2009 Vienna - European Society of Human Genetics

Concurrent Symposia
s13.2
A novel genetic mechanism for Lynch syndrome resulting in
heritable somatic methylation of MSH
M. Ligtenberg 1,2 , R. Kuiper 2 , T. L. Chan 3,4 , M. Goossens 1 , K. Hebeda 1 , M.
Voorendt 2 , T. Lee 3 , D. Bodmer 2 , E. Hoenselaar 2 , S. Hendriks-Cornelissen 1 , W.
Tsui 3 , C. Kong 5 , H. Brunner 2 , A. Geurts van Kessel 2 , S. Yuen 3,4 , J. van Krieken 1 ,
S. Y. Leung 3,4 , N. Hoogerbrugge 2 ;
1 Department of Pathology, Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands, 2 Department of Human Genetics, Radboud University
Nijmegen Medical Centre, Nijmegen, The Netherlands, 3 Department of
Pathology, The University of Hong Kong, Hong Kong, Hong Kong, 4 Department
of Pathology, St. Paul’s Hospital, Hong Kong, Hong Kong, 5 Department of Surgery,
Yan Chai Hospital, Hong Kong, Hong Kong.
Lynch syndrome (HNPCC) patients are susceptible to colorectal, endometrial
and a range of other cancers due to heterozygous inactivating
mutations in one of the mismatch repair genes, MLH1, PMS2,
MSH2 or MSH6. In multiple patients with an MSH2-deficient tumor, in
whome no germline mutation in MSH2 could be detected, a heterozygous
germline deletion of 4.9 kb encompassing the last exons of
EPCAM (formerly known as TACSTD1) was found. EPCAM is located
directly upstream of MSH2 and encodes the epithelial cell adhesion
molecule Ep-CAM. Due to the deletion of the transcription termination
signal transcription of EPCAM was shown to extend into MSH2. As
antisense transcription of CpG islands may lead to methylation, we
tested whether the transcription of the MSH2 promoter would lead to
methylation of its CpG dinucleotides. Indeed, the MSH2 promoter in
cis with the deletion is methylated in Ep-CAM positive, but not in Ep-
CAM negative, normal tissues, thus revealing a correlation between
transcriptional read-through of the mutated EPCAM allele and epigenetic
inactivation of the corresponding MSH2 allele. A distinct deletion
that also includes the 3’ end of EPCAM was detected in two Chinese
families, one of which was previously described with mosaic MSH2
methylation. Also in these families transcriptional read-through correlates
with subsequent promoter methylation. Gene-silencing by transcriptional
read-through of a neighboring gene as demonstrated here
in sense direction for MSH2, has been described earlier in antisense
direction for HBA2 in a patient with alpha-thalassemia and thus could
represent a general mutational mechanism. Depending on the expression
pattern of the neighboring gene that lacks its normal polyadenylation
signal, this may cause either generalized or mosaic patterns of
epigenetic inactivation, that are inherited over generations. Moreover,
abrogation of polyadenylation signals due to chromosomal aberrations
in cancer cells may result in aberrant promoter methylation and inactivation
of tumor suppressor genes.
s13.3
Functional mechanism of genomic imprinting
A. Ferguson-Smith;
University of Cambridge, Department of Physiology, Development and Neuroscience,
Cambridge, United Kingdom.
No abstract received as per date of printing. Please see www.eshg.
org/eshg2009 for updates.
s14.1
the P53 pathway acts to delay in-vivo senescence and aging
J. van Deursen 1 , D. J. Baker 1 , C. Perez-Terzic 2 , F. Jin 1 , N. J. Niederländer 2 , K.
Jeganathan 1 , S. Yamada 2 , R. Lois 2 , A. Terzic 2 ;
1 Department of Pediatric and Adolescent Medicine, Mayo Clinic College of
Medicine, Rochester, MN, United States, 2 Department of Medicine, Mayo Clinic
College of Medicine, Rochester, MN, United States.
Cellular senescence of cultured cells relies heavily on activation of
the p19 Arf -p53 tumor suppressor pathway. This together with the observation
that p19 Arf expression increases with age in many tissues
of humans and rodents, led to speculation that p53 activity drives in
vivo senescence and natural aging. However, it has been difficult to
experimentally test this hypothesis in vivo using a model system, because
inactivation of p19 Arf or p53 in mice results in early death from
tumors with 100% penetrance. One approach to test the role of the p53
pathway in organismal aging would be to inactivate p19 Arf or p53 in a
mouse model that develops age-related pathologies at a young age.
BubR1 insufficient mice (BubR1 hypomorphic), which die five times
faster than wild-type mice, develop a variety of early-aging associated
phenotypes including cachetic dwarfism, skeletal muscle atrophy
(sarcopenia), cataracts, arterial stiffening, loss of subcutaneous fat,
reduced stress tolerance and impaired wound healing. We show that
BubR1 hypomorphic mice exhibit high expression of p19 Arf in skeletal
muscle and fat. Surprisingly, inactivation of p19 Arf exacerbates in vivo
senescence and aging specifically in these tissues, suggesting that
p19 Arf is an attenuator, rather than an effector of aging and senescence.
Furthermore, in accordance with a generalized anti-aging effect
of the p53 pathway, we find that abrogation of p53 also selectively
accelerates senescence and aging in skeletal muscle and fat of BubR1
hypomorphic mice. Importantly, BubR1 hypomorphic mice lacking the
cell cycle inhibitor p21, a key target of p53 activation, exhibit the same
accelerated aging characteristics and senescent cell accumulation as
BubR1 mutants lacking p19 Arf or p53, suggesting that p53 exerts its
anti-aging effect through p21, and not through targets that mediate
apoptosis. Based on these data, we propose that chronic stress associated
with BubR1 insufficiency or normal aging, induces a relatively
mild p53 transcriptional response that instead of promoting aging and
senescence acts to attenuate aging by providing stress resistance.
s14.2
Aging and cancer: Rival Demons?
J. Campisi1,2 ;
1 2 Lawrence Berkeley National Laboratory, Berkely, CA, United States, Buck
Institute for Age Research, Novato, CA, United States.
Age is the largest single risk factor for developing cancer. In this regard,
cancer is no different from a host of other age-related diseases --
cardiovascular disease, osteoporosis, neurodegeneration, etc. Nonetheless,
cancer appears to differ from other age-related pathologies in
conspicuous ways. First, cancer is dominated by hyperproliferation,
rather than degeneration. Second, somatic are an essential driving
force behind cancer development, but it is not clear whether is the
case for other aging phenotypes. Third, cancer arises from renewable
tissues, which promote longevity by allowing repair and regeneration,
but are perennially and inherently at risk for developing malignant tumors
due to mutations that can arise during DNA replication. Nonetheless,
mutations are known to accumulate very early in life, and it is now
clear that mutations alone are rarely enough to fully drive malignant tumorigenesis.
How then do fundamental aging processes set the stage
for the development of cancer, and do these processes differ from
those that set the stage for other age-related pathologies? We present
a model and supporting data to suggest that evolutionarily conserved
tumor suppressive pathways, which evolved to protect complex multicellular
organisms from cancer, can have deleterious late-life effects.
We propose that the evolutionary antagonistic pleiotropy of certain
tumor suppressor responses can drive aging phenotypes, including,
ironically, late-life cancer. We suggest that these deleterious effects
arise, in part, from the transcriptional response of normal cells to damage
and other potentially oncogenic insults, which leads to the secretion
of factors that can alter normal tissue structure and function, and
ultimately create a tissue milieu that is conducive for the development
of cancer. This model offers a new paradigm for understanding both
aging and cancer phenotypes, and new possibilities for ameliorating
the deleterious effects of certain tumor suppressive strategies.
s14.3
insulin signalling, ageing and age-related disease
D. Withers;
Centre for diabetes and endocrinology, University College London, London,
United Kingdom.
Although aging appears to be stochastic in nature, involving accumulation
of molecular damage caused by such processes as oxidation
or glycation, the rate of ageing is also influenced by genetic variation.
For example, there are striking differences in longevity between
animal species and mutations in single genes can extend lifespan in
laboratory animals. There is growing evidence that the insulin/insulinlike
growth factor (IGF) signalling (IIS) pathway, which has long been
known to play pleiotropic roles in the development, growth, reproduction,
stress resistance and metabolism of multicellular animals, is a key
evolutionarily conserved regulator of longevity. The pleiotropic effects
of IIS upon organismal physiology are largely mediated by intracellular
signalling adaptor proteins the best characterised of which are the
insulin receptor substrate (IRS) proteins. We recently undertook a systematic
analysis of the role of IRS proteins in mammalian lifespan. Fe-