The Third Crick Symposium and Talks about TORCs

Last month, the Third Crick Symposium was held in London (UK), with the aim of discussing ways in which basic biological research could progress from “Genetics to molecules to therapies”. In particular, this meeting brought together chemists, biologists and clinicians from what will be the new Francis Crick Institute in London, which is scheduled to open in 2015.

Of note, Professor Charles Swanton (CRUK London Research Institute and UCL Cancer Institute, UK) described four cases of intra-tumour heterogeneity in metastatic renal cell carcinoma (RCC). These findings demonstrated that certain mutations were ubiquitous, shared or unique within specific regions of the metastatic RCC (Gerlinger et al., 2012). For example, using exome sequencing, chromosome aberration analysis and DNA ploidy profiling it was noted that VHL was mutated in all analysed tumour regions within one patient. An activating mutation in mammalian target of rapamycin (mTOR) was also observed in all but one primary tumour region. However, there were distinct SETD2 and KDM5C mutations present within the primary and metastatic regions of the RCC, and these genes have been previously discussed here. This study by Gerlinger et al. highlights that a single biopsy may not represent the mutational load within a tumour, and that certain tumour cell populations may react differently to treatments. Accordingly, therapies which target ubiquitous mutations may prove to be more successful. It would be particularly interesting to see if there is similar intra-tumour heterogeneity within BHD-associated RCCs, as alluded to in this earlier blog post.

The FLCN-associated signalling diagram and the work described above underlines the importance of mTOR complex (mTORC) signalling in the development of RCC. Thus in mid-March, we attended a set of “Talks about TORCs” organised by the Biochemical Society in London. Recent advances in TOR signalling were shared and its role in a variety of processes was introduced. For example, the first talk by Professor Michael Hall (University of Basel, Switzerland) discussed TOR signalling in relation to growth and metabolism. Notably, Professor Hall suggested that mammalian TOR should be renamed mechanistic TOR, as the pathway is not unique to mammals. This was aptly demonstrated by Dr Miguel Navarro (Institute of Parasitology and Biomedicine “López-Neyra”, Spain) with his work on TOR signalling in Trypanosoma brucei (Barquilla et al., 2012). In addition, Professor Thomas Weichhart (Medical University of Vienna, Austria) and Professor Doreen Cantrell (University of Dundee, UK) introduced the role of mTOR signalling in immunity, which is of interest as FLCN/FNIP1 may be associated with B-cell development (as discussed here and here). Professor Linda Partridge (UCL, UK) also introduced the connection between mTOR signalling and ageing. This is especially relevant as recent work has connected FLCN with longevity in C. elegans (Gharbi et al., 2013), which will be discussed in our BHD Research Blog soon. Moreover, Dr Andrew Tee presented his work on ULK1 and mTOR signalling (Dunlop et al., 2011), as well as a poster on BHD. For more information regarding the work of Dr Tee, please look at our lab profile here.

Finally, do visit our Conferences and Events page to keep updated with meetings that are of relevance to BHD syndrome. In particular, the Fifth BHD Symposium and Second HLRCC Symposium will be held in Paris on 28-29th June 2013, and the abstract and earlybird registration deadline is 15th April 2013.

 

  • Barquilla, A., Saldivia, M., Diaz, R., Bart, J., Vidal, I., Calvo, E., Hall, M., & Navarro, M. (2012). Third target of rapamycin complex negatively regulates development of quiescence in Trypanosoma brucei Proceedings of the National Academy of Sciences, 109 (36), 14399-14404 DOI: 10.1073/pnas.1210465109
  • Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, & Tee AR (2011). ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy, 7 (7), 737-47 PMID: 21460630
  • Gerlinger, M., Rowan, A., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., Varela, I., Phillimore, B., Begum, S., McDonald, N., Butler, A., Jones, D., Raine, K., Latimer, C., Santos, C., Nohadani, M., Eklund, A., Spencer-Dene, B., Clark, G., Pickering, L., Stamp, G., Gore, M., Szallasi, Z., Downward, J., Futreal, P., & Swanton, C. (2012). Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing New England Journal of Medicine, 366 (10), 883-892 DOI: 10.1056/NEJMoa1113205
  • Gharbi, H., Fabretti, F., Bharill, P., Rinschen, M., Brinkkötter, S., Frommolt, P., Burst, V., Schermer, B., Benzing, T., & Müller, R. (2013). Loss of the Birt-Hogg-Dubé gene product Folliculin induces longevity in a hypoxia-inducible factor dependent manner Aging Cell DOI: 10.1111/acel.12081

3 thoughts on “The Third Crick Symposium and Talks about TORCs

  1. Related to intra-tumor heterogeneity, there is a fascinating review in a recent issue of Science magazine:

    Cancer Genome Landscapes, Bert Vogelstein et al.
    Science 29 March 2013: Vol. 339 no. 6127 pp. 1546-1558
    http://www.sciencemag.org/content/339/6127/1546.full (subscription required)
    Supplementary material at http://www.sciencemag.org/content/suppl/2013/03/27/339.6127.1546.DC1

    “To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. ”

    This article discusses extensively two types of driver genes altered by mutations (Mut-Drivers) (as opposed to those with aberrant expression): oncogenes, and tumor suppressors. (Some genes, e.g. NOTCH1, can act as either type depending on the tissue). To be classified as an oncogene, >20% of the recorded mutations must be missense, and tend to be clustered. To be classified as a tumor suppressor gene, >20% of the recorded mutations must be inactivating. For gene categorization for this work, the authors use a fascinating resource, the Catalogue of Somatic Mutations in Cancer (COSMIC) database
    http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/

    In the article, FLCN is mentioned only in Table S4, as a Cancer Predisposition Gene affecting the phosphatidylinositide 3-kinase pathway. FLCN was not flagged as a tumor suppressor gene in this work, apparently because in the COSMIC database the number of inactivating mutations observed was below the threshold used by the authors. The authors required 7 inactivating mutations to be observed in the COSMIC database for a gene to be considered a tumor suppressor. I found only 6 instances of inactivating FLCN mutations in COSMIC. (I found at least 16 missense and 4 synonymous substitutions.) See
    http://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=FLCN&start=1&end=580&id=6911#ts (click on the “mutations” tab, then drill down further to the mutation, sample name, overview). Most (4/6) of these inactivating FLCN mutations were found in lung carcinomas, although FLCN mutations were only observed in 1.3% of lung cancer samples tested (13/999).

    The article brings out many fascinating observations, including:
    * Next-generation sequencing is very problematic as far as identifying mutations, with a false-negative rate of ~40% in one study.
    * ~20% of mutations may be in noncoding regions, missed when only coding regions are sequenced.
    * Other reasons for missing altered gene expression intumors include copy number variations and epigenetic alterations.
    * The rate and timing of the occurrence of mutations in tumors is discussed. Slow-growing or pediatric tumors differ from those of self-renewing tissues. In self-renewing tissues [relevant to BHD], more than half of the somatic mutations occur during the preneoplastic phase. All of these pre-neoplastic mutations are “passenger mutations” that have no effect on the neoplastic process.
    * Consistent genetic alterations that distinguish cancers that metastasize from cancers that have not yet metastasized remain to be identified. Metastasis is, in principle, explicable by stochastic processes alone.
    * Four types of genetic heterogeneity are relevant to tumorigenesis: intratumoral, intermetastatic, intrametastatic, and interpatient.
    * For those oncogenes with enzymatic activity, small molecule inhibitor drugs are conceivable. However only a fraction of oncogenes are targetable in this way. Also, few tumors contain more than one oncogene mutation.
    * Drugs cannot, in general, replace the function of mutant tumor suppressor genes. Unfortunately, tumor suppressor gene–inactivating mutations predominate in the most common solid tumors.
    * Based on these considerations, for the future the authors consider prevention and detection to be likely to be FAR more effective than drug therapy in reducing morbidity and mortality due to cancer .

    In the authors’ words (Box 2):

    1. Most human cancers are caused by two to eight sequential alterations that develop over the course of 20 to 30 years.

    2. Each of these alterations directly or indirectly increases the ratio of cell birth to cell death; that is, each alteration causes a selective growth advantage to the cell in which it resides.

    3. The evidence to date suggests that there are ~140 genes whose intragenic mutations contribute to cancer (so-called Mut-driver genes). There are probably other genes (Epi-driver genes) that are altered by epigenetic mechanisms and cause a selective growth advantage, but the definitive identification of these genes has been challenging.

    4. The known driver genes function through a dozen signaling pathways that regulate three core cellular processes: cell fate determination, cell survival, and genome maintenance.

    5. Every individual tumor, even of the same histopathologic subtype as another tumor, is distinct with respect to its genetic alterations, but the pathways affected in different tumors are similar.

    6. Genetic heterogeneity among the cells of an individual tumor always exists and can impact the response to therapeutics.

    7. In the future, the most appropriate management plan for a patient with cancer will be informed by an assessment of the components of the patient’s germline genome and the genome of his or her tumor.

    8. The information from cancer genome studies can also be exploited to improve methods for prevention and early detection of cancer, which will be essential to reduce cancer morbidity and mortality.

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