2008 Barcelona - European Society of Human Genetics

Concurrent Symposia
s04.1
microRNA Regulation of cardiac Development and Disease
D. Srivastava;
Gladstone Institute of Cardiovascular Disease, UCSF – Dep. of Pediatrics and
Biochemistry & Biophysics, San Francisco, CA, United States.
Gradients of signaling and transcription factors result in distinct cellular
responses during organ formation suggesting that the precise dose of
major regulatory proteins must be tightly controlled . MicroRNAs (miR-
NAs) are phylogenetically conserved small RNAs that regulate translation
or stability of target messenger RNAs providing a mechanism for
protein dose regulation . Studies in our lab of multiple cardiac-enriched
miRNAs reveal that they coordinate decisions of cellular proliferation,
differentiation and response to stress via intricate transcriptional and
translational networks . In addition to our previous work demonstrating
the role of miR-1 in differentiation of mouse and fly cardiac progenitors,
we found that targeted deletion of miR-1-2 in mouse causes defects
in cardiac morphogenesis as well as cardiac conduction and cell cycle
abnormalities. Consistent with this finding, manipulation of miR-1 and
the co-transcribed miR-133 in mouse and human embryonic stem cells
revealed that these miRNAs can be used to guide pluripotent stem
cells into mesodermal cells and ultimately into the cardiac lineage,
while repressing neuroectodermal and endodermal differentiation . Finally,
novel approaches of miRNA target identification to explain the
mechanisms underlying the described effects of cardiac miRNAs will
be discussed .
s04.2
A rapidly evolved RNA gene may have played a role in the
evolution of the cerebral cortex
D. Haussler;
Center for Biomolecular Science & Engineering, University of California, Santa
Cruz, CA, United States.
We have scanned the human genome for segments that have been
under negative selection during most of mammalian evolution, but
experienced a burst of changes during the last few million years of
human evolution . The most dramatic such segment occurs in a previously
unstudied RNA gene expressed specifically in the Cajal-Retzius
neurons in the developing cerebral cortex, during the time these neurons
guide the development of the 6-layer cortical structure . Examples
like this demonstrate the power of computational reconstruction of the
evolution of the human genome, and argue that changes in non-coding
functional regions may have played a significant role in the molecular
events that forged our species .
s04.3
the RNAi strategy in cancer: towards the Achilles Heal of
cancer
R. L. Beijersbergen;
The Netherlands Cancer Institute , Division of Molecular Carcinogenesis and
NKI Robotics and Screening Center, Amsterdam, Netherlands.
The development of the RNA interference (RNAi) technology has
changed the way how we approach target discovery and validation in
cancer research . The potential to study the consequence of the inactivation
of each individual gene is a very effective tool to identify novel
targets . In addition, high content imaging allows us to identify novel
components of cellular pathways involved in complex cellular phenotypes
in a high throughput manner . The combination of RNA interference
and high content imaging will lead to the discovery of a new class
of targets that can be used for development of novel cancer therapies
or to improve existing therapies .
We have constructed a large set of retroviral vectors encoding more
than 50 .000 shRNAs, which target 15 .000 different human or mouse
genes for suppression . This RNA interference library has been used
to identify genes involved in major cellular pathways such as the p53
tumor suppressor pathway . In particular we have focused on genes
that modulate the cytotoxic response to small molecules that target the
MDM2-p53 interaction . In addition we have developed novel screening
methods with the use of shRNA libraries and DNA micro-arrays to be
able to rapidly screen large numbers of shRNA vectors . This technology
is applied to identify the mechanism of action of novel anti-cancer
drugs and to identify genes involved in resistance to anti-cancer
drugs .
Recently, we have extended our efforts into synthetic siRNA screens to
allow genome wide single well high throughput screening with the goal
to study more complex phenotypes and, importantly, to identify targets
that upon inhibition would only affect tumor cells where normal cells
would remain unaffected . The concept that a particular mutation has
deleterious consequences under specific conditions is known as synthetic
lethality. Two genes are defined as synthetic lethal when cells die
if they have both genes mutated but can survive if either gene alone is
mutated . The approach of exploring synthetic lethal gene-gene interactions
is attractive because it turns a hallmark of cancer cells, specific
mutations, into a weakness that can be explored therapeutically . We
explore the existence of synthetic lethal interactions with tumor specific
genetic alterations and large scale siRNA screens.
These approaches illustrate the power of RNAi to gain insight in the
mode of action of novel cancer drugs with the goal to accelerate their
development and as a powerful way to identify a whole new class of
more specific and more efficient anticancer drugs.
s05.1
Guidelines for the clinical management of Lynch syndrome and
adenomatous polyposis
H. F. A. Vasen;
Department of Gastroenterology & Hepatology, Leiden University Medical Centre,
Leiden, Netherlands.
The Lynch syndrome (LS)(HNPCC) is characterized by the development
of colorectal cancer (CRC), endometrial cancer and various
other cancers and is caused by a mutation in one of the mismatch
repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2 . Familial
adenomatous polyposis (FAP) is a well-described inherited
syndrome, characterized by the development of hundreds to thousands
of adenomas in the colorectum . The syndrome is caused by
mutations in the APC-gene or the MUTYH-gene . Both syndromes
(LS, FAP) are responsible for at least 5-7 % of all cases of CRC .
Since 2006, annual workshops were organized by a group of European
experts in hereditary gastrointestinal cancer (the Mallorca group)
aiming to establish guidelines for the clinical management of hereditary
CRC syndromes . Thirty-one experts from nine European countries
participated in these workshop . Prior to the meeting, various participants
prepared the key management issues of debate according to
the latest publications . A systematic literature search using Pubmed
and the Cochrane Database of Systematic Reviews, reference lists of
retrieved articles, and manual searches of relevant articles was performed
. During the workshop all recommendations were discussed in
detail . Part of the guidelines will be discussed . Moreover, the results of
recent studies on cancer risk and experience of longterm surveillance
for CRC in the Lynch syndrome will be presented .
References:
1 . H .F .A .Vasen & G .Möslein & the Mallorca group . Guidelines for the clinical
management of Lynch syndrome (HNPCC) J Med Genet 2007; 44: 353-61
2 . H .F .A .Vasen & G .Möslein & the Mallorca group . Guidelines for the
clinical management of Familial adenomatous polyposis . Gut 2008;
57:704-13
s05.2
Evaluation of breast and ovarian cancer screening programmes
in BRCA1 and BRCA2 mutation carriers: the UK, Norwegian and
Dutch experience
D. G. Evans 1 , K. N. Gaarenstroom 2 , D. Stirling 3 , A. Shenton 1 , L. Maehle 4 , A.
Dørum 4 , M. Steel 5 , F. Lalloo 1 , J. Apold 6 , M. E. Porteous 3 , H. F. A. Vasen 7 , C. J.
van Asperen 8 , P. Moller 4 ;
1 Medical Genetics Research Group and Regional Genetics Service, University
of Manchester and Central Manchester and Manchester Children’s University
Hospitals NHS Trust, St Mary’s Hospital, Manchester, United Kingdom, 2 Department
of Gynaecology, Leiden University Medical Center, Leiden, Netherlands, 3 South
East of Scotland Genetics Service, Western General Hospital, Edinburgh,
United Kingdom, 4 Section for Inherited Cancer, Department of Medical Genetics,
Rikshospitalet Radiumhospitalet Clinical Center, Oslo, Norway, 5 University
of St Andrews, Bute Medical Buildings, St Andrews, United Kingdom, 6 Centre
of Medical Genetics and Molecular Medicine, Haukeland University Hospital,
and Institute of Clinical Medicine, University of Bergen, Bergen, Norway, 7 The
Netherlands Foundation for the Detection of Hereditary Tumours and the Department
of Gastroenterology, Leiden University Medical Center, Leiden, Norway,
8 Center for Human and Clinical Genetics, Department of Clinical Genetics,