In the United States, prostate cancer affects about one in every six men.  Genomewide association studies aimed at finding common genetic variants associated with this common disease have been particularly successful. More than a dozen SNPs have been associated with prostate cancer, but researchers calculate that these variants represent only a tiny fraction of the genetic component of the disease.

To fill in the genetic gaps, researchers are turning to studies that include larger numbers of participants than ever before.  The hard work is paying off, as can be seen in four recent reports published in the journal Nature Genetics.  These analyses, based on the DNA of tens of thousands of men, have added at least 12 new variants to the roster of prostate cancer-associated SNPs.

One of the most striking features of these new studies is that they have identified two new SNPs on chromosome eight in a region known as 8q24.  Three other variants in this same region have already been linked to prostate cancer in both African American and European samples.  Other SNPs in the 8q24 region have been associated with breast, bladder and colorectal cancer.

(The new 8q24 SNPs as well as the others associated with prostate cancer are detailed in a table at the end of this post.)

The bounty of cancer-related SNPs in the 8q24 region is puzzling to scientists because there are no actual genes in this stretch of DNA.  The closest gene, MYC, is known to be involved in cancer, but so far there is no evidence that the cancer-associated 8q24 SNPs are affecting MYC. Future research will hopefully identify what these SNPs are doing and how they affect cancer risk.

Even though prostate cancer genomewide association studies have been fruitful, critics such as John Witte of UCSF argue that the findings may not be clinically useful (read his February Nature Genetics review of prostate cancer genomics here).

But that doesn’t mean that looking for variants associated with prostate cancer should be abandoned.  Finding SNPs associated with the disease could lead scientists to new treatments.

There is also the possibility of finding variants that don’t just predict whether someone is at risk for prostate cancer, but whether they are at risk for a particularly aggressive form of the disease. This could help doctors discriminate between those men whose cancers require immediate treatment and those who can avoid the side effects of surgery and radiation in favor of “watchful waiting.”

“There is clear clinical utility in identifying markers that can distinguish which prostate tumors will progress rapidly and be life-threatening versus those that are relatively latent and may not substantively impact a man’s health,” Witte writes.

As has been the case with most other studies looking for genetic variants associated with prostate cancer, none of the four new studies found an association between the identified SNPs and disease severity. Scientists have suggested that this indicates the studies are mainly finding variations associated with increased risk for the initiation of cancer. To find disease aggression-associated variants, more large studies will be needed, and researchers will need to focus on SNPs correlated with disease recurrence following treatment and/or mortality instead of just presence or absence of disease.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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Prostate cancer, the most common cancer to affect men, kills 30,000 men of all ethnicities each year. The disease is known to have a strong genetic component, and several common DNA variations have been found to affect a man’s risk of prostate cancer. However, previous research has analyzed men of only European and African ancestry, leaving the effects of these genetic variants in Asian men undetermined.

Recently, researchers analyzed Japanese men for several genetic variants previously linked to prostate cancer in European and African American populations. The study found that some of these variants also affect the risk of developing prostate cancer in Asian men.

A team from Boston and Japan led by Matthew Freedman searched for risk variants by scanning the genomes of nearly 1,350 Japanese men, including more than 300 prostate cancer patients. The results, published online last week in the Journal of the National Cancer Institute, provide evidence that five out of 23 SNPs previously associated with prostate cancer among Europeans and African Americans also impact risk in this Asian population.

(23andMe customers can use the links in the table at the end of this post to see their data for the five SNPs using the Browse Raw Data feature. Note: Even though only men can develop prostate cancer, women may pass on the risk versions of these SNPs to their sons, possibly increasing their risk.)

Although not every one of the five SNPs had a statistically significant association on its own, the group of SNPs had an association with prostate cancer. Men who carry six or more of the 10 possible risk copies at any of the five associated SNPs (people have two copies of each SNP) had 6.22 times increased odds of developing prostate cancer than men with two or fewer risk copies. The SNPs were not linked to the progression of prostate cancer, but SNPs rs6983561 and rs4430796 were associated with a younger age at diagnosis.

Further research with a larger number of patients will be needed to determine how several of these SNPs may have differing effects between populations of different ancestry, suggests John Ioannidis in an accompanying editorial published in the Journal of the National Cancer Institute.

“When each SNP is analyzed separately, there are clear signs of divergent risks in Asian versus European populations,” Ioannidis wrote. Several other SNPs may also have considerably different effects in these and African American populations, so more research is needed to accurately determine an individual’s risk for prostate cancer.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

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BRCA1 and BRCA2 (BRCA1/2) mutations account for most (though not all) cases of inherited breast cancer in women. These mutations are also associated with an increased risk for ovarian cancer. In men, BRCA1/2 mutations increase the risk for breast cancer and may also increase prostate cancer risk.  Research has indicated there may also be an increased risk of melanoma and pancreatic cancer in people with BRCA1/2 mutations.

Although BRCA1/2 mutations significantly increase the risk of cancer, having one of these mutations doesn’t mean a person actually has cancer or will necessarily ever get the disease.   But new research from scientists at the National Cancer Institute and the National Human Genome Research Institute, published online this week in the journal PLoS ONE, suggests that those BRCA1/2 carriers who do escape cancer may still be at risk of a shorter than average lifespan.

In a study of almost 5,300 people with Ashkenazi Jewish ancestry researchers found that, on average, both men and women who carry BRCA1/2 mutations die younger — even when cancer deaths are excluded from the analysis.  Among women free of melanoma, breast, ovarian and pancreatic cancer, BRCA1/2 mutation carriers died 5.8 years earlier (age 75.0 vs. 80.5) than those women without the mutations. In men, after excluding cases of melanoma, prostate and pancreatic cancer, BRCA1/2 mutation carriers died about 3.7 years earlier than those without the mutations (71.0 years old vs. 74.7).

“Theoretically, these mutations may either be associated with a small increase in risk of a variety of different diseases, or they may be associated with moderate increase in risk of a few major diseases,” the authors write.  They note that the current study is unable to make this distinction because it did not collect information on non-cancer related causes of death.

The researchers analyzed the effects of only the three BRCA mutations that are most common in Ashkenazi Jewish people: 185delAG in BRCA1, 5382insC in BRCA1, and 6174delT in BRCA2.  The mutations account for 80-90% of hereditary breast and ovarian cancer in this ethnic group.  But there are hundreds of other BRCA1/2 mutations that have been associated with cancer, and the authors caution that further studies taking these other BRCA1/2 mutations into account and using study subjects from diverse groups will be needed to confirm their results.

(23andMe provides data for the three BRCA1/2 mutations most commonly found in people with Ashkenazi Jewish ancestry in the BRCA Cancer Mutations (Selected) Carrier Status Clinical Report.)

The authors conclude that understanding the effects of BRCA1/2 mutations on non-cancer related deaths could eventually help scientists understand how the mutations affect cancer risk and may even facilitate efforts aimed at finding new ways of preventing disease in BRCA1/2 mutation carriers.

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Each type of cancer has its own idiosyncrasies, but when it comes down to it, they all have one thing in common: failure to control cellular growth. So it’s somewhat surprising that when genome-wide association studies have looked for single common variations associated with the risks for multiple types of cancer, they have for the most part identified only SNPs that are peculiar to just one form of the disease.

A new study published online Sunday in Nature Genetics may signal a change in this trend. A team of researchers led by Thorunn Rafnar and Patrick Sulem of deCODE Genetics in Iceland describes how a SNP they originally found to be associated with the risk for developing basal cell carcinoma (BCC), a type of skin cancer, is also linked to increased odds for four other cancers.

In a study of more than 33,800 cancer patients and 45,800 controls, the scientists found that the C version of rs401681 is associated with increased odds of lung, bladder, prostate and cervical cancer, in addition to the previously found association with BCC. This variation decreases the odds of cutaneous melanoma, another type of skin cancer.

(23andMe customers can check their data for this SNP, rs401681, using the Browse Raw Data feature. A table at the end of this post provides details about its effect on different cancers).

The C version of rs401681 was also marginally, although not significantly, associated with increased odds of endometrial cancer and decreased odds of colorectal cancer.

There was no association of the SNP with cancer of the breast, kidney, stomach, thyroid, ovary or pancreas, nor with lymphoma, multiple myeloma or squamous cell carcinoma (a third type of skin cancer). The authors say that further investigation in even larger samples will be needed to determine if there truly is no association, or if they just haven’t picked it up yet.

An association was also found between rs2736098, a nearby SNP, and four of the five cancers that were associated with rs401681. 23andMe does not currently provide data for rs2736098.

Both SNPs are near a gene involved in maintaining the protective stretches of DNA attached to the ends of chromosomes called telomeres. The authors suggest that these SNPs, or other nearby variations, may lead to shortened telomeres, which are associated with several types of cancer.

Telomere length is determined in part by genetics, but environmental factors such as smoking and radiation can also shorten them. The authors note “four of the five cancers associated with the risk variants are cancer types that have strong environmental contributions to risk – smoking and occupational exposures for lung and bladder cancer, UV irradiation for BCC and infection with human papillomavirus for cervical cancer.” More research could help explain the exact relationship between the genetic variations found in this study and the environmental causes of these cancers.

*Effect is the increase or decrease in odds compared with someone with two copies of the T version of rs401681.

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Following on the heels of last month’s New England Journal of Medicine study on genetic associations with prostate cancer risk are three new papers in Nature Genetics. The new batch not only replicates earlier discoveries but adds at least 16 potential new associations to the mix. While there are too many to list here individually, a few are worthy of particular mention. (Links to 23andMe’s Genome Explorer (now called Browse Raw Data) are provided for each.)

Iceland’s deCODE Genetics compared the genotypes of 10,000 men diagnosed with prostate cancer with those of 29,000 healthy controls. Instead of conducting a genome-wide association study (GWAS) of hundreds of thousands of single nucleotide polymorphisms (SNPs), the authors chose to follow up on two promising candidates identified in previous GWAS. In the current study, both showed associations to prostate cancer risk.

One of the candidates, rs5945572, is located on the X chromosome. Men only have one X chromosome and thus one copy of rs5945572. Those who had the “A” version of the SNP had slightly higher odds of prostate cancer.

The fact that the SNP is located on the X chromosome—which sons inherit only from their mothers—may help to explain why brothers of men with prostate cancer are at greater risk of being affected than fathers are. If a father has the protective “G” version of the SNP on his X chromosome, he cannot pass it on to his sons; the contribution of this SNP to a man’s risk of prostate cancer is determined by which version his mother passes to him.

The second SNP identified in the deCODE study was rs721048, on chromosome 2. This SNP was analagous to rs2710646, which is in 23andMe’s Genome Explorer (Browse Raw Data). Each copy of the “A” version of rs2710646 slightly raised men’s odds of prostate cancer.

The other two studies each examined 5,000 cases and 5,000 controls. While the studies found a number of significant associations, both independently identified a link between rs10993994 and prostate cancer risk. Each copy of the “T” version of rs10993994 raised men’s odds of prostate cancer. This SNP is located in a gene called MSMB, which encodes a prostate-specific protein thought to be a biomarker for advanced forms of prostate cancer. The authors speculate that the different versions of this SNP might affect levels of the MSMB protein, but this will have to be shown in future experiments.

Further replication studies will have to be performed before all of these associations are fully accepted by the scientific community. But because rs10993994 has already been identified in two large studies, we’ll get it into the Gene Journal article (now called Health and Traits) on prostate cancer as soon as possible. Check back soon to see how this SNP fits into the picture!

(2/12/08 update: added PubMed links to study abstracts. -Andro Hsu)

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