Scientists Identify Genetic Causes For Prostate, Breast And Ovarian Cancer In Breakthrough Research

More than 80 genome regions that can raise a person's risk of developing prostate, breast and ovarian cancers, have been identified in a huge study led by scientists from the University of Cambridge and The Institute of Cancer Research, London.

Scientists say that the work, conducted through COGS (Collaborative Oncological Gene-Environment Study), will push forward our understanding of the biological causes of cancer. They warn, however, that the findings do not provide enough data to currently predict who will develop breast, prostate or ovarian cancers on the basis of genetics alone.

COGS is an EU-based consortium where more than 160 research groups from all over the world coordinate their work.

Coordinator of the COGS, Per Hall, said "People are already asking us, 'Shouldn't you genotype all people, to determine their individual risk for being diagnosed with these cancers?',... But it's too early."

COGS has released a batch of 13 papers in five journals this week, including: Nature Communications, Nature Genetics, PLOS Genetics, the American Journal of Human Genetic, and Human Molecular Genetics.

The study will lead to a deeper understanding of how these cancers develop, and hopefully new therapies and targeted screening, the authors explained.

Seeking out SNPs or "spelling mistakes"

The researchers were specifically looking for SNPs (single nucleotide polymorphisms) - genetic variations - that might be associated with a greater risk of developing cancer. Authors from the Karolinska Institute in Sweden, who were involved in the study, describe the SNPs as "genetic spelling mistakes" or "typos".

An SNP ("typo" or "spelling mistake") is a change of a nucleotide at a single base-pair location on DNA

SNPs are part of our natural heritage, genetic "typos" we inherit. How they affect a person depends on where on the DNA strand the genetic defect is found.

The scientists studied the DNA of more than 100,000 cancer patients and an additional 100,000 individuals from the general population. They discovered mutations that patients with ovarian, breast or prostate cancers had in common.

Each DNA alteration slightly increases the risk of cancer. However, people with many SNPs may have a nearly 30% higher risk of developing breast cancer and 50% higher risk of prostate cancer.

Targeting screening tests to those most at risk of developing cancer

Co-author, Professor Doug Easton, from the Centre for Cancer Genetic Epidemiology at the Department of Public Health and Primary Care and the Department of Oncology at the University of Cambridge, said:

"We're on the verge of being able to use our knowledge of these genetic variations to develop tests that could complement breast cancer screening and take us a step closer to having an effective prostate cancer screening program.

By looking for people who carry most of these variations we will be able to identify those who are at the greatest risk of getting these cancers and then targeting screening tests to these individuals."

Many of the SNPs the scientists discovered were located near areas of the genome that control gene behavior.

When these "control areas" are altered, the "brakes" that prevent cells from growing out of control stop working, resulting in metastasis (cancer spreading throughout the body) or out-of-control cancer cell growth.

The more we understand how these genes affect the emergence and progression of cancer, the more effective treatments and prevention programs will become.

Professor Paul Pharoah, from the Centre for Cancer Genetic Epidemiology at the Department of Public Health and Primary Care, the Cambridge Institute of Public Health (CIPH) and the Department of Oncology at the University of Cambridge, said:

"The identification of genetic variants that are associated with cancer risks will give us important insights into the basic biology of cancer that may lead to the development of new therapies or better ways to target existing therapies."

SNPs linked to Prostate, Breast and Ovarian Cancers

• Prostate cancer - the scientists found 23 genetic variations associated with prostate cancer, bringing the total to 78. Sixteen of these variations are specifically linked to the more aggressive and fatal forms of the disease.
  
  

  

  This groundbreaking research potentially brings us a step closer to the development of saliva tests to assess cancer risk

  Scientists at the Institute of Cancer Research, London, explained that following these discoveries, it is now possible to identify the top 1% of males with the greatest risk of developing prostate cancer - these men are 4.7 times more likely to develop the disease compared to the rest of the population. These men would be screened and monitored closely so that if they develop the disease, it is caught early enough when treatment is much more effective.
  
  Dr Jyotsna Batra, a Genetics scientist with Queensland University of Technology's (QUT's) Institute of Health and Biomedical Innovation, Australia, explained that scientists can now explain 35% of the hereditary risk of prostate cancer by combining the effects of the 78 variations - but it also means we still have 65% to go. QUT's main contribution to the study was in the area of prostate cancer.
  
  The scientists suggest that 78 may be just the tip of the iceberg and that there might be over 2,000 such markers that influence a man's risk of developing the disease.


• Ovarian cancer - the scientists found 11 SNPs associated with ovarian cancer. It will also become possible to identify high risk females so that they may be offered more regular and earlier screening and closer monitoring.
  
  The Moffitt Cancer Center, Florida, focused on regions of the genome that influence ovarian cancer risk. Moffitt's Director, Thomas A. Sellers, Ph.D., M.P.H., and 17 other co-authors explained that through large-scale analysis of over 18,000 women with ovarian cancer and over 26,000 healthy women, scientists are now much closer to understanding the inherited factors that contribute to this disease.


• Breast cancer - 49 SNPs associated with breast cancer were identified, more than doubling the number previously identified with the disease.

Some of the SNPs are located in regions that are associated with other cancers. This means several cancers share the same underlying mechanisms that can cause disease.

Faults in BRCA genes

The researchers also sought SNPs that might influence how different cancers behave and which regions impact on cancer risk for patients with faults in the BRCA genes.

We know that women who carry the BRCA gene defects have a higher risk of developing both ovarian and breast cancers. However, it is still not possible to determine which of them will go on to develop the diseases.

The study found that:

• 5% of the females who carry the BRCA1 fault as well as most of the genetic mutations linked to BRCA1 have a higher than 80% risk of developing breast cancer by the time they reach 80 years of age.


• Females with the BRCA1 defects and few of these variants have a 50% chance of developing beast cancer.

What does this mean for women with defects in their BRCA genes? - it will soon be possible for genetic counselors to tell them what their risk is of developing ovarian or breast cancers. It will help determine who should have earlier and more regular screenings.

Dr Kerstin Meyer, Senior Research Associate at the Cancer Research UK Cambridge Institute and affiliated with the Department of Oncology at the University of Cambridge, said:

"Current research is identifying many variants in the genome that are associated with breast cancer. My work at the CRUK Cambridge Institute studies the mechanisms underlying these associations. We examine how variants function to regulate specific target genes and what these target genes are.

Although some well-known cancer genes have been identified as targets, for example the cell cycle regulator CCND1, we have found that its dysregulation leading to breast cancer risk confounds expectations. Through a better understanding of the biology of cancer risk we hope to find interventions and therapies."

Antonis Antoniou, Cancer Research UK Senior Cancer Research Fellow from the Department of Public Health and Primary Care at the University of Cambridge, said "Women with BRCA 1 or 2 faults are more likely to get breast or ovarian cancer but have to live with the uncertainty of whether they will actually develop the disease. Our research puts us on the verge of being able to give women a much more accurate picture of how likely they are to develop breast or ovarian cancer and would help to guide them about the most appropriate type and timing of prevention or monitoring options for them. We need to now see how it could work in the clinic."

In a series of Accompanying Papers, the scientists investigated the changes that affect the behavior of different types of breast cancers. They identified some SNPs that are only linked to ER-Negative breast cancers (ER = estrogen receptor). This suggests that ER-negative breast cancers develop in a unique way, a discovery that should lead us to new therapies.

Dr Alison Dunning, from the Department of Oncology at the University of Cambridge said "Once the SNPs were discovered, we next needed to begin working out their mode of action, how some of these genetic changes cause cancer. When we examined the numerous genetic changes in the TERT gene, for example, we discovered very little evidence that they cause cancer by altering the length of chromosome end-caps, telomeres - countering previously held beliefs about using telomere length to predict cancer risk.

These types of genetic discoveries that we made during this study give us a new, exciting understanding of cancer biology and will hopefully lead to new drug targets."