A new breast cancer susceptibility gene discovered by exome sequencing
Researchers identified mutations in rare gene run in families with unknown genetic cause and where breast cancer occurs at an early age
- Date : 05 Apr 2012
- Topic : Breast cancer
Mutations in a gene XRCC2 increases breast cancer risk, according to a study published on 30 March in the American Journal of Human Genetics. The mutations in the newly identified gene, although rare, explain another proportion of breast cancers that run in families where there is no known genetic cause of cancer, and which particularly occurs at an early age.
Researchers led by three co-principal investigators from the Genetic Epidemiology Laboratory, Department of Pathology at the University of Melbourne, the Huntsman Cancer Institute and University of Utah, identified this gene using exome capture massively parallel sequencing (exome sequencing). It is a significant discovery and the first breast cancer risk gene to be discovered using the latest genetic sequencing technology.
The discovery could assist some families to determine individual risk and which family members are at high risk of contracting the disease. Unaffected relatives of people with a mutation in this gene could also be offered predictive testing, subsequent genetic counselling and ongoing clinical management on the basis of their mutation status.
Currently, only about 30% of the familial risk for breast cancer has been explained, leaving the substantial majority still unaccounted for. Research indicates that no single gene is likely to account for a large proportion of the remaining unexplained genetic susceptibility to breast cancer.
XRCC2 may also provide a new target for chemotherapy. PARP inhibitors appear to kill tumour cells that have gene mutations in a particular DNA repair pathway. XRCC2 is in this pathway, as are BRCA1 and BRCA2. It's reasonably likely that a breast cancer patient who has a mutation in XRCC2 will respond well to treatment with PARP inhibitors.
A large series of massively parallel sequencing studies
Initially, using massively parallel sequencing, researchers identified XRCC2 mutations in two families in Melbourne and the Netherlands. This was followed by a larger series of studies using DNA from blood samples of 689 families with multiple members affected by breast cancer, and from 1308 women who were affected at an early age by breast cancer and recruited from the general population, as well as 1120 controls. More XRCC2 mutations were detected in the breast cancer cases but not in the controls. These additional studies were conducted in Melbourne and at the International Agency for Research on Cancer (IARC) in France.
This study demonstrated the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases like breast cancer. The study approach could be applied to many other common, complex diseases with components of unexplained heritability, such as colorectal and prostate cancers.
The researchers used exome sequencing, which shows the exact order of the nucleotides in all of the protein coding genes in the human genome. The ability of this technology to analyze the DNA of all of the genes in the genome in a single experiment, makes it an amazingly powerful tool for genetic research.
Genes involved in a particular type of DNA repair
The researchers focused on the genes involved in DNA repair, because most known breast cancer genes have been found there. That focused analysis allowed them to identify XRCC2 as a breast cancer susceptibility gene in individuals with a family history of breast cancer.
From the exome sequencing data, they found two different types of XRCC2 mutations that occur in breast cancer patients. One type of mutation causes the gene to create an incomplete version of the protein. The resulting protein is usually dysfunctional. The other type occurs when a single amino acid in the protein is changed.
It's a subtle change to the protein, but the resulting change in function could range anywhere from innocuous to even worse dysfunction than the incomplete protein causes. Further research is underway. A worldwide effort has already been launched to figure out what fraction of breast cancer is due to mutations in this gene and how high the risk conferred by these mutations actually is.
The research was conducted in a large collaborative network including researchers from North America, Australia, and Europe: the Huntsman Cancer Institute, The University of Utah, USA; The Breast Cancer Family Registry, Australia; the Victorian Life Sciences Computation Initiative, hosted by The University of Melbourne; The International Agency for Research on Cancer, France; The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer and The Cancer Council Victoria, Australia.
The work was supported by The Cancer Council Victoria, The National Institutes of Health (USA) and the National Health and Medical Research Council of Australia plus several worldwide research foundations.
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