UCL Scientists Discover How To Switch On Critical Ovarian Cancer “Protector” Gene & Arrest Tumor Growth

A new University College London study reveals that a gene [EPB41L3] which normally protects against ovarian cancer is switched off in 66% of ovarian cancer cases and switching it back on arrests tumor growth.

A new University College London study reveals that a gene which normally protects against ovarian cancer is switched off in 66% of ovarian cancer cases and switching it back on arrests tumor growth.

The researchers found that the “protector gene,” known as EPB41L3, is inactivated in 65 per cent of ovarian cancers and reactivating the gene halted tumor growth and triggered large numbers of ovarian cancer cells to commit suicide.

The research, co-funded by Cancer Research UK and the gynecological cancer research charity The Eve Appeal, raises the prospect for developing therapies that mimic or restore the function of the gene to kill ovarian cancer cells in a targeted way.

UCL’s Dr. Simon Gayther, who led the study, said:

“Previous studies have found similar ‘protector genes’ but ours is the first to uncover EPB41L3 as a gene specific to ovarian cancer. We also discovered that the gene is completely lost in about two-thirds of the ovarian tumours we looked at. When we switched it back on in these tumours, it had a positive effect in killing cancer cells. This is a very exciting result because it means therapies that mimic or reactivate this gene could be a way to kill many ovarian cancers.”

The scientists, based at UCL’s Institute of Women’s Health, used a cutting-edge approach which involves transferring whole chromosomes into ovarian cancer cells. They found that introducing an additional copy of chromosome 18 boosted the activity of 14 key genes, triggering large numbers of the cancer cells to die.

The scientists examined more than 800 ovarian tumors and found that one of the 14 genes – EPB41L3 – was inactivated in around 66% of malignant ovarian tumors, compared to 24% of benign tumors and 0% of normal ovarian cells.

Reactivating the gene had the same deadly effect on the cancer cells, suggesting that it was the trigger that was causing the cells to self-destruct.

Jane Lyons, CEO of The Eve Appeal, said:

“This research is an exciting step forward – a gene has been identified that can help halt the growth and spread of ovarian cancers. The challenge now is for the researchers and clinicians to find a way to use this new information to increase survival from the disease.”

Dr. Lesley Walker, director of cancer information at Cancer Research UK, said:

“We know that there is a class of genes that protect us from developing cancer. This is an exciting new one specific to ovarian cancer. Advanced ovarian cancer is very difficult to cure, which makes this type of research even more important.”

Sources:

Beyond BRCA1 & BRCA2: U.K. Researchers Identify Genetic Defect That Could Increase Risk of Ovarian Cancer Up To 40%

Scientists have located a region of DNA which – when altered – can increase the risk of ovarian cancer according to research published in Nature Genetics today. An international research group led by scientists based at the Cancer Research UK Genetic Epidemiology Unit, at the University of Cambridge and UCL (University College London) searched through the genomes of 1,810 women with ovarian cancer and 2,535 women without the disease from across the UK. …The scientists estimate that there is a 40 per cent increase in lifetime risk for women carrying the DNA variation on both copies of chromosome nine compared with someone who doesn’t carry it on either chromosome. The risk for women carrying the variation on both chromosomes is 14 in 1000 – compared with [10] ten in 1000 [in the general population]. … The lifetime risk for a woman carrying the DNA variant on one copy of the chromosome is increased by 20 per cent from ten in 1000 to 12 in 1000. …

Genetic link to ovarian cancer found

Cancer Research UK

SUNDAY 2 AUGUST 2009

Cancer Research UK Press Release

Scientists have located a region of DNA which – when altered – can increase the risk of ovarian cancer according to research published in Nature Genetics today.

An international research group led by scientists based at the Cancer Research UK Genetic Epidemiology Unit, at the University of Cambridge and UCL (University College London) searched through the genomes of 1,810 women with ovarian cancer and 2,535 women without the disease from across the UK. They analysed 2.5 million variations in DNA base pairs – the letters which spell out the genetic code – to identify common spelling ‘errors’ linked to ovarian cancer risk.

The scientists identified the genetic ‘letters’- called single nucleotide polymorphisms (SNPs) – which when spelled slightly differently increase ovarian cancer risk in some women. This is the first time scientists have found a SNP linked uniquely to risk of ovarian cancer and is the result of eight years of investigations. With the help of the international Ovarian Cancer Association Consortium (OCAC), they then looked at more than 7,000 additional women with ovarian cancer and 10,000 women without disease from around the world to confirm this finding.

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The region of risk DNA is located on chromosome nine – there are 23 pairs of each chromosome in humans, one of each pair inherited from each parent. The scientists estimate that there is a 40 per cent increase in lifetime risk for women carrying the DNA variation on both copies of chromosome nine compared with someone who doesn’t carry it on either chromosome. The risk for women carrying the variation on both chromosomes is 14 in 1000 – compared with [10] ten in 1000 [in the general population].

Approximately 15 per cent of women in the UK population carry two copies of the variant DNA.

The lifetime risk for a woman carrying the DNA variant on one copy of the chromosome is increased by 20 per cent from ten in 1000 to 12 in 1000. Approximately 40 per cent of women in the UK carry one copy.

Senior author Dr. Simon Gayther, whose work is supported by Cancer Research UK and The Eve Appeal charity which fundraises for the gynaecological cancer research team based at UCL, said: “The human DNA blueprint contains more than 10 million genetic variants. These are part and parcel of our characteristics and make-up – but a handful will also increase the chances of some women getting ovarian cancer and we have found the first one of these.”

“There is now a genuine hope that as we find more, we can start to identify the women at greatest risk and this could help doctors to diagnose the disease earlier when treatment has a better chance of being successful.”

Dr. Andrew Berchuck, head of the international Ovarian Cancer Association Consortium steering committee, said: “This study confirms that ovarian cancer risk is partly determined by genetic variants present in a large number of women. This initial discovery and others that will likely follow in the future lay the groundwork for individualised early detection and prevention approaches to reduce deaths from ovarian cancer.”

Ovarian cancer is the fifth most common cancer in women in the UK with around 6,800 new cases diagnosed each year in the UK – 130 women every week. It is the fourth most common cause of cancer death in women in the UK with around 4,300 deaths from the disease in the UK each year.

BRCA1 and BRCA2 are high risk genes which cause breast cancer and are already known to significantly increase the risk of ovarian cancer- but faults in these genes are rare and probably cause less than five per cent of all cases of ovarian cancer.

Lead author, Professor Dr Paul Pharoah, a Cancer Research UK senior research fellow at the University of Cambridge, said: “We already know that people with mistakes in the BRCA1 and BRAC2 genes have a greater risk of ovarian cancer – but on their own they don’t account for all of the inherited risk of the disease. “It is likely that the remaining risk is due to a combination of several unidentified genes – which individually carry a low to moderate risk. Now we have ticked one off, the hunt is on to find the rest.”

Rose Lammy, the mother of David Lammy MP [Member of Parliament] for Tottenham and Minister for Higher Education and Intellectual Property, died of ovarian cancer in 2008. Rose Lammy’s DNA sample was included in the study, and she carried both risk alleles of the new genetic marker that researchers have identified.

David Lammy said: “I am pleased that Mum’s sample was included in this study as it is one step towards earlier diagnosis of ovarian cancer when treatment is more successful. We now know the fact that she had this altered DNA meant that her lifetime risk had risen from 10 in 1,000 to 14 in 1,000, an increase of 40 per cent compared to those women who don’t carry this DNA variation. Dr Lesley Walker, director of cancer information at Cancer Research UK, added: “This is an important discovery. Our researchers have worked as part of a huge collaboration to establish the regions of DNA that can increase someone’s risk of developing ovarian cancer. “This research paves the way for scientists to discover even more genes linked to ovarian cancer and could lead to new approaches to treat or prevent the disease – crucially it will help doctors manage women who are at increased risk.”

Source: Genetic link to ovarian cancer found, Cancer Research U.K. Press Release & Video, 02 Aug. 09.

Reference: Honglin Song et al. (2009). A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2 Nature Genetics 10.1038/ng.424.

Preliminary Findings of a Large British Study Indicate That CA-125 Blood Test & Transvaginal Ultrasound Test Can Detect Early Ovarian Cancer

“Ovarian cancer has a high case—fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. …”

“Background

Ovarian cancer has a high case—fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS.

earlydetecttrialdesign1

The United Kingdom Collaborative Trial of Ovarian Cancer Screening - Overall Trial Design

Methods

Between 2001 and 2005, a total of 202,638 post-menopausal women aged 50—74 years were randomly assigned to [1] no treatment (control; n=101,359); [2] annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50,640); or [3] annual screening with transvaginal ultrasound (USS; n=50,639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032.

Findings

In the prevalence screen, 50,078 (98.9%) women underwent MMS, and 48,230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1,490 USS). Overall, 4,355 of 50,078 (8.7%) women in the MMS group and 5,779 of 48,230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1,894 (3.9%) women in the USS group required clinical evaluation. 97 of 50,078 (0.2%) women from the MMS group and 845 of 48,230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0—61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers.

Interpretation

The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

Funding

Medical Research Council, Cancer Research UK and the Department of Health, UK; with additional support from the Eve Appeal, Special Trustees of Bart’s and the London, and Special Trustees of University College London Hospital.”

Primary Source

Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS); Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS); Usha Menon MD, Aleksandra Gentry-Maharaj Ph.D., Rachel Hallett Ph.D. et. al, The Lancet Oncology, Early Online Publication, 11 March 2009 doi:10.1016/S1470-2045(09)70026-9.

Comment

During an interview with the New York Times, Dr. Ian Jacobs, director of the Institute for Women’s Health at University College London, and director of the trial, discussed the optimism and the caveats associated with the preliminary clinical study results as follows:

We have now demonstrated we can pick up the vast majority of women with ovarian cancer earlier than they would have otherwise been detected and before they have symptoms, .. and that a good proportion of those women have earlier stage disease than we would normally expect them to have. … [W]omen thinking of having this must understand and realize that there’s a possibility it will do more harm than good. We have reason to think it will save lives, … and then the question is, will it save enough lives to balance out the harm it does? [Emphasis added].

Robert Smith, director of cancer screening for the American Cancer Society informed the New York Times that “[w]e’re not even remotely close to knowing how to screen women of average risk with these tests, or even if we should.” Mr Smith added that it is important to run large clinical trials, but that the preliminary results of this study must be interpreted with caution.

Secondary Sources