadth using multiple platforms, we demonstrate the inability of standard 30x50x wgs sequencing to capture both lowfrequency variants and clonal complexity. Dna synthesis reactions in four separate tubes radioactive datp is also included in all the tubes so the dna products will be radioactive. Participant engagement and cancer genome sequencing pecgs. Key aspects of secondgeneration cancer genomesequencing study design include full sequencing of the matched normal genome of the cancer type, at least 30fold redundant sequence coverage for the. The global cancer genome sequencing market is segmented on the basis of technology and geography.
Whole genome sequencing is a key driver for many medical research projects in cancer and complex genetic disorders. Clinical research sequencing clinical trial sequencing. Realworld evidence in support of precision medicine. Tumor dna sequencing in cancer treatment national cancer. Genetic counselling and testing should be used as a standardofcare procedure in patients with mbwnt and mbshh because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. A broad catalogue of genetic mutations enable data from whole genome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically predicted. A proper study design in ngs studies can be achieved with. Another front is now opening with whole genome sequencing for direct patient care. Study design a qualitative approach using onetoone interviews for. The national cancer institute nci intends to support the participant engagement and cancer genome sequencing pecgs network, which will include.
These systematic studies of these cancer genome data have reveled scores of new. This flow diagram is intended to highlight the diversity of secondgeneration cancer genome sequencing study designs. Wholegenome sequencing can be used to identify patients risk for hereditary cancer, researchers have demonstrated. Druginduced interstitial lung disease diild is a serious side effect of chemotherapy in cancer patients with an extremely high mortality rate. Review cancer genome landscapes stanford university. An exploratory ethnographic study of issues and concerns with. They reside, by definition, in the subset of genes known as. Initiative that is intended to accelerate cancer research.
To test the analytic implications of a study design that uses its resources solely for the sequencing of cases and collects controls from an external source, we merged genotypes from the als cases. Wholegenomesequencing of triple negative breast cancers. Whole genome sequencing analysis for cancer genomics and. Recruitment was conducted through nhs genomic medicine centres gmcs located across the uk. However, a recent study interrogating a variety of cancer cell lines using an integrative framework for detecting svs, consisting essentially of whole genome sequencing, optical genome mapping and. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches forreducingcancermorbidity and mortality. Implementing personalized cancer genomics in clinical trials. Whole exome sequencing is not designed to capture the 16kb mito. Pdf whole genome sequencing analysis for cancer genomics. Oct 12, 2017 proper study design is crucial for obtaining meaningful results and reaching correct conclusions in scientific investigations. Setting four national health service hospitals in london. Whole genome medical sequencing for genome discovery. As a significant number of proofofconcept studies have been published, it is important to analyze. Yet, for wgs to become adopted clinically, systematic demonstrations of utility in wellcharacterised populationbased studies and validation in clinical trials are required.
Apr 18, 20 key aspects of secondgeneration cancer genome sequencing study design include full sequencing of the matched normal genome of the cancer type, at least 30fold redundant sequence coverage for the. Figure 1 cancer genome secondgenerationsequencing study designs. Open access original research delivering genome sequencing. Figure 1 cancer genome secondgeneration sequencing study designs. Whole genome sequencing to identify predictive markers for. The cancer genome atlas tcga, a landmark cancer genomics program, molecularly characterized over 20,000 primary cancer and matched normal samples spanning 33 cancer types.
Wholegenomesequencing of triple negative breast cancers in. In the uks 100,000 genomes project, mutations in 16 genes including. Study design choices are in yellow, green and blue boxes. Just as the key elements and determinants of outcomes of war are fixed even before it is fought i. Malignant pleural mesothelioma mpm is an aggressive neoplasm associated with asbestos exposure. Mar 16, 2010 whole genome medical sequencing for genome discovery the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. They can study which mutations make cells resistant to drug therapy, and are learning which drugs are the most effective for that patients cancer. Successful studies need to address two important dimen.
We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour. To study gene expression in a specific tissue, organ or tumor to study human variation to study how humans relate to other organisms to find correlations how genome information relates to development of cancer, susceptibility to certain diseases and drug metabolism pharmacogenomics. Clinical trial design is dictated by the type of biomarker being testing or developed. Applied to cancer, the availability of cancer genome sequences permits realtime decisionmaking with the potential to affect diagnosis, prognosis, and. This flow diagram is intended to highlight the diversity of secondgeneration cancer genomesequencing study designs. Cancer panel analysis can be performed on as little as 10 ng of dna, but work from the 100,000 genomes project and tracerx study tracking nonsmall cell lung cancer evolution through therapy has shown that whole genome sequencing wgs or whole exome sequencing wes, respectively, requires 12. We evaluate current stateoftheart sequencing and analytic techniques and offer a dataset that will serve as a valuable resource for developing the next generation of genomic. Whole exome sequencing is not designed to capture the 16. Genome sequencing of human cancer tissues the safety and scientific validity of this study is the responsibility of the study sponsor and investigators.1458 297 736 914 646 918 1501 1476 398 800 1240 1441 1441 99 1195 285 1018 352 1077 1360 969 1528 970 859 1626 731 143 950 919 313 665 556 550 438 1073 1158 735 632 1304 587 39 1269