A Quarterly Newsletter from GeneInsightIssue 6: December 2015
We are pleased to share the Winter 2015 edition of our newsletter, GeneInsights. In this edition, we feature a Q&A session with Neil Lindeman, M.D., from Brigham and Women’s Hospital Pathology and we highlight a somatic variant in exon 20 of the EGFR gene as part of our ongoing Featured Assessment series.
We hope you enjoy the latest issue of GeneInsights. Happy Winter!
Q and A Session with Neal Lindeman, M.D., about the new collaboration between GeneInsight and his pathology lab at Brigham and Women’s Hospital.
Dr. Neal Lindeman is the Director of the CLIA-approved molecular diagnostic laboratory for Brigham and Women’s Hospital (BWH), which serves BWH patients as well as patients at the Dana Farber/Brigham and Women’s Cancer Center (DF/BWCC) and Boston Children’s Hospital (CHB).
Tell me more about the existing genomics collaboration between Brigham and Women’s Hospital, Dana Farber/Brigham and Women’s Cancer Center and Boston Children’s Hospital?
The collaboration centers around a program called Profile, which is a joint program between Dana Farber/Brigham and Women’s Cancer Center and Boston Children’s Hospital to provide comprehensive genomic assessment of tumor samples for every cancer patient who comes through these hospitals. It is a great example of how different hospitals can successfully interact together around a centralized clinical program. The laboratory testing and interpretation is performed at the BWH CLIA laboratory, and the results are returned to our clinical colleagues at their respective hospitals. The laboratory and clinical teams then work together to figure out how to use the information to impact patient care.
Can you describe the collaboration that was just announced between your laboratory and GeneInsight? What type of content will be provided from this relationship?
GeneInsight was originally developed at the Laboratory for Molecular Medicine, a molecular diagnostic laboratory within Partners HealthCare Personalized Medicine center. There has been a long-standing relationship between LMM and Brigham and Women’s Hospital; it was originally conceived around constitutional genomic disorders and inherited diseases and we are now extending that collaboration into the cancer space. There are two main elements to this relationship. The first is the GeneInsight tool itself, which we will used to combine the sequence data that comes off the instrument with the knowledge that we have accumulated through the course of clinical practice. Additionally, we can use the various tools within GeneInsight to further our understanding of the clinical implications of variants identified via testing. The second element of this relationship is making the knowledge that we have accumulated, and will continue to accumulate, available to other GeneInsight users.
Why is it important for this type of data to be made available to GeneInsight users?
There are a lot of commercial knowledge bases available for purchase today. The difference between those commercially available knowledge bases and the one we have created in our laboratory is that our knowledge base is curated by 15 board certified molecular pathologists. We also work very closely with our molecular oncologists, which makes our knowledge base more clinically-focused and less straight biochemistry. I think GeneInsight’s somatic customers will benefit greatly from the interpretations we have gathered over time.
Why has Brigham and Women’s somatic tumor laboratory chosen to enter into this partnership with GeneInsight?
About two years ago we realized that the system we had built for ourselves wasn’t going to scale properly for the long term. While it worked to get us to where we are today, we realized that it wasn’t going to get us to where we are ultimately going. When we started to look around at different commercial solutions we realized that just about every commercial solution available didn’t recognize the difference between genomic testing for inherited diseases and genomic testing for somatic cancer. There are fundamental differences about the way this information is structured and the way this knowledge is utilized when comparing inherited disease and cancer genomics. We were committed to creating something not only better for us, but a better option for any cancer testing lab. Many germline-based software programs were not built with cancer in mind, which is critically important. The enhancements we will focus on will be done with cancer testing in mind.
What are some of the key challenges that pathologists face when choosing to set up or offer somatic testing?
Before we started offering testing we were really focused on the technology. What is the right instrument? What is the right platform? What are the right genes? How do we optimize the signal? As pathologists, we spend a lot of time worrying about the right technology in the course of single gene tests. In the end, this was less of a concern. Where we underestimated the challenge was on the backend - our ability to interpret and report on this massive amount of data. And people warned us about it, and now I will warn others: Don’t underestimate the challenge of determining the clinical significance of all these variants. Twenty million sequences come off the sequencer for each sample. After using computational tools and robust pipelines to resolve the data, you may still be left with 15-30 genetic variants on each case. Out of those variants, you may have heard of only 2 or 3 of them before. Interpreting the remaining variants requires going into the literature to better understand their implications. Tools like GeneInsight make that a lot easier. Storing that data is extremely important since the last thing you want to do after spending considerable time interpreting a variant is lose that information and have to do the variant assessment all over again.
How does this type of somatic tumor testing impact the care of a patient?
There are lots of different ways to treat cancer patients. If it is early and the cancer is localized then treatment is usually surgical; but for patients who have either progressed after an initial treatment or present later in the disease, the idea is that systemic therapy should be given. Traditional chemotherapy regiments rely on poisoning basic cellular processes like DNA replication. This type of therapy has high toxicity and somewhat limited efficacy. Somatic tumor testing enables the application of molecularly targeted therapies. This means understanding which genetic changes in a tumor are causing it to behave in a certain way and targeting treatment based on those changes. Instead of preventing all cells in the body from dividing, you can target treatment to the cause of the cancer, which leads to less toxicity. There are a couple of clinical applications where this type of treatment is really valuable and has become standard of care, such as giving an EGFR inhibitor to a lung cancer patient with an EGFR mutation. We believe that this same model is going to be extended across most kinds of cancers. The key to unlocking the power of this testing is to better understand the genetic changes in each type of tumor and to use that information to develop drugs.
Given the role of genomics, how is somatic cancer testing different today than it was 10 years ago? Can you speculate on how it may be different 10 years from now?
Ten years ago the EGFR mutations had just been discovered. The initial report was in 2004 and we were actually in the group that made that discovery. There was no next generation sequencing so the field was limited to one gene at a time or single gene tests. The analysis of the data was relatively straightforward. Ten years later the world has flipped upside down. We have scores of genes that are important in a wide variety of different tumors. We have targeted therapies for all kind of alterations that weren’t known 10 years ago. And we have the technical capability to look at not just a handful of genes a time, but the whole genome at once. There has also been a tremendous explosion in our knowledge and our ability to turn these results into medical action.
I suspect that 10 years from now there will be another technical leap and we will be able to rapidly analyze a whole genome. Whether it is 10 years or 20 years from now, this will happen. The world of RNA will be unraveled and we will have a better understanding of epigentics. I think there will also be a big focus on the non-coding regions of genes, which right now is largely ignored because we don’t quite know what to do with it.
Our Featured Assessment is intended to highlight the assessment of a specific gene or variant as part of an ongoing series included in the GeneInsights newsletter. This segment will review the process of assigning significance to a variant or gene in the clinical and/or research setting.
Variant: p.A763_Y764insFQEA (c.2291_2302 dup) in the EGFR gene
Clinical interpretation of a somatic variation:
Molecular testing in tumor cells aims to identify somatic variants that can potentially guide diagnostic, prognostic and therapeutic decisions for patient care. The Brigham and Women’s hospital pathology OncoPanel assay interrogates the exonic sequence of 300 cancer genes and 113 introns across 35 genes for rearrangement detection. Somatic variants identified by the OncoPanel testing undergo an assessment process, which interrogates 4 major topics of consideration:
- Gene function (What is the role of the gene?)
- Variant function (What is the impact of the variant on the gene function?)
- Biology (What is the biological significance of the gene in the patient’s cancer type?)
- Clinical (Is the evidence of clinical utility for therapy, diagnosis, or prognosis?)
The goal of the assessment is to classify the variants into one of 5 categories:
- Tier 1: Gold standard - a clinically actionable variant
- Tier 2: Potentially actionable variant
- Tier 3: Biologically significant variant (a driver mutation)
- Tier 4: Variant of Unknown Significance (ex. passenger variants, germline single nucleotide polymorphisms)
- Tier 5: Known benign single nucleotide polymorphisms (SNPs)
Current Clinical Classification: Tier 1
EGFR encodes a receptor tyrosine kinase with important functions in cell signaling and cancer development. EGFR mutations are recurrently seen in lung adenocarcinoma. The vast majority of EGFR variants in non small cell lung cancer are located in the tyrosine kinase domain (exons 18-21), most commonly in frame deletions in exon 19 and the p.L858R missense mutations in exon 21, and are associated with response to tyrosine kinase inhibitors such as gefitinib and erlotinib.1 Typically, exon 20 insertions (~10% of all EGFR mutations) are associated with lack of response to EGFR inhibitors. However, cell lines with EGFR p.A763_Y764insFQEA are sensitive to tyrosine kinase inhibition in vitro, and this variant has been associated with clinical response to EGFR inhibition in clinical case series.2-4 This evidence predicts that the patient’s cancer would be response to targeted therapy, and therefore the patient should be treated with an tyrosine kinase inhibitor rather than chemotherapy.
1. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014 Jul 31;511(7511):543-50.
2. Chen Z, Feng J, Saldivar JS, Gu D, Bockholt A, Sommer SS. EGFR somatic doublets in lung cancer are frequent and generally arise from a pair of driver mutations uncommonly seen as singlet mutations: one-third of doublets occur at five pairs of amino acids. Oncogene. 2008 Jul 17;27(31):4336-43.
3. Russo A, Franchina T, Ricciardi GR, Picone A, Ferraro G, Zanghì M, Toscano G, Giordano A, Adamo V. A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives. Oncotarget. 2015 Sep 29;6(29):26814-25.
4. Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, Huberman MS, Cohen DW, Nakayama S, Ishioka K, Yamaguchi N, Hanna M, Oxnard GR, Lathan CS, Moran T, Sequist LV, Chaft JE, Riely GJ, Arcila ME, Soo RA, Meyerson M, Eck MJ, Kobayashi SS, Costa DB. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med. 2013 Dec 18;5(216):216ra177.
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