Forum:Publications for individualized medicine in cancer by whole genome, exome or transcriptome sequencing

Question

[Obi Griffith]

This post lists papers that describe the use of high-throughput sequencing for precision medicine in cancer. Such papers should attempt the following: (1) Whole genome, exome and/or transcriptome (RNA) sequencing of (2) live patient tumor samples in an attempt to (3) guide clinical decision making for cancer? The omic events could provide diagnostic, prognostic or treatment response predictions. This approach is widely referred to as personalized medicine, individualized medicine, precision medicine, or precision oncology. There are many reviews describing this idea and many examples that make use of small targeted panels (one to dozens of molecular events). This post focused on proof-of-principle papers, describing the paradigm where researchers (or tumor genome boards) attempt to use omic (genome-wide) NGS data to alter or inform clinical care. It also includes larger gene panels that attempt to comprehensively sequence "relevant" cancer genes (e.g., MiSeq/Ion/Proton/NextSeq500 scale approaches). For example, Foundation Medicine provides a list using their targeted panel. Relevant studies can be N-of-1 case reports or overviews describing experiences with small to large cohorts.

A prototypical example was published by Jones et al in 2010 in which an oral adenocarcinoma was sequenced by whole genome and transcriptome sequencing and analysis done to suggest a particular target/pathway for therapy that might not otherwise have been considered in this disease type at that time. This is the earliest example that I am aware of but I would appreciate if anyone can point me to earlier examples.

UPDATE: I am collecting and organizing the responses here and also adding updates as I find them. They are listed chronologically and broken into prospective and retrospective categories (sometimes this distinction is fuzzy).

Prospective or pseudo-prospective studies:

• Jones et al. Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors. Genome Biology. 11:R82 (9 Aug 2010).
• Link et al. Identification of a Novel TP53 Cancer Susceptibility Mutation Through Whole-Genome Sequencing of a Patient With Therapy-Related AML. JAMA. 305(15):1568-1576 (20 Apr 2011).
• Welch et al. Use of Whole-Genome Sequencing to Diagnose a Cryptic Fusion Oncogene. JAMA. 305(15):1577-1584 (20 Apr 2011).
• Roychowdhury et al. Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study. Sci Transl Med. 3(111):111ra121 (30 Nov 2011).
• Borad et al. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLoS Genet. 10(2):e1004135. (13 Feb 2014).
• Van Allen et al. Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine. Nat Med. 20(6):682-8 (18 May 2014).
• Wagle et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med. 371(15):1426-33. (9 Oct 2014).
• Juric et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature.518(7538):240-4. (17 Nov 2014).
• Sekulic et al. Personalized treatment of Sézary syndrome by targeting a novel CTLA4:CD28 fusion. Mol Genet Genomic Med. 3(2):130-6. (27 Nov 2014).
• Robinson et al. Integrative clinical genomics of advanced prostate cancer. Cell. 161(5):1215-28 (21 May 2015).
• Ravegnini et al.. Personalized Medicine in Gastrointestinal Stromal Tumor (GIST): Clinical Implications of the Somatic and Germline DNA Analysis.Int J Mol Sci. 16(7):15592-608(9Jul2015).
• Beltran et al. Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response. JAMA.1(4):466-74 (July 2015)
• Griffith et al. Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B lymphoblastic leukemia. Exp Hematol.pii: S0301-472X(16)30115-1. (May 2016)
• Johanns et al. Immunogenomics of Hypermutated Glioblastoma: A Patient with Germline POLE Deficiency Treated with Checkpoint Blockade Immunotherapy. Cancer Discov. 6(11):1230-1236. (Sept 2016)

Retrospective studies:

• Iyer et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 338(6104):221 (23 Aug 2012).
• Papaemmanuil et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013 Nov 21;122(22):3616-27. (12 Sept 2013)
• Pritchard et al. Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens. J Mol Diagn. 16(1):56-67. (Jan 2014)
• Pennington et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 20(3):764-75. (1 Feb 2014).
• Turajlic et al. Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition. Ann Oncol. 25(5):959-67 (6 Feb 2014).
• Wagle et al. Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib. Cancer Discov. 4(5):546-53 (13 Mar 2014).
• Wilson et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. [Epub ahead of print] (20 July 2015).

Relevant reviews and special issues:

• Garraway and Lander. Lessons from the cancer genome. Cell. 153(1):17-37. (28 Mar 2013).
• Special Series: Precision Oncology. JCO. (20 May 2013).
• Shrager and Tenenbaum. Rapid learning for precision oncology. Nature Reviews Clinical Oncology. 11:109-118 (21 Jan 2014).
• Special Issue: The genomics of cancer progression and heterogeneity. Genome Biology. (7 Aug 2014).
• Gagan and Van Allen. Next-generation sequencing to guide cancer therapy. Genome Medicine. 7(1):80 (29 Jul 2015).

Relevant journals:

• Molecular Case Studies. A new journal (started accepting submissions in 2015) from CSHL Press that will present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal's purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches.
• NPJ Genomic Medicine. A new journal (started accepting submissions in 2015) from Nature Partner Journals Relevant that aims to publish high impact papers that encompass studies of individuals (including case reports), families, or populations. An emphasis is on coupling detailed phenotype and genome sequencing information, enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
• Human Genome Variation. A new journal (2014) from Nature Publishing Group that includes a new article type called Data Reports. Data Reports are short standardized reports about genomic variation and variability, especially in relation to disease. An accompanying database, The HGV Database, hosts data derived these Data Reports.
• Genome Medicine. One of the first journals (2009) to specifically focus on the application of genomics to medicine. Genome Medicine publishes peer-reviewed research articles, new methods, software tools, reviews and comment articles in all areas of medicine studied from a post-genomic perspective. Areas covered include, but are not limited to, disease genomics (including genome-wide association studies and sequencing-based studies), disease epigenomics, pathogen and microbiome genomics, immunogenomics, translational genomics, pharmacogenomics and personalized medicine, proteomics and metabolomics in medicine, systems medicine, and ethical, legal and social issues.
• Molecular Genetics and Genomic Medicine. Published since 2013 this journal does not have a specific case report article type but publishes on genetic analysis of rare and common disorders and has published articles highly relevant to personalized medicine in the past.
• Cancer Genetics. Published since 1979 this journal does not (yet) have a specific case report article type but publishes on cellular, genetic and molecular aspects of cancer, including cancer predisposition and clinical diagnostic applications. It is also the official journal of the Cancer Genomics Consortium
• JCO Precision Oncology. A new ASCO journal that publishes, among other article types, well-described and clinically informative small case series or n-of-1 reports, including exceptional response results.

[Malachi Griffith]

"Precision oncology" is another term that is used to describe this area. You mention that there are many reviews that describe this area. Perhaps we should also gather these here. Some of them may reference primary reports that meet your criteria.

[Malachi Griffith]

Robinson et al., 2015. Integrative clinical genomics of advanced prostate cancer. Cell. 2015 May 21;161(5):1215-28.

From the abstract:

Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals.

[Malachi Griffith]

Papaemmanuil et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013 Nov 21;122(22):3616-27.

From the abstract:

We sequenced 111 genes across 738 patients with MDS or closely related neoplasms ... analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.

[Malachi Griffith]

The "Applying the Knowledge: Diagnostics and Therapeutics" section of this review seems directly relevant to this issue and the rest of the article seems an excellent introductory resource.Garraway and Lander. Lessons from the cancer genome. Cell. 2013 Mar 28;153(1):17-37.

[Malachi Griffith]

Some papers that advocate the use of genetic markers for guiding therapy: "Histological and genetic markers for non-small-cell lung cancer: customizing treatment based on individual tumor biology." [20044377] and "Impact of genetic markers on treatment of non-small cell lung cancer" [23288638]

[Malachi Griffith]

A relevant review: Jeffrey Gagan and Eliezer M. Van Allen. Next-generation sequencing to guide cancer therapy. Genome Medicine. 2015.

[Malachi Griffith]

Another review, specific to GIST. Ravegnini et al. 2015. Personalized Medicine in Gastrointestinal Stromal Tumor (GIST): Clinical Implications of the Somatic and Germline DNA Analysis.

Answer 1

[Giovanni M Dall'Olio]

I would recommend you this article from the MassGenomics blog. It describes two studies in which whole genome sequencing has helped diagnosis and treatment of two patients affected by cancer. (link to study 1 - link to study 2)

Answer 2

[Mattias Aine]

I think there are few of these out there yet, and I'm not sure you could publish the study you linked to if it was done in Sweden. Patient consent would not be enough and you would need to obtain carte blanche approval from an ethical committee to play around like this (rare).

There are however 2 nice retrospective reports from clinical trials on Everolimus that use WGS/WES to identify mutations that probably conferred drug sensitivity. But I guess this is not what you are after.

• http://www.ncbi.nlm.nih.gov/pubmed/22923433
• http://www.ncbi.nlm.nih.gov/pubmed/24625776

Answer 3

[sheenams]

Here are two that come out of a lab at University of Washington Medical Center:

• Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens
• Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas

[DG]

I was going to add as a reply that as well as Exome, Genome, and Transcriptome the original poster should also consider NGS-based panel sequencing, which we now have covered with the WashU paper you linked here. This sort of work is somewhat smaller in scope but is no actually being implemented into routine clinical care all over the place.

[Obi Griffith]

Yeah. I purposely excluded these from my original question because I was really interested in what has been done at the *omic level and I suspect that there will be many, many examples once we start considering single gene or targeted panels. I'm certainly interested in such studies though.

[DG]

When you are dealing with MiSeq/Ion proton/NextSeq 500 scale panels I think you are still well into 'omics territory versus single-gene tests and "panels" done via Sanger Sequencing, etc. Whole Exome Sequencing is, for all intents and purposes, merely the largest available targeted panel on the market. Most of the TruSeq type panels are still a considerable number of genes (all exons), just restricted to genes with actionable mutations for the most part. The constitutional disorder panels TruSight inherited disease is 448 genes.

[Obi Griffith]

Very good points. I'll edit the question to include such panels. If we get flooded with examples, maybe you can help me organize them. ;-)

Answer 4

[Charles Warden]

Here is an example of a pilot study where sequencing tumor board reviewed cases (DNA-Seq + RNA-Seq) for 4 patients:

http://stm.sciencemag.org/content/3/111/111ra121.full

Answer 5

[mikhail.shugay]

How about this report? Its not a tumor study, but something that could become a "book" example.

Elizabeth A. Worthey et al. Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 2011:13(3):255-262

[Obi Griffith]

Sorry. I should have been more clear in my original post. I am looking for examples specifically related to cancer. Other genetic/hereditary/childhood diseases are a whole other topic and perhaps we could start a separate post to organize those?

Answer 6

[candyswift90s]

I would love to recommend Dr. Elaine Mardis' DNA Sequencing Lays Foundation for Personalized Cancer Treatment and a series related sources by Duke Center for Personalized Precision Medicine, also Should Babies Have Their Genes Sequenced for Early Recognition of Diseases.

[Obi Griffith]

Thanks! I'm looking mainly for primary research papers and reviews in scientific journals. But, popular science articles like these are also very helpful.

Answer 7

[Steven Lakin]

The ClinSeq project at the NIH, which I believe is headed by Dr. Leslie Biesecker, is of relevance to your question. As far as I know of, it is the largest-scale use of exome screening for clinical decision making in the US currently. Papers on cancer and other diseases come out of their group every month, and a simple search on Biesecker's name will bring them up.