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SECTION OF CANCER GENETICS
Section Chairman: M R Stratton PhD MRCPath FMedSci
Introduction
The major scientific focus of the Section of Cancer Genetics has
been the study of inherited susceptibility to cancer. Most common
types of human cancer appear to include a proportion of cases
that are attributable to inherited susceptibility to the disease.
Individuals carrying susceptibility genes are frequently at very
high risk of developing cancer that is often diagnosed at an early
age. Study of this group of people is important for two major
reasons. Firstly, identification of individuals who are at high
risk before they develop the disease may allow them to take avoiding
action, and secondly, elucidation of the genetic mechanisms underlying
the susceptibility often generates important insights into the
development of the common forms of non-familial cancer.
Within the Section of Cancer Genetics there are
five teams engaged in research programmes studying predisposition
to a wide range of adult cancers, including breast cancer, colorectal
cancer, prostate cancer, testis cancer, thyroid cancer and leukaemias
(see opposite team list for more detailed information). In addition,
we are expanding our investigation of childhood cancers such as
Wilms tumour. These programmes range from locating and cloning
the genes responsible, through characterisation and evaluation
of their importance, to the implementation of the findings in
the clinic.
The Cancer Genome Project was established by Professor
Mike Stratton and Dr Richard Wooster at the Wellcome Trust Sanger
Institute at Hinxton. The announcement of the finished human genome
sequence in April 2003 provides the platform from which the systematic
search for somatically acquired abnormalities in DNA of cancer
cells can be launched. The close collaboration between the Sanger
Centre and The Institute of Cancer Research will enable both institutions
to maximise their contributions to a major medical research aim
of the next decade: the exploitation of the human genome sequence
in cancer research. The Cancer Genome Project in association with
the Cancer Research UK Centre for Cell and Molecular Biology at
The Institute reported its first discovery in 2002: mutations
of the B-RAF gene in 70% of malignant melanomas and lesser numbers
of other cancers. B-RAF is now being developed as a target for
drug discovery together with the Cancer Research UK Centre for
Drug Development at The Institute.
Over the past few years the Section of Cancer Genetics
has had success in mapping (localisation) of high risk cancer
susceptibility genes using genetic linkage analysis. Groups within
the Section have mapped predisposition genes for breast cancer
(BRCA2 on chromosome 13q), testicular germ cell tumours
(TGCT1 on the X chromosome), cylindromatosis (CYLD
on chromosome 16q), Wilms tumour (FWT1 on chromosome
17q), thyroid cancer (MNG1 on chromosome 14q), juvenile
hyaline fibromatosis (JHF on chromosome 4), leiomyomas
and renal cell cancer (MCUL1 on chromosome 1) and colorectal
cancer (CRAC1 on chromosome 15). We are continuing these
mapping studies with further analyses of colorectal cancer, testicular
cancer, prostate
cancer, chronic lymphocytic leukaemia, multisite cancer families,
radiosensitivity, childhood cancer, overgrowth syndromes and coeliac
disease.
Following the localisation of such genes, we have
led or collaborated in studies resulting in the identification
of several genes including BRCA2, CYLD, LKB1
(STK11, in the Peutz-Jeghers syndrome), SMAD4
(Juvenile Polyposis), JHF (CMG2) and MCUL1.
Gene identification studies continue for a number of other susceptibility
genes.
Following the identification of susceptibility genes,
the genetic
epidemiology (including the risks associated with mutations and
their prevalence in various populations) associated with the diseases
has been analysed and this information is taken through to counselling
of families in the clinic and the development of novel clinical
screening and management approaches. This approach has been facilitated
by the development of the carrier clinic model for the management
of gene mutation carriers. Individuals with mutations are offered
oncogenetics expertise in this clinic with an integrated translational
clinical research programme.
Currently, our studies are extending into
lower penetrance cancer susceptibility genes. Two examples of
progress in this area have already been demonstrated by a collaboration
involving all groups within the Section. A sequence variant in
a gene known as CHEK2 was found and is believed to be
a low penetrance breast cancer susceptibility gene. In addition
mutations in the BRCA2 gene have been demonstrated to
act as high penetrance prostate cancer susceptibility alleles.
Highlights of Previous Year
In 2003 we:
- Identified the gene, CMG2, causing predisposition to juvenile
hyaline fibromatosis, a disease in which there are nodular tumours
of the skin and other organs in children.
- Published and analysed an international database of germline
mutations in the TP53 gene.
Future Aims
Identifying, characterising and implementing cancer susceptibility
genes in clinical practice continues to be our main aim.
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Staff Contacts
Publications
Jobs
Molecular
Pathology Team
Molecular & Population Genetics Team
Translational Cancer Genetics Team
Cancer & Developmental
Genetics Team
Cancer Gene Cloning Laboratory
Last Modified 12/07/04
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