Abstract
Further insight into genetic risk of breast cancer revealed
It is well known that women possessing the BRCA1 gene have an increased risk for both breast and ovarian cancer. A recent study has now found a separate region of DNA that appears to modulate this BRCA1-related risk.
The work was carried out by three separate groups and published simultaneously in the journal Nature Genetics.
The key finding of the research was that the configuration of one specific region on chromosome 19 appeared to either slightly reduce or increase the risk of developing cancer. It is hoped that this finding may be used to improve genetic testing to offer high-risk women a more personalized risk assessment. In future, the results could help women to decide on the most appropriate preventative treatment.
One group carried out a genome-wide association study of 1193 individuals carrying a mutated BRCA1 gene who had been diagnosed with breast cancer under the age of 40 years and another 1190 BRCA1 carriers, over the age of 35 years, who had not developed the disease. This enabled the researchers to identify 96 SNPs for replication in another 5986 BRCA1 carriers (2974 had breast cancer and 3012 were unaffected). From this research five SNPs located on 19p13 were found to modify breast cancer risk.
“…one specific region on chromosome 19 appeared to either slightly reduce or increase the risk of developing cancer.”
Lead author of one of the studies, Antonis Antoniou (University of Cambridge, UK), explained “We've found a DNA region that acts like a volume control – to turn up or turn down the risk of developing breast cancer from faults in the BRCA1 gene”.
“Our discovery is the first step in a much larger study to identify genetic factors that modify breast cancer risk in women carrying BRCA1 mutations, and ultimately could help assess the risk for each woman and monitor for the disease”, he commented.
“…it is hoped that this finding can be combined with analysis of other DNA regions yet to be identified to offer a more accurate individual prediction of cancer risk.”
There is also some evidence to suggest that, the risk for hormone receptor-negative breast cancer was raised and lowered by changes in the 19p13 DNA region, even for people not carrying the mutated BRCA1 gene. The newly-identified region may also play a role in ovarian cancer risk in women without the BRCA1 fault.
Another study revealed four separate genetic regions that may be linked with cancer risk in the general population.
Although the increase or decrease in risk attributed this DNA region is modest, it is hoped that this finding can be combined with analysis of other DNA regions yet to be identified to offer a more accurate individual prediction of cancer risk.
Sources: Antoniou AC, Wang X, Fredericksen ZS et al.: A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population. Nat. Genet. 42(10), 885–892 (2010); Bolton KL, Tyrer J, Song H et al.: Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat. Genet. 42(10), 880–884 (2010).
Study finds metabolic markers that could potentially predict a women's risk of pre-eclampsia in early pregnancy
In a study recently published in Hypertension, investigators have discovered metabolic markers that could potentially predict the risk of pre-eclampsia early on in pregnancy.
The etiology of pre-eclampsia is not completely understood, and there is no clinically useful screening test. Pre-eclampsia is potentially lethal, and women with the condition have high blood-pressure, and protein in their urine, along with possible other symptoms or complications. Furthermore, pre-eclampsia causes substantial maternal and fetal morbidity and mortality’.
An author of the study, Louise Kenny (University College Cork, Cork, Ireland) explains, “Everything we know about this condition suggests women do not become sick and present with pre-eclampsia until late in pregnancy, but the condition originates in early pregnancy. To develop effective treatment and prevention strategies – our ultimate goal – we need to be able to start treatment in early pregnancy. We need to be able to tell who is at risk and who is not”.
In this investigation scientists carried out a ‘two-phase discovery/validation metabolic profiling study’. The discovery phase of the investigation employed a nested case–control study in which samples of 60 women at approximately 15 weeks gestation, who later developed pre-eclampsia, were taken, along with 60 controls. All women were part of the Screening for Pregnancy Endpoints (SCOPE) trial. Ultra performance liquid chromatography mass spectrometry was used to examine plasma samples.
“…women do not become sick and present with pre-eclampsia until late in pregnancy, but the condition originates in early pregnancy … We need to be able to tell who is at risk and who is not.”
The study's second phase validated the initial findings in a different group of younger (average age: 22–23 years), more ethnically diverse women at a participating center in a different country. Plasma was obtained from 39 women at approximately 15 weeks gestation who later developed pre-eclampsia, as well as 40 matched controls.
In both studies, investigators were able to detect 14 metabolites (with odds ratio for developing pre-eclampsia of 36 [95% CI: 12-108] and 23 [95% CI: 7–73], respectively) and the authors conclude that ‘the finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of pre-eclampsia offers insight into disease pathogenesis and offers the tantalizing promise of a robust presymptomatic screening test’.
Phil Baker (University of Alberta, Alberta, Canada) states, “In the next 5 years our aim is to develop a simple blood test that will be available to all pregnant women that will detect the risk of pre-eclampsia in early pregnancy”.
Sources: Kenny LC, Broadhurst DI, Dunn W et al.: Robust early pregnancy prediction of later pre-eclampsia using metabolomic biomarkers. Hypertension 56(4), 741–749 (2010); American Heart Association News Releases: www.newsroom.heart.org/index.php?s=43&item=1111
in brief …
Researchers find a new cancer gene and a possible link between ovarian cancer and endometriosis
Results from a study carried out by researchers with the Ovarian Cancer Research Programme (OvCaRe) suggest that ARID1A is a tumor suppressor in ovarian clear-cell and endometrioid carcinomas.
ARID1A was discovered by investigators as a new cancer gene in which mutations often take place. Kim Wiegand (University of British Columbia, British Columbia, Canada) comments, “When we first saw these mutations we were very excited because ARID1A has several functions that made it a potential cancer gene yet mutations in this gene have never been identified before in ovarian cancer”.
Targeted exon resequencing on certain sample cohorts was carried out in order to find out how frequently ARID1A mutations in ovarian clear-cell carcinoma and other subtypes of ovarian cancer occur.
David Huntsman (University of British Columbia) states, “Our discovery of the dominant mutation in clear-cell ovarian cancer raises hope for much needed treatments for this little understood cancer type. Connecting ARID1A gene mutations to endometriotic lesions accelerates us toward the development of tools to determine which women with endometriosis are at increased risk for ovarian cancer”.
Andrew Berchuck (Duke University Medical Center, NC, USA) explains, “The finding that ARID1A is the most frequently mutated gene described thus far in endometrioid and clear-cell ovarian cancers represents a major scientific breakthrough. This discovery also sheds light on how endometriosis predisposes to the development of these cancers. The novel insights provided by this work have the exciting potential to facilitate advances in early diagnosis, treatment and prevention of endometrioid and clear-cell cancers, which account for over 20% of ovarian cancer cases”.
Sources: Wiegand KC, Shah SP, Al-Agha OM et al.: ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. doi: 10.1056/NEJMoa1008433 (2010); Vancouver Coastal Health Research Institute news and information: www.vchri.ca/s/NewsReleases.asp
Bacteria-sensing protein may provide opportunities for preventing infections in the womb
Recent research by a team at Swansea University's School of Medicine (Swansea, UK) may pave the way for the development of new approaches to prevent infections and disease of the womb, such as chlamydia, which can cause the infertility-linked pelvic inflammatory disease, and has been the most common STI in the UK since the year 2000.
The group, led by Martin Sheldon, has determined the mechanism in mice that detects and responds to the presence of bacteria in the womb.
“Infections of the womb are common and can lead to infertility and early labor, but we don't have any vaccines or other ways of preventing these problems”, explains Sheldon. “The womb is a unique environment and responds to infection in different ways to other parts of the body. What we've established is that in mice the womb relies on cells not normally involved in immunity to detect and respond to bacteria. This is crucial information as it will hopefully provide us with new targets for preventing disease”.
The womb is usually a sterile environment and relies on innate immunity for protection. Compared with sites such as the gut, the womb is relatively undeveloped in terms of immunity and, as such, the innate response is not followed by an adaptive immune response. This means that long lasting humoral or cell-based immunity is not developed and vaccination is consequently problematic.
The team has determined that a protein present on the surface of the epithelial and stromal cells lining the womb plays a key role in detecting bacterial cells in the womb of mice. They now plan to work with industrial collaborators to develop new strategies to prevent infection.
Sources: BBSRC press release: www.bbsrc.ac.uk/media/releases/2010/100923-pr-discovery-to-prevent-infections-in-the-womb.aspx; Office for national statistics: www.statistics.gov.uk/cci/nugget.asp?id=4; Sheldon IM, Roberts MH: Tolllike receptor 4 mediates the response of epithelial and stromal cells to lipopolysaccharide in the endometrium. PLoS ONE 5(9), e12906 (2010).