Posts Tagged ‘Nature (journal)’

Eppendorf Award for Young European Investigators

Curator: Larry H. Bernstein, MD, FCAP

Series E. 2; 8.11

The independent Eppendorf Award Jury chaired by Prof. Reinhard Jahn selected Dr. Thomas Wollert (Research Group Leader at the Max Planck Institute of Biochemistry in Martinsried, Germany) as the 2015 winner of the Eppendorf Award for Young European Investigators.

Thomas receives the €20,000 prize for his groundbreaking work in reconstituting complex intracellular membrane events in the test tube using artificial membranes and purified components. His experiments have paved the way for understanding key steps in autophagy, a fundamental process required for the clearance of damaged cell parts in all eukaryotic cells.

Listen to a podcast with Thomas Wollert and learn more about his work, and read excerpts from the interview in a Q&A feature article.

Presented in partnership with Nature The Eppendorf Award for Young European Investigators was established in 1995 to recognize outstanding work in biomedical science. It also provides the opportunity for European researchers to showcase their work and communicate their research to a scientific audience. Nature is pleased to partner with Eppendorf to promote the award and celebrate the winner’s work in print and online. Nature’s Julie Gould talks to the 2015 winner Thomas Wollert (Max Planck Institute of Biochemistry, Germany) about his work — which looks at the complex molecular process that cells use to remove their waste — and how it felt to win the award.
To listen to the full interview, visit: go.nature.com/cszfl1

About the Award Thomas Wollert is the twentieth recipient of the Eppendorf Award for Young European Investigators, which recognizes talented young individuals working in the field of biomedical research in Europe. The Eppendorf Award is presented in partnership with Nature. The winner is selected by an independent jury of scientists under the chairmanship of Reinhard Jahn, Director at the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany. Nature and Eppendorf do not influence the selection. For more information see: eppendorf.com/award


Julie Gould: Congratulations on being awarded this year’s prize. How did it feel when you found out that you had won?

Thomas Wollert: That came as a big surprise to me. It’s a great honor and it’s of course a major recognition of our work; not only my work, but also the work that my laboratory has done over the past five years. So this is very important to me.

JG: Tell us a little bit about the research you are working on.

TW: The cells in our bodies recycle almost everything — they do not waste much. The question in the past has been: how is this achieved? The process needs to be highly regulated. You don’t want to degrade something that you still need, but you do want to get rid of dangerous material that accumulates in the cell. We became interested in one pathway that is involved in transporting this sort of trash, or unwanted material, to recycling stations in the cell. We are particularly interested in how the molecular mechanism is driven.

JG: What sort of molecular trash are we talking about?

TW: Everything that needs to be degraded in a cell has to end up at a recycling station, one of which is called the lysosome. What ends up there is chemically degraded, and the building blocks are reused by the cell to build material. Proteins that become aggregated, big material or composite structures, and everything else in the cell cytoplasm (such as mitochondria) need to be transported to the lysosome. There is a specialized pathway to do that — this has been called autophagy for self-digestion. During autophagy, crescent-shaped membranes are formed, which expand and capture cytoplasmic components. These structures become autophagosomes, which are like entire organelles and are the containers that transport the trash to the lysosomes for degradation.

JG: How do these autophagosomes form in the cell?

TW: In yeast the system is fairly well understood. Small membrane vesicles are recruited and fuse to form the crescents haped autophagic precursor membrane. This membrane then surrounds and captures material, and, after sealing, the full autophagosome is formed and finally fuses with the lysosome. There are 40 different proteins in yeast that have been identified as those that have an essential function in autophagy — they are specific to the autophagy pathway. The question was, what are they doing with the membrane and what is their molecular function? And that was the major interest of my lab.

JG: What did you discover? TW:

We analysed two important steps in autophagy. The first is initiation and the second is expansion.

An autophagosome is built from small vesicles, which come together and fuse. This process is driven by one big complex called the Atg1-kinase complex. This complex is known to be involved in recruiting the donor vesicles that create the autophagosome. We recently published work on the expansion step. This is an interesting step that involves a small ubiquitin-like molecule, Atg8. The unique feature of this particular molecule is that it becomes covalently attached to autophagic precursor membranes. Many Atg8 molecules get conjugated to these membranes, so the question has been: why is there so much Atg8 on the membrane and what is its job there? To answer this, we analyzed the proteins independently of the complex cellular environment. We produced recombinant molecular machines that drive the formation of autophagosomes and analyzed their function in the test tube. The test-tube components include the protein subunits of these molecular machines and model membranes that serve as the platform for proteins to assemble into large complexes. What we realized — and what came as a surprise to us — was that the molecular machine that drives conjugation of Atg8 stays with Atg8 at the membrane, rather than leaving after conjugation. We predicted that something needs to happen, some bigger structure needs to form on the membrane to keep the conjugation machine there. Using high-resolution approaches, we observed that Atg8 forms together with its conjugation machine, a protein shell on membranes. It’s like a meshwork that sits on top of the membrane and stabilizes the forming autophagosome. Presumably.

JG: Why presumably?

TW: Because the details of how this expansion is driven by the scaffold is something that we are investigating.

JG: Will you be following this up over the next few years?

TW: Yes. This is an interesting question, but not an easy one to answer. We need to understand the direct relationship of how this really works in vivo.

JG: How does the autophagosome capture material from cells?

TW: The selection of cargo comes in two flavours. Under normal conditions, when the cell is happy, it only wants to degrade unwanted material or something damaged. It chooses these materials quite selectively. For example, it might only want to degrade dysfunctional mitochondria, the cell’s power plants. The membrane then wraps tightly around these structures. However, if a cell becomes stressed or starved, it can use autophagy to degrade anything that’s around. That means bulk cytoplasm without any selectivity. Imagine a big happy cell that is starved and goes on a low-value nutritional diet. The cell will shrink, but it survives. If nutritional conditions improve, it can grow again.

JG: What big impacts will this research have?

TW: The research focus at the moment is neurodegenerative disease and cancer. In certain neurodegenerative diseases, some proteins can accumulate in cells. There are a couple of diseases, such as Huntington’s disease, in which particular genetic modifications lead to alterations in proteins, which then tend to aggregate. In other diseases, such as Alzheimer’s disease, proteins also accumulate, and those protein oligomers, or aggregates, are toxic to the cell. In some neurodegenerative diseases, it has been observed that increasing autophagy is beneficial for cells, and thus patients, because increasing autophagy increases the removal of the toxic material. Neurodegenerative disease is usually not observed until the later stages, when this material has already accumulated. If you could remove this harmful material from cells, you could maybe rescue some neurons from dying. This is one application where you would really want to increase autophagy. In cancer, it has already been shown that combining chemotherapy with an inhibitor of autophagy is beneficial because autophagy just counteracts chemotherapy.

JG: What is it about this field that you find so interesting?

TW: What excites me the most is that you can use a minimal system, combining a few components and then trying to get them to work in a test tube. Our major goal, and our holy grail in this research, is to have the full autophagy pathway in a test tube, combining the autophagy components, step by step, to produce an autophagosome from small membranes, and to have some material wrapped in the autophagosome.

Award Winners

2015 Winner

In 2015 Eppendorf AG is presenting the Eppendorf Award for Young European Investigators for the 20th time. The independent Eppendorf Award Jury chaired by Prof. Reinhard Jahn selected Dr. Thomas Wollert (Research Group Leader Molecular Membrane and Organelle Biology at the Max Planck Institute of Biochemistry in Martinsried, Germany) as the 2015 winner of the Eppendorf Award for Young European Investigators. Thomas Wollert, born 1979, receives the €20,000 prize for his groundbreaking work in reconstituting complex intracellular membrane events in the test tube using artificial membranes and purified components. Thomas talks about his work in this Award Feature

The official prize ceremony took place at the EMBL Advanced Training Centre in Heidelberg, Germany, on June 25, 2015.

To hear an interview with prize winner Thomas, listen here.

2014 Winner

The independent Eppendorf Award Jury chaired by Prof. Reinhard Jahn selected Madeline Lancaster, Ph.D., of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria, as the 2014 winner of the Eppendorf Award for Young European Investigators. Madeline Lancaster, born 1982, receives the € 15,000 research prize for her work showing that complex neuronal tissues resembling early states of fetal human brain can be created in vitro from pluripotent stem cells. Madeline talks about her work in this Award Feature

To hear an interview with prize winner Madeline, listen here or watch the video from the award ceremony.

2013 Winner

The independent Eppendorf Award Jury chaired by Prof. Reinhard Jahn selected Ben Lehner, Ph.D., of the Centre de Regulació Genòmica, Barcelona, Spain, as the 2013 winner of the Eppendorf Award for Young European Investigators. Ben, born 1978, receives the € 15,000 research prize for his discoveries concerning the fundamental question why mutations in the genome result in variable phenotypes. Ben talks about his work in this Award Feature.

To hear an interview with prize winner Ben, listen here or watch the video from the award ceremony.

2012 Winner

The 2012 prize was awarded to Elizabeth Murchison, Ph.D. (Wellcome Trust Sanger Institute, Cambridge, United Kingdom) for her discoveries concerning a deadly cancer that is spreading among the endemic population of Tasmanian devils in Tasmania and threatening the survival of the species. Elizabeth talks about her work in this Award Feature.

To hear an interview with prize winner Elizabeth, listen here or watch the video from the award ceremony in Heidelberg.

2011 Winner

The 2011 Eppendorf Young European Investigator Award goes to Suzan Rooijakkers for her contribution to discovering how Staphylococcus aureus evades immune attack. Suzan talks about her work on this Award Feature.

To hear an interview with prize winner Suzan, listen here.

Listen here to the podcast from the award ceremony in Heidelberg.

2009 Winner

In 2009 the prize was awarded to Óscar Fernández-Capetillo, head of the Genomic Instability Group at the Spanish National Cancer Center. Read the highlights of his interview with Nature in this Award Feature.

Listen here to learn about the impact the Award had on his career.

2008 Winner

The 2008 prize was awarded to Dr. Simon Boulton of the London Research Institute. Read the highlights of his interview with Nature in this Award Feature.

Listen here to learn about the impact the Award had on his career.

2007 Winner

Dr Mónica Bettencourt-Dias is the 2007 winner of the Eppendorf Young European Investigator Award. Monica gives a personal account of her research and the Eppendorf Award in an Award Feature forNature.

Listen here to learn more about the impact the award had on her career.

2006 Winner

Dr Luca Scorrano won the award in 2006. Read more about his research on the Eppendorf Young Investigator website.

Listen here to learn more about Dr Scorrano’s work and the impact the award has had on his career.

http://www.nature.com/multimedia/podcast/eppendorf/eppendorf-podcast-15.mp3   2015

https://www.youtube.com/watch?feature=player_embedded&v=N3SXLURTI_w   2014

https://www.youtube.com/watch?feature=player_embedded&v=ntU_Ve3x6oI     2013

https://www.youtube.com/watch?feature=player_embedded&v=E2mhX9ccEHs    2012





Read Full Post »

Targeting Untargetable Proto-Oncogenes

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

The following is a summary of a just published cancer research paper that describes the discovery of targetting proteins previously thought to be untargetable.

Getting Around “Undruggable” Proto-Oncogenes

Patricia Fitzpatrick Dimond, Ph.D.
The Notch1 protein and BET bromodomains are among the targets researchers are investigating. [© iQoncept – Fotolia.com]
    While multiple human cancers are associated with oncogene amplification,
  • epigenetic targets causing amplification such as transcription factors were once considered “undruggable,” or
  • unlikely to be modulated with a small molecule drug.
Generally, these proteins lack surface involutions suitable for high-affinity binding by small molecules. But by thinking outside the “loop” or the usual structures required for drug targets, investigators have been making headway in targeting the formerly untargetable.
    Multiple human cancers are associated with c-Myc gene amplification including lung carcinoma breast carcinoma, colon carcinoma, and neuroblastoma. The protogene also plays a key role in cell cycle regulation, metabolism, apoptosis, differentiation, cell adhesion, as well as in tumorigenesis, and participates in regulating hematopoietic homeostasis. Its gene product functions as a transcription regulator, part of
an extensive network of interacting factors regulating the expression, it has been estimated, of more than 15 percent of all human genes.
    While Myc oncogene family members, for example, act as key drivers in human cancers,
  • they have been considered undruggable as
  • they encode transcription factors and carry out essential functions in proliferative tissues,
  • suggesting that their inhibition could cause severe side effects.
And from a chemist’s point of view, these proteins’ surfaces are not amenable to binding drugs. In an online dialog posted on the NCI’s website in October of 2010, an investigator noted, “We don’t know how to interfere with these factors or their activities in clinical settings because, in general,
  • we lack the means to inhibit proteins that are not enzymes.”
    But by preventing key protein-protein interactions that enable the actions of these transcriptional drivers, scientists are drugging the formerly undruggable.

To Drug the Undruggable Target

    One such approach published  in Nature in 2009 by a team of Harvard scientists who was reported that they had successfully targeted a “master” protein, Notch1, which had been considered “untouchable” by conventional drugs. The protein is a
  • key transcription factor regulating genes involved in cell growth and survival but
  • like other transcription factors has proven an elusive drug target due to its structure.
The scientists said they had designed
  • a synthetic, cell-permeable alpha-helical peptide, SAHM1,
  • which could target a critical protein-protein interface in the notch transactivation complex.
The drug molecule enters cells and interferes with a protein-protein interaction essential for the transmission of cell growth signals via the Notch pathway.
    The researchers tested the drug using cells from patients with T-cell acute lymphoblastic leukemia (T-ALL) and a mouse model of the disease. The Notch1 gene is mutated in half of patients with T-ALL and
  • produces an inappropriately active Notch1 protein.
Activated Notch signaling has been seen in several other cancers including lung, ovarian, and pancreatic cancer, and melanoma.
    “We’ve drugged a so-called undruggable target,” said Gregory L. Verdine, Ph.D., Erving professor of chemistry at Harvard University. “This study validates the notion that you can target a transcription factor
  • by choosing a new class of molecules, namely stapled peptides.”

He added that, because the molecular logic of these proteins is similar to Notch1’s,

  • this strategy might work for other transcription factors as well.

Targeting BET

    Another emerging approach to drugging the undruggable is to target the bromo and extra C-terminal domain (BET) family of bromodomains that are
  • involved in binding epigenetic “marks” on histone proteins.
Four members of this 47-protein family interact with chromatin including histone acetylases and nucleosome remodeling complexes. Bromodomain proteins act as chromatin “readers” to recruit chromatin-regulating enzymes, including
  • “writers” and “erasers” of histone modification, to target promoters and to regulate gene expression.
As mentioned in a previous GEN article, epigenetic control systems generally involve three types of proteins:
  1. “writers”,   Writers attach chemical marks, such as methyl groups (to DNA) or acetyl groups (to the histone proteins that DNA wraps around)
  2. “readers”,  Readers bind to these marks, thereby influencing gene expression
  3. “erasers.”  Erasers remove the marks
    While investigators have considered that the precise function of the so-called BET bromodomain remains incompletely defined,
  • proteins containing this domain have become another epigenetic target for drug development companies.
  • these domains may allow researchers a way to get at oncogenic targets that were once thought undruggable including the proto-oncogene Myc.
    Small molecule inhibition of BET protein bromodomains also selectively suppresses other genes such as Bcl-2 that have important roles in cancer, as well as some NF-κB-dependent genes that have roles in both cancer and inflammation. Small molecule inhibition of BET bromodomains
  • leads to selective killing of tumor cells across a range of hematologic malignancies and in subsets of solid tumors.
In particular, the bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt’s lymphoma, human nuclear protein in testis (NUT) midline carcinoma, colon cancer, and inflammatory disease;
  • its loss is a prognostic signature for metastatic breast cancer.
    BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus (HPV). Despite its role in a broad range of biological processes, the precise molecular mechanism of BRD4 function, until very recently, remained unknown.
    In 2010, investigators reported in Nature that they had identified a cell-permeable small molecule that bound competitively to bromodomains, or acetyl-lysine recognition motifs. Competitive binding by the small molecule JQ1, the investigators reported,
  • displaces the BRD4 fusion oncoprotein from chromatin,
  • prompting squamous differentiation and
  • specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models.
    The authors say that these data established proof-of-concept for targeting protein–protein interactions of epigenetic readers, and could provide a versatile
  • chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.
    More recently, writing in the Journal of Medicinal Chemistry, investigators at GlaxoSmithKline reported that they had successfully optimized
a class of benzodiazepines as BET bromodomain inhibitors, apparently without any prior knowledge of identified molecular targets.
Significant medicinal chemistry provided the bromodomain inhibitor, I-BET762 or GSK525762, which is currently in a Phase I clinical trial for the treatment of NUT midline carcinoma, a rare but lethal form of cancer, and other cancers.

 Casting a Wide Net

    Constellation Pharmaceuticals of Cambridge, MA, announced that it has initiated a Phase I clinical trial of CPI-0610, a novel small molecule BET protein bromodomain inhibitor, in patients with previously treated and progressive lymphomas. This first-in-human trial is currently open at Sarah Cannon Research Institute in Nashville, Tennessee, and at the John Theurer Cancer Center in Hackensack, New Jersey. Additional study sites in the U.S. will join the trial over the next several months. Studies of CPI-0610 are also planned in patients with multiple myeloma and in patients with acute leukemia or myelodysplastic syndrome.
    Constellation’s CMO, Michael Cooper, M.D. told GEN that “small molecule inhibitors of BET protein bromodomains have demonstrated broad activity against hematologic malignancies in preclinical models. And this activity can be achieved in vivo with levels of compound exposure that are well tolerated. While we are encouraged by these observations, what really makes the area interesting is
  • the novel mechanism by which BET protein bromodomain inhibitors elicit their biologic effects.
  • They disrupt the interaction of BET proteins with acetylated lysine residues on histones and thereby
  • suppress the transcription of key cancer-related genes such as MYC, BCL-2, and a subset of NF-κB-dependent genes.
These genes have in the past been difficult to target with small molecules. In light of the breadth of the activity in preclinical models of hematologic malignancies and the important genes that are targeted, we intend to cast a wide net across hematologic malignancies in the clinic.”
    Robert Sims, Ph.D., and senior director of biology at Constellation explained that BET protein bromodomain inhibition is only of several areas of interest for the company. “The BET proteins constitute one class of epigenetic targets, namely
  • molecules that recognize patterns in chromatin architecture and
  • either enhance or suppress gene transcription.
Constellation’s approach to epigenetics also includes programs in the enzymes that modify the architecture of chromatin, for example by the
  • methylation or demethylation of histone proteins (writers and erasers, respectively).
Even though our first drug candidate is directed against a set of reader proteins, we are also looking at inhibitors of the writer protein, EZH2, which is mutated in some types of non-Hodgkin lymphoma and overexpressed in many malignancies.”
    In January 2012, Constellation and Genentech announced collaboration based on the science of epigenetics and chromatin biology to discover and develop innovative treatments for cancer and other diseases. Each company will each commit a significant portion of their research and development efforts to the advancement of programs under the collaboration, and each party will have the right to retain exclusive rights to programs emerging from the collaboration.
    And more biotech giants can be expected to enter the field of epigenetics as smaller companies advance into the clinic with this novel approach to controlling gene expression gone wrong in cancer cells.
Patricia Fitzpatrick Dimond, Ph.D. (pdimond@genengnews.com), is technical editor at Genetic Engineering & Biotechnology News
Employing Metabolomics in Cell Culture and Bioprocessing: Gaining greater predictability, control and quality
Challenges in developing and producing biotherapeutics are numerous and dynamic, including various market drivers and industry responses. Finding effective measures to support a foundation of control, predictability, and quality have been a concern and have paved the way to seeking out and applying newer technologies such as metabolomics successfully to bioprocessing. This webinar will first navigate through the landscape and challenges in developing and producing biotherapeutics. The journey continues with a walk through of the rationale for why metabolomics is a key tool for addressing critical bioprocessing needs followed by specific case studies and examples of how a functional metabolomic approach has been applied.
There are many relevant applications for functional metabolomics in bioprocessing starting with process development that include being able to: boost titer or productivity, improve product quality, enhance viability, or optimize defined media. The technology has be employed in biomarker discovery applications for the following purposes: to identify predictors of lactate consumption, to assess product quality, to predict indicative biomarkers of bioreactor performance or identify ideal clones. Lastly, functional metabolomics has been applied to enrich DOE experiments and troubleshooting for: historical deviation, process transfer, scale-up issues, disposable concerns, and lot or performance changes.

Read Full Post »

Reporter: Aviva Lev-Ari, PhD, RN

Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility

Nature 496, 523–527 (25 April 2013)


24 April 2013

Germinal centres support antibody affinity maturation and memory formation1. Follicular T-helper cells promote proliferation and differentiation of antigen-specific B cells inside the follicle23. A genetic deficiency in the inducible co-stimulator (ICOS), a classic CD28 family co-stimulatory molecule highly expressed by follicular T-helper cells, causes profound germinal centre defects45, leading to the view that ICOS specifically co-stimulates the follicular T-helper cell differentiation program267. Here we show that ICOS directly controls follicular recruitment of activated T-helper cells in mice. This effect is independent from ICOS ligand (ICOSL)-mediated co-stimulation provided by antigen-presenting dendritic cells or cognate B cells, and does not rely on Bcl6-mediated programming as an intermediate step. Instead, it requires ICOSL expression by follicular bystander B cells, which do not present cognate antigen to T-helper cells but collectively form an ICOS-engaging field. Dynamic imaging reveals ICOS engagement drives coordinated pseudopod formation and promotes persistent T-cell migration at the border between the T-cell zone and the B-cell follicle in vivo. When follicular bystander B cells cannot express ICOSL, otherwise competent T-helper cells fail to develop into follicular T-helper cells normally, and fail to promote optimal germinal centre responses. These results demonstrate a co-stimulation-independent function of ICOS, uncover a key role for bystander B cells in promoting the development of follicular T-helper cells, and reveal unsuspected sophistication in dynamic T-cell positioning in vivo.

Read Full Post »

Reporter: Aviva Lev-Ari, PhD, RN

Screen Shot 2021-07-19 at 7.33.50 PM

Word Cloud By Danielle Smolyar

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Nature (2012) 

doi:10.1038/nature11547 Received 09 January 2012  Accepted 04 September 2012 

Published online 24 October 2012

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRASTP53CDKN2A, SMAD4MLL3TGFBR2, ARID1A andSF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2,MAP2K4NALCNSLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Figures at a glance


The research network comprising the Australian Pancreatic Cancer Genome Initiative, the Baylor College of Medicine Cancer Genome Project and the Ontario Institute for Cancer Research Pancreatic Cancer Genome Study (ABO collaboration) contributed collectively to this study as part of the International Cancer Genome Consortium. Biospecimens were collected at affiliated hospitals and processed at each biospecimen core resource centre. Data generation and analyses were performed by the genome sequencing centres, cancer genome characterization centres and genome data analysis centres. Investigator contributions are as follows: S.M.G., A.V.B., J.V.P., R.L.S., R.A.G., D.A.W., M.-C.G., J.D.M., L.D.S and T.J.H. (project leaders); A.V.B., S.M.G. and R.L.S. (writing team); A.L.J., J.V.P., P.J.W., J.L.F., C.L., M.A., O.H., J.G.R., D.T., C.X., S.Wo., F.N., S.So., G.K. and W.K. (bioinformatics/databases); D.K.M., I.H., S.I., C.N., S.M., A.Chr., T.Br., S.Wa., E.N., B.B.G., D.M.M., Y.Q.W., Y.H., L.R.L., H.D., R. E. D., R.S.M. and M.W. (sequencing); N.W., K.S.K., J.V.P., A.-M.P., K.N., N.C., M.G., P.J.W., M.J.C., M.P., J.W., N.K., F.Z., J.D., K.C., C.J.B., L.B.M., D.P., R.E.D., R.D.B., T.Be. and C.K.Y. (mutation, copy number and gene expression analysis); A.L.J., D.K.C., M.D.J., M.P., C.J.S., E.K.C., C.T., A.M.N., E.S.H., V.T.C., L.A.C., E.N., J.S.S., J.L.H., C.T., N.B. and M.Sc. (sample processing and quality control); A.J.G., J.G.K., R.H.H., C.A.I.-D., A.Cho., A.Mai., J.R.E., P.C. and A.S. (pathology assessment); J.W., M.J.C., M.P., C.K.Y. and mutation analysis team (network/pathway analysis and functional data integration); K.M.M., N.A.J., N.G.C., P.A.P.-M., D.J.A., D.A.L., L.F.A.W., A.G.R., D.A.T., R.J.D., I.R., A.V.P., E.A.M., R.L.S., R.H.H. and A.Maw. (functional screens); E.N., A.L.J., J.S.S., A.J.G., J.G.K., N.D.M., A.B., K.E., N.Q.N., N.Z., W.E.F., F.C.B., S.E.H., G.E.A., L.M., L.T., M.Sam., K.B., A.B., D.P., A.P., N.B., R.D.B., R.E.D., C.Y., S.Se., N.O., D.M., M-S.T., P.A.S., G.M.P., S.G., L.D.S., C.A.I.-D., R.D.S., C.L.W., R.A.M., R.T.L., S.B., V.C., M.Sca., C.B., M.A.T., G.T., A.S. and J.R.E. (sample collection and clinical annotation); D.K.C., M.P., C.J.S., E.S.H., J.A.L., R.J.D., A.V.P. and I.R. (preclinical models).

Competing financial interests

The authors declare no competing financial interests.

International Team Reports on Large-Scale Pancreatic Cancer Analysis

October 24, 2012

NEW YORK (GenomeWeb News) – A whole-exome sequencing and copy number variation study of pancreatic cancer published online today in Nature suggests that the disease sometimes involves alterations to genes and pathways best known for their role in axon guidance during embryonic development.

The work was conducted as part of the International Cancer Genome Consortium effort by researchers with the BCM Cancer Genome Project, the Australian Pancreatic Cancer Genome Initiative, and the Ontario Institute for Cancer Research Pancreatic Cancer Genome Study.

As they reported today, the investigators identified thousands of somatic mutations and copy number alterations in pancreatic ductal adenocarcinoma cancer, the most common form of pancreatic cancer. Some of the mutations affected known cancer genes and/or pathways implicated in pancreatic cancer in the past. Other genetic glitches pointed to processes not previously linked to the disease including mutations to axon guidance genes such as SLIT2, ROBO1, and ROBO2.

“This is a category of genes not previously linked to pancreatic cancer,” Baylor College of Medicine researcher William Fisher, a co-author on the new paper, said in a statement. “We are poised to jump on this gene list and do some exciting things.”

Pancreatic cancer is among the deadliest types of cancer, he and his colleagues explained, with a grim five-year survival rate of less than 5 percent. But despite its clinical importance, direct genomic studies of primary tumors had been stymied in the past due to difficulties obtaining large enough samples for such analyses.

“Genomic characterization of pancreatic ductal adenocarcinoma, which accounts for over 90 [percent] of pancreatic cancer, has so far focused on targeted polymerase chain reaction-based exome sequencing of primary and metastatic lesions propagated as xenografts or cell lines,” the study authors noted.

“A deeper understanding of the underlying molecular pathophysiology of the clinical disease is needed to advance the development of effective therapeutic and early detection strategies,” they added.

For the current study, researchers started with a set of tumor-normal samples from 142 individuals with stage I or stage II sporadic pancreatic ductal adenocarcinoma. Following a series of experiments to assess tumor cellularity and other features that can impact tumor analyses, they selected 99 patients whose samples were assessed in detail.

For whole-exome sequencing experiments, the investigators nabbed coding sequences from matched tumor and normal samples using either Agilent SureSelectII or Nimblegen capture kits before sequencing the exomes on SOLiD 4 or Illumina sequencing platforms. They also used Ion Torrent and Roche 454 platforms to validate apparent somatic mutations in the samples.

For its copy number analyses, meanwhile, the team tested the pancreatic cancer and normal tissue samples using Illumina HumanOmni1 Quad genotyping arrays.

When they sifted through data for the 99 most completely characterized pancreatic tumors, researchers uncovered 1,628 CNVs and roughly 2,000 non-silent, somatic coding mutations. More than 1,500 of the non-silent mutations were subsequently verified through additional sequencing experiments.

On average, each of the tumors contained 26 coding mutations. And despite the variability in mutations present from one tumor to the next, researchers identified 16 genes that were mutated in multiple tumor samples.

Some were well-known cancer players such as KRAS, which was mutated in more than 90 percent of the 142 pancreatic tumors considered initially. Several other genes belonged to cell cycle checkpoint, apoptosis, blood vessel formation, and cell signaling pathways, researchers reported, or to pathways involved in chromatin remodeling or DNA damage repair.

For example, some 8 percent of tumors contained mutations to ATM, a gene participating in a DNA damage repair pathway that includes the ovarian/breast cancer risk gene BRCA1.

Genes falling within axon guidance pathways turned up as well. That pattern was supported by the researchers analyses of data from published pancreatic cancer studies — including two studies based on mutagenesis screens in mouse models of the disease — and by their own gene expression experiments in mice.

The team also tracked down a few more pancreatic ductal adenocarcinoma cases involving mutations to axon guidance genes such as ROBO1, ROBO2, and SLIT2 through targeted testing on 30 more pancreatic cancer patients.

The findings are consistent with those found in some other cancer types, according to the study’s authors, who noted that there is evidence indicating that some axon guidance components feed into signaling pathways related to cancer development, such as the WNT signaling pathway. If so, they explained, it’s possible that mutations to axon guidance genes might influence the effectiveness of therapies targeting such downstream pathways or serve as potential treatment targets themselves.

Still, those involved in the study cautioned that more research is needed not only to explore such possibilities but also to distinguish between driver and passenger mutations in pancreatic cancer.

“The potential therapeutic strategies identified will … require testing in appropriate clinical trials that are specifically designed to target subsets of patients stratified according to well-defined molecular markers,” the study’s authors concluded.

Read Full Post »

Expanding the Genetic Alphabet and Linking the Genome to the Metabolome

English: The citric acid cycle, also known as ...

English: The citric acid cycle, also known as the tricarboxylic acid cycle (TCA cycle) or the Krebs cycle. Produced at WikiPathways. (Photo credit: Wikipedia)

Expanding the Genetic Alphabet and Linking the Genome to the Metabolome


Reporter& Curator:  Larry Bernstein, MD, FCAP


















Unlocking the diversity of genomic expression within tumorigenesis and “tailoring” of therapeutic options

1. Reshaping the DNA landscape between diseases and within diseases by the linking of DNA to treatments

In the NEW York Times of 9/24,2012 Gina Kolata reports on four types of breast cancer and the reshaping of breast cancer DNA treatment based on the findings of the genetically distinct types, which each have common “cluster” features that are driving many cancers.  The discoveries were published online in the journal Nature on Sunday (9/23).  The study is considered the first comprehensive genetic analysis of breast cancer and called a roadmap to future breast cancer treatments.  I consider that if this is a landmark study in cancer genomics leading to personalized drug management of patients, it is also a fitting of the treatment to measurable “combinatorial feature sets” that tie into population biodiversity with respect to known conditions.   The researchers caution that it will take years to establish transformative treatments, and this is clearly because in the genetic types, there are subsets that have a bearing on treatment “tailoring”.   In addition, there is growing evidence that the Watson-Crick model of the gene is itself being modified by an expansion of the alphabet used to construct the DNA library, which itself will open opportunities to explain some of what has been considered junk DNA, and which may carry essential information with respect to metabolic pathways and pathway regulation.  The breast cancer study is tied to the  “Cancer Genome Atlas” Project, already reported.  It is expected that this work will tie into building maps of genetic changes in common cancers, such as, breast, colon, and lung.  What is not explicit I presume is a closely related concept, that the translational challenge is closely related to the suppression of key proteomic processes tied into manipulating the metabolome.

Saha S. Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations. 9/12/2012. PharmaceuticalIntelligence.Wordpress.com

Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature  Sept 14-20, 2012

Sarkar A. Prediction of Nucleosome Positioning and Occupancy Using a Statistical Mechanics Model. 9/12/2012. PharmaceuticalIntelligence.WordPress.com

Heijden et al.   Connecting nucleosome positions with free energy landscapes. (Proc Natl Acad Sci U S A. 2012, Aug 20 [Epub ahead of print]).  http://www.ncbi.nlm.nih.gov/pubmed/22908247

2. Fiddling with an expanded genetic alphabet – greater flexibility in design of treatment (pharmaneogenesis?)

Diagram of DNA polymerase extending a DNA stra...

Diagram of DNA polymerase extending a DNA strand and proof-reading. (Photo credit: Wikipedia)

A clear indication of this emerging remodeling of the genetic alphabet is a new
study led by scientists at The Scripps Research Institute appeared in the
June 3, 2012 issue of Nature Chemical Biology that indicates the genetic code as
we know it may be expanded to include synthetic and unnatural sequence pairing (Study Suggests Expanding the Genetic Alphabet May Be Easier than Previously Thought, Genome). They infer that the genetic instructions for living organisms
that is composed of four bases (C, G, A and T)— is open to unnatural letters. An expanded “DNA alphabet” could carry more information than natural DNA, potentially coding for a much wider range of molecules and enabling a variety of powerful applications. The implications of the application of this would further expand the translation of portions of DNA to new transciptional proteins that are heretofore unknown, but have metabolic relavence and therapeutic potential. The existence of such pairing in nature has been studied in Eukariotes for at least a decade, and may have a role in biodiversity. The investigators show how a previously identified pair of artificial DNA bases can go through the DNA replication process almost as efficiently as the four natural bases.  This could as well be translated into human diversity, and human diseases.

The Romesberg laboratory collaborated on the new study and his lab have been trying to find a way to extend the DNA alphabet since the late 1990s. In 2008, they developed the efficiently replicating bases NaM and 5SICS, which come together as a complementary base pair within the DNA helix, much as, in normal DNA, the base adenine (A) pairs with thymine (T), and cytosine (C) pairs with guanine (G). It had been clear that their chemical structures lack the ability to form the hydrogen bonds that join natural base pairs in DNA. Such bonds had been thought to be an absolute requirement for successful DNA replication, but that is not the case because other bonds can be in play.

The data strongly suggested that NaM and 5SICS do not even approximate the edge-to-edge geometry of natural base pairs—termed the Watson-Crick geometry, after the co-discoverers of the DNA double-helix. Instead, they join in a looser, overlapping, “intercalated” fashion that resembles a ‘mispair.’ In test after test, the NaM-5SICS pair was efficiently replicable even though it appeared that the DNA polymerase didn’t recognize it. Their structural data showed that the NaM-5SICS pair maintain an abnormal, intercalated structure within double-helix DNA—but remarkably adopt the normal, edge-to-edge, “Watson-Crick” positioning when gripped by the polymerase during the crucial moments of DNA replication. NaM and 5SICS, lacking hydrogen bonds, are held together in the DNA double-helix by “hydrophobic” forces, which cause certain molecular structures (like those found in oil) to be repelled by water molecules, and thus to cling together in a watery medium.

The finding suggests that NaM-5SICS and potentially other, hydrophobically bound base pairs could be used to extend the DNA alphabet and that Evolution’s choice of the existing four-letter DNA alphabet—on this planet—may have been developed allowing for life based on other genetic systems.

3.  Studies that consider a DNA triplet model that includes one or more NATURAL nucleosides and looks closely allied to the formation of the disulfide bond and oxidation reduction reaction.

This independent work is being conducted based on a similar concep. John Berger, founder of Triplex DNA has commented on this. He emphasizes Sulfur as the most important element for understanding evolution of metabolic pathways in the human transcriptome. It is a combination of sulfur 34 and sulphur 32 ATMU. S34 is element 16 + flourine, while S32 is element 16 + phosphorous. The cysteine-cystine bond is the bridge and controller between inorganic chemistry (flourine) and organic chemistry (phosphorous). He uses a dual spelling, using  sulfphur to combine the two referring to the master catalyst of oxidation-reduction reactions. Various isotopic alleles (please note the duality principle which is natures most important pattern). Sulfphur is Methionine, S adenosylmethionine, cysteine, cystine, taurine, gluthionine, acetyl Coenzyme A, Biotin, Linoic acid, H2S, H2SO4, HSO3-, cytochromes, thioredoxin, ferredoxins, purple sulfphur anerobic bacteria prokaroytes, hydrocarbons, green sulfphur bacteria, garlic, penicillin and many antibiotics; hundreds of CSN drugs for parasites and fungi antagonists. These are but a few names which come to mind. It is at the heart of the Krebs cycle of oxidative phosphorylation, i.e. ATP. It is also a second pathway to purine metabolism and nucleic acids. It literally is the key enzymes between RNA and DNA, ie, SH thiol bond oxidized to SS (dna) cysteine through thioredoxins, ferredoxins, and nitrogenase. The immune system is founded upon sulfphur compounds and processes. Photosynthesis Fe4S4 to Fe2S3 absorbs the entire electromagnetic spectrum which is filtered by the Allen belt some 75 miles above earth. Look up chromatium vinosum or allochromatium species.  There is reasonable evidence it is the first symbiotic species of sulfphur anerobic bacteria (Fe4S4) with high potential mvolts which drives photosynthesis while making glucose with H2S.
He envisions a sulfphur control map to automate human metabolism with exact timing sequences, at specific three dimensional coordinates on Bravais crystalline lattices. He proposes adding the inosine-xanthosine family to the current 5 nucleotide genetic code. Finally, he adds, the expanded genetic code is populated with “synthetic nucleosides and nucleotides” with all kinds of customized functional side groups, which often reshape nature’s allosteric and physiochemical properties. The inosine family is nature’s natural evolutionary partner with the adenosine and guanosine families in purine synthesis de novo, salvage, and catabolic degradation. Inosine has three major enzymes (IMPDH1,2&3 for purine ring closure, HPGRT for purine salvage, and xanthine oxidase and xanthine dehydrogenase.

English: DNA replication or DNA synthesis is t...

English: DNA replication or DNA synthesis is the process of copying a double-stranded DNA molecule. This process is paramount to all life as we know it. (Photo credit: Wikipedia)

3. Nutritional regulation of gene expression,  an essential role of sulfur, and metabolic control 

Finally, the research carried out for decades by Yves Ingenbleek and the late Vernon Young warrants mention. According to their work, sulfur is again tagged as essential for health. Sulfur (S) is the seventh most abundant element measurable in human tissues and its provision is mainly insured by the intake of methionine (Met) found in plant and animal proteins. Met is endowed with unique functional properties as it controls the ribosomal initiation of protein syntheses, governs a myriad of major metabolic and catalytic activities and may be subjected to reversible redox processes contributing to safeguard protein integrity.

Consuming diets with inadequate amounts of methionine (Met) are characterized by overt or subclinical protein malnutrition, and it has serious morbid consequences. The result is reduction in size of their lean body mass (LBM), best identified by the serial measurement of plasma transthyretin (TTR), which is seen with unachieved replenishment (chronic malnutrition, strict veganism) or excessive losses (trauma, burns, inflammatory diseases).  This status is accompanied by a rise in homocysteine, and a concomitant fall in methionine.  The ratio of S to N is quite invariant, but dependent on source.  The S:N ratio is typical 1:20 for plant sources and 1:14.5 for animal protein sources.  The key enzyme involved with the control of Met in man is the enzyme cystathionine-b-synthase, which declines with inadequate dietary provision of S, and the loss is not compensated by cobalamine for CH3- transfer.

As a result of the disordered metabolic state from inadequate sulfur intake (the S:N ratio is lower in plants than in animals), the transsulfuration pathway is depressed at cystathionine-β-synthase (CβS) level triggering the upstream sequestration of homocysteine (Hcy) in biological fluids and promoting its conversion to Met. They both stimulate comparable remethylation reactions from homocysteine (Hcy), indicating that Met homeostasis benefits from high metabolic priority. Maintenance of beneficial Met homeostasis is counterpoised by the drop of cysteine (Cys) and glutathione (GSH) values downstream to CβS causing reducing molecules implicated in the regulation of the 3 desulfuration pathways

4. The effect on accretion of LBM of protein malnutrition and/or the inflammatory state: in closer focus

Hepatic synthesis is influenced by nutritional and inflammatory circumstances working concomitantly and liver production of  TTR integrates the dietary and stressful components of any disease spectrum. Thus we have a depletion of visceral transport proteins made by the liver and fat-free weight loss secondary to protein catabolism. This is most accurately reflected by TTR, which is a rapid turnover protein, but it is involved in transport and is essential for thyroid function (thyroxine-binding prealbumin) and tied to retinol-binding protein. Furthermore, protein accretion is dependent on a sulfonation reaction with 2 ATP.  Consequently, Kwashiorkor is associated with thyroid goiter, as the pituitary-thyroid axis is a major sulfonation target. With this in mind, it is not surprising why TTR is the sole plasma protein whose evolutionary patterns closely follow the shape outlined by LBM fluctuations. Serial measurement of TTR therefore provides unequaled information on the alterations affecting overall protein nutritional status. Recent advances in TTR physiopathology emphasize the detecting power and preventive role played by the protein in hyper-homocysteinemic states.

Individuals submitted to N-restricted regimens are basically able to maintain N homeostasis until very late in the starvation processes. But the N balance study only provides an overall estimate of N gains and losses but fails to identify the tissue sites and specific interorgan fluxes involved. Using vastly improved methods the LBM has been measured in its components. The LBM of the reference man contains 98% of total body potassium (TBK) and the bulk of total body sulfur (TBS). TBK and TBS reach equal intracellular amounts (140 g each) and share distribution patterns (half in SM and half in the rest of cell mass). The body content of K and S largely exceeds that of magnesium (19 g), iron (4.2 g) and zinc (2.3 g).

TBN and TBK are highly correlated in healthy subjects and both parameters manifest an age-dependent curvilinear decline with an accelerated decrease after 65 years. Sulfur Methylation (SM) undergoes a 15% reduction in size per decade, an involutive process. The trend toward sarcopenia is more marked and rapid in elderly men than in elderly women decreasing strength and functional capacity. The downward SM slope may be somewhat prevented by physical training or accelerated by supranormal cytokine status as reported in apparently healthy aged persons suffering low-grade inflammation or in critically ill patients whose muscle mass undergoes proteolysis.

5.  The results of the events described are:

  • Declining generation of hydrogen sulfide (H2S) from enzymatic sources and in the non-enzymatic reduction of elemental S to H2S.
  • The biogenesis of H2S via non-enzymatic reduction is further inhibited in areas where earth’s crust is depleted in elemental sulfur (S8) and sulfate oxyanions.
  • Elemental S operates as co-factor of several (apo)enzymes critically involved in the control of oxidative processes.

Combination of protein and sulfur dietary deficiencies constitute a novel clinical entity threatening plant-eating population groups. They have a defective production of Cys, GSH and H2S reductants, explaining persistence of an oxidative burden.

6. The clinical entity increases the risk of developing:

  • cardiovascular diseases (CVD) and
  • stroke

in plant-eating populations regardless of Framingham criteria and vitamin-B status.
Met molecules supplied by dietary proteins are submitted to transmethylation processes resulting in the release of Hcy which:

  • either undergoes Hcy — Met RM pathways or
  • is committed to transsulfuration decay.

Impairment of CβS activity, as described in protein malnutrition, entails supranormal accumulation of Hcy in body fluids, stimulation of activity and maintenance of Met homeostasis. The data show that combined protein- and S-deficiencies work in concert to deplete Cys, GSH and H2S from their body reserves, hence impeding these reducing molecules to properly face the oxidative stress imposed by hyperhomocysteinemia.

Although unrecognized up to now, the nutritional disorder is one of the commonest worldwide, reaching top prevalence in populated regions of Southeastern Asia. Increased risk of hyperhomocysteinemia and oxidative stress may also affect individuals suffering from intestinal malabsorption or westernized communities having adopted vegan dietary lifestyles.

Ingenbleek Y. Hyperhomocysteinemia is a biomarker of sulfur-deficiency in human morbidities. Open Clin. Chem. J. 2009 ; 2 : 49-60.

7. The dysfunctional metabolism in transitional cell transformation

A third development is also important and possibly related. The transition a cell goes through in becoming cancerous tends to be driven by changes to the cell’s DNA. But that is not the whole story. Large-scale techniques to the study of metabolic processes going on in cancer cells is being carried out at Oxford, UK in collaboration with Japanese workers. This thread will extend our insight into the metabolome. Otto Warburg, the pioneer in respiration studies, pointed out in the early 1900s that most cancer cells get the energy they need predominantly through a high utilization of glucose with lower respiration (the metabolic process that breaks down glucose to release energy). It helps the cancer cells deal with the low oxygen levels that tend to be present in a tumor. The tissue reverts to a metabolic profile of anaerobiosis.  Studies of the genetic basis of cancer and dysfunctional metabolism in cancer cells are complementary. Tomoyoshi Soga’s large lab in Japan has been at the forefront of developing the technology for metabolomics research over the past couple of decades (metabolomics being the ugly-sounding term used to describe research that studies all metabolic processes at once, like genomics is the study of the entire genome).

Their results have led to the idea that some metabolic compounds, or metabolites, when they accumulate in cells, can cause changes to metabolic processes and set cells off on a path towards cancer. The collaborators have published a perspective article in the journal Frontiers in Molecular and Cellular Oncology that proposes fumarate as such an ‘oncometabolite’. Fumarate is a standard compound involved in cellular metabolism. The researchers summarize that shows how accumulation of fumarate when an enzyme goes wrong affects various biological pathways in the cell. It shifts the balance of metabolic processes and disrupts the cell in ways that could favor development of cancer.  This is of particular interest because “fumarate” is the intermediate in the TCA cycle that is converted to malate.

Animation of the structure of a section of DNA...

Animation of the structure of a section of DNA. The bases lie horizontally between the two spiraling strands. (Photo credit: Wikipedia)

The Keio group is able to label glucose or glutamine, basic biological sources of fuel for cells, and track the pathways cells use to burn up the fuel.  As these studies proceed, they could profile the metabolites in a cohort of tumor samples and matched normal tissue. This would produce a dataset of the concentrations of hundreds of different metabolites in each group. Statistical approaches could suggest which metabolic pathways were abnormal. These would then be the subject of experiments targeting the pathways to confirm the relationship between changed metabolism and uncontrolled growth of the cancer cells.

Related articles

Read Full Post »

Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Reporter: Aviva Lev-Ari, PhD, RN

Nature (2012) doi:10.1038/nature11404

Received 09 March 2012 
Accepted 09 July 2012 
Published online 09 September 2012
Correspondence to: 

The primary and processed data used to generate the analyses presented here can be downloaded by registered users fromThe Cancer Genome Atlas (https://tcga-data.nci.nih.gov/tcga/tcgaDownload.jsp,https://cghub.ucsc.edu/ and https://tcga-data.nci.nih.gov/docs/publications/lusc_2012/).

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 andKEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers.

Read Full Post »

%d bloggers like this: