2008 Barcelona - European Society of Human Genetics

Concurrent Symposia
Leiden University Medical Center, Leiden, Norway.
The management of the high risk of breast and ovarian cancer in
female BRCA1/BRCA2 mutation carriers remains a vexing issue . In
order to provide alternatives to risk reducing surgery, surveillance programmes
have to detect the disease sufficiently early to provide a very
high likelihood of cure . In particular there have been substantial doubts
about the ability of routine annual mammography and ovarian ultrasound
plus serum CA125 to meet this goal . Collaborative research between
the UK, the Netherlands and Norway has enabled us to provide
a more accurate assessment of the likelihood of cure within these programmes.
Additionally the benefits of MRI screening for breast cancer
have been demonstrated by National studies in each country .
To assess the effectiveness of annual ovarian cancer screening (transvaginal
ultrasound and serum CA125 estimation) in reducing mortality
from ovarian cancer in women at increased genetic risk . A cohort
of 3532 women at increased risk of ovarian cancer was screened at
five centres between January 1991 and March 2007. Survival from
diagnosis of ovarian cancer was calculated using Kaplan-Meier analysis
and compared for proven BRCA1/2 carriers with non-carriers and
whether the cancer was detected at prevalence or post prevalent scan .
Screening was performed by annual transvaginal ultrasound and serum
CA125 measurement
64 epithelial ovarian malignancies (59 invasive and 5 borderline), developed
in the cohort . 26 tumours were detected at prevalent round,
there were 27 incident detected cancers and 11 interval. Sixty-five percent
of cancers were stage 3 or 4, however, stage and survival were little
different for prevalent versus post prevalent cancers . Five year and
10-year survival in 49 BRCA1/2 mutation carriers was 58 .6% (95%
CI 50.9-66.3%) and 36% (95% CI 27-45%), which was significantly
worse than for 15 non BRCA-carriers (91 .8% (95% CI 84-99 .6%) both
5 and 10-year survival p=0 .015) . Annual surveillance, by trans-vaginal
ultrasound scanning and serum CA125 measurement in women
at increased familial risk of ovarian cancer is ineffective in detecting
tumours at a sufficiently early stage to substantially influence survival
in BRCA1/2 carriers .
A collaborative study between Norway and the UK has shown that
survival in prospectively detected breast cancers in BRCA1 carriers in
an annual mammography screening programme is significantly worse
than for BRCA2 and other familial groups . It appears this may be due
to relatively poor survival for small node negative cancers . Some of
this poor survival may be attributable to the failure to treat these small
tumours with chemotherapy . This is particularly relevant when assessing
the benefits of MRI which in combination with mammography has
>90% sensitivity at detecting breast cancers in an annual programme .
The benefits of the combined approach for BRCA2 appear robust with
survival likely to exceed 90% for breast cancers identified in surveillance
programmes .
s05.3
managing genetic risk: some issues for BRCA and BRCA
mutation carriers
N. Hallowell;
Public Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Men and women who have a number of relatives with breast, ovarian
and prostate cancer in close relatives may be at risk of developing
these diseases because they carry a dominantly inherited (BRCA1/2)
mutation . These individuals need to reach a decision about managing
their cancer risks . There are a number of risk management strategies
available - which can be divided into familial and individual strategies
. The former entails DNA screening - determining whether individuals
and, subsequently, their relatives carry a mutation . The latter
include: bodily surveillance (breast, ovarian and prostate screening),
chemoprevention (e .g . tamoxifen, oral contraception), risk-reducing
pre-symptomatic surgery (e .g . mastectomy, oophorectomy), which are
available to at-risk confirmed and unconfirmed mutation carriers.
This presentation will present an overview of some of the main issues
emerging from research which investigates the psychosocial implications
of cancer risk management . I will argue that both risk management
decisions and the process of managing risk have both an individual
and familial dimension. Some of the factors influencing risk
management decisions such as: gender, cancer status and stage in
the lifecycle will be discussed as will the repercussions for identity of
adopting particular risk management practices . Finally, some of the
implications of this research for service delivery in cancer genetics will
be considered .
s06.1
common, low-penetrance breast cancer susceptibility alleles:
the clinical relevance
P. Pharoah;
University of Cambridge Dept of Oncology, Strangeways Research Laboratory,
Cambridge, United Kingdom.
Empirical, genome-wide association studies have discovered seven
breast cancer susceptibility alleles that are common in the population .
These findings have brought the promise of a “polygenic” approach to
the prevention of breast cancer a step nearer . The risks conferred by
individual loci are small, but risk alleles seem to act multiplicatively . As
a result there is an approximately six-fold difference in risk of breast
cancer between women carrying 14 risk alleles and those carrying no
risk alleles at these loci . Overall, the distribution of relative risk in the
population based on combinations of genotypes at these loci is approximately
log-normal. The efficiency of population-based preventive
programs, such as screening mammography, could be improved by
targeting women at greatest risk based on genotype .
s06.2
What GWAs have taught us about the genetic architecture and
pathogenesis of the inflammatory bowel diseases (IBD).
J. Rioux;
Université de Montréal and the Montreal Heart Institute Research Center, Montreal,
QC, Canada.
Crohn’s disease and ulcerative colitis are debilitating, inflammatory
diseases of the gastrointestinal tract, collectively known as the inflammatory
bowel diseases (IBDs) . Genetic studies have been particularly
successful in the identification of genes for Crohn’s disease. In fact,
in 2001 one of the first successful discoveries of a causal gene for
a complex trait was the identification of three genetic variants in the
NOD2 gene that are associated with Crohn’s disease as well as the
identification of an associated haplotype on chromosome 5q31, known
as IBD5, containing five genes: IRF1, SLC22A5, SLC22A4, PDLIM4,
and P4HA2 .
Recent GWAS of CD has identified and confirmed an additional set of
nine genetic risk factors . These studies have since led to an international
collaboration to combine the data from over 3,000 patients with
CD, examined in the individual screens, in order to identify the most
significant associations for replication in an independent set of nearly
4,000 patients with CD. This collaborative work has identified a minimum
of 20 additional risk factors for susceptibility to CD . It is estimated
that the 31 loci identified to date explain about 10% of the overall variance
in disease risk; providing some indications of the extent of the
complexity in genetic architecture for this chronic immune-mediated
disease. Some of the pathogenic pathways newly identified by these
GWAS include autophagy, novel innate immunity mechanisms, and
T H 17 mediated immune responses . Interestingly, a subset of the genes
identified to date are also seen to influence other immune mediated
diseases and thus provide a window into the disease-specific and
shared pathogenic pathways . In this presentation we will discuss the
results from these recent discoveries and some of conclusions that can
currently be drawn from this data in terms of the genetic architecture
and pathogenesis of IBD as a model for other complex human traits .
s06.3
title to be announced
G. Abecasis;
University of Michigan, School of Public Health, M4132 SPH II, Ann Arbor, MI.
s07.1
Genomic encoding of positional identity
H. Y. Chang;
Program in Epithelial Biology, Stanford University School of Medicine, Stanford,
CA, United States.
The problem of how genetic information gives rise to the spatial organization
has long intrigued biologists . While cellular differentiation
addresses the control of expression of specific genes within a cell,
pattern formation addresses the spatial arrangement of distinct cell
types . A major mechanism of pattern formation in the embryo is the