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A paper published in the New England Journal of Medicine (NEJM) this week, entitled &#8220;<a href="http://content.nejm.org/cgi/content/short/362/11/986" target="_blank" rel="noopener">Performance of Common Genetic Variants in Breast-Cancer Risk Models</a>,&#8221; has led several media outlets to declare that common genetic variants have nothing to add when it comes to predicting breast cancer risk.   Here we&#8217;ll explain how the results of this study have been misinterpreted.
Researchers from the National Cancer Institute and other institutions looked at data from 5,590 women with breast cancer and 5,998 women without the disease.   These women, all between 50 and 79 years old, had participated in one of five studies, four in the United States and one in Poland.   Since it&#8217;s known already which women have or have had breast cancer, and which have not, the researchers were able to use their data, both genetic and non-genetic, to test the predictive power of different types of risk calculations.
The study tested five different models.   The &#8220;demographic model&#8221; considered only age, year of entry into the study and which study the woman was originally part of.   The &#8220;nongenetic model&#8221; added in several variables that are part of the so-called &#8220;Gail model,&#8221; which is the standard model used in clinical practice today to counsel women about their risk.   These variables were the number of first-degree relatives with a diagnosis of breast cancer, age at menarche, age at first live birth, and number of previous breast biopsies.   Two models used the demographic information plus genetic information for 10 SNPs (they differed in details of how the genetic risk score was calculated).   Finally, the &#8220;inclusive model&#8221; combined demographics, the Gail model and the genetic information.
The genetic models and the nongenetic model performed about the same, with genetics doing just a little bit better.   Perhaps not surprisingly, the best model was the one that used the most information.   With the inclusive model, which is based on genetic and non-genetic information, there was a net 12% improvement in risk classification over the nongenetic model for women with breast cancer.
So, SNPs did add something.   The improvement in prediction seen when SNPs are added to the nongenetic model is about the same as the improvement seen when the Gail model information is added to the simplistic demographic model.   Discounting the benefit of adding SNP information to the Gail model implicitly discounts the utility of the Gail model itself.   Peter Devilee and Matti A. Rookus made this very point in a <a href="http://content.nejm.org/cgi/content/short/362/11/1043" target="_blank" rel="noopener">NEJM editorial</a> that accompanied the study.
It&#8217;s also important to remember that the study of common variations and their effect on common diseases like breast cancer is a relatively young science.   Many more variants are bound to be discovered, and these will only help further refine risk predictions.
It&#8217;s true that there is a cost associated with collecting a person&#8217;s genetic information, while collecting the information needed for the Gail model is essentially free.   (In fact, a risk calculator based on the Gail model is available at the <a href="http://www.cancer.gov/bcrisktool/" target="_blank" rel="noopener">National Cancer Institute website</a>.) But for those people who do have their genetic information in hand, the current study shows that it can improve the estimation of their risk for breast cancer.   It should be remembered, too, that not everyone is fortunate enough to have access to their family medical history. Adoptees, for example, cannot get an accurate picture of their breast cancer risk from the Gail model.   For such women, the ability to use their own genetics to help assess their risk for breast cancer is an option that should not be dismissed.
Ultimately, it&#8217;s not about genetics vs. non-genetics &#8212; it&#8217;s about getting accurate estimates of risk to help doctors catch cancers early on, when they&#8217;re easiest to beat. Researchers should welcome any tool that can help them move closer to keeping more women healthy.   Giving up on genetics this early on in the game would be a real disservice.
Note: A similar study can be found in <a href="http://precedings.nature.com/documents/4295/version/1" target="_blank" rel="noopener">Nature Precedings</a>.   The results are consistent with the NEJM study regarding the improvement in risk prediction when SNP information is added to the Gail model.   This work also shows that the improvement is larger for women at intermediate risk who are more likely to be reclassified.   Senior author David Hinds was at Perlegen Sciences when this paper was written and is currently an employee of 23andMe, Inc.

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Confusion Over Utility of Common Genetic Variations in Breast Cancer Risk Prediction

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No matter when it happens, puberty is no fun. &nbsp; But for girls, entering womanhood earlier or later than average can mean more than just the social awkwardness of being quick to mature or a late bloomer. &nbsp; It can have important health consequences later in life.
In general, girls in the developed world are maturing faster now than ever before. &nbsp; In the mid-nineteenth century the age at menarche (the first menstrual period, a milestone usually reached about two to three years after puberty begins) was about 16, but by the end of the twentieth century that number had fallen to about 13. Earlier age at menarche has been associated with an increased risk for breast, ovarian and endometrial cancer. On the other hand, later menarche is linked to increased risk for osteoporosis and cardiovascular disease.
Much of the change in the rate of maturation for girls has been attributed to better nutrition and rising rates of obesity, but new research shows that the age at menarche is also influenced by genetics.
Four papers (<a href="https://dx.doi.org/10.1038/ng.382" target="_blank" rel="noopener">Ong et al.</a>, <a href="https://dx.doi.org/10.1038/ng.383" target="_blank" rel="noopener">Sulem et al.</a>, <a href="https://dx.doi.org/10.1038/ng.386" target="_blank" rel="noopener">Perry et al.</a>, and <a href="https://dx.doi.org/10.1038/ng.385" target="_blank" rel="noopener">He et al.</a>), published online yesterday in the journal Nature Genetics, analyzed data from a total of more than 60,000 women with European ancestry and identified two regions of the genome that contain variations associated with small differences in age at menarche. &nbsp; One of these four studies, and a fifth paper (<a href="https://dx.doi.org/10.1038/ng.387" target="_blank" rel="noopener">Stolk et al.</a>), also found variations associated with the timing of menopause, the other end of the reproductive spectrum for women.
All four studies looking at age of menarche found a connection with a region of chromosome 6. Each paper identified slightly different variants, but they all appear to be zeroing in on a single, yet to be found, causative variation in the DNA. &nbsp; As an example of the effect of the chromosome 6 SNPs, Ong et al. found that compared to those with two Cs, each T at meant that woman got her first period about six weeks earlier.
Each T at was also associated with 1.20 times greater odds of breast development at age 10, 1.26 times greater odds of advanced breast development between the ages of 9 and 16 and a faster rate of increase in height and weight.
Although girls who go through puberty earlier than their peers are tall for their age during childhood, their growth stops sooner and they are generally shorter as adults. &nbsp; Ong et al. found that each T at was associated with a reduction in adult height of about 0.15 inches.
Two studies also found an association between variations on chromosome 9 with age at menarche. &nbsp; Each C at (the most significant SNP found in He et al.), for example, translated into about five weeks earlier menarche.
He et al. and Stolk et al. found variations in five regions of the genome associated with another big change in a woman&#8217;s life: menopause. The risks associated with the timing of menopause are the reverse of those associated with menarche: later menopause has been associated with higher risk for certain cancers and earlier menopause is linked to increased risk for osteoporosis and cardiovascular disease.
Finally, all of you boys and men out there need not feel left out: &nbsp; Ong et al. also looked at the effects of on puberty in males. &nbsp; They found that each copy of an T translated into 1.26 greater odds of advanced voice breaking at age 15, 1.19 times greater odds of advanced pubic hair at age 13, faster rate of growth at age 10 and about a tenth of an inch less in adult height.

Researchers Link Common Genetic Variations To Those Changes A Woman’s Body Goes Through

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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.
<h6>Other Risks</h6>
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 <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004812" target="_blank" rel="noopener noreferrer">PLoS ONE</a>, 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 &#8212; even when cancer deaths are excluded from the analysis.
<h6>Males and Females</h6>
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.
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.

BRCA1/2 Mutations May Decrease Lifespan Even In The Absence of Cancer

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The cells in our bodies are subject to a constant onslaught of potentially damaging chemicals. Some of these come from the environment — the toxins in cigarette smoke, for an example — while others are natural byproducts of cellular life. Regardless of their origin, these chemicals have the potential to cause serious DNA damage that can eventually result in cancer.
Cells have evolved numerous mechanisms for defusing the danger posed by these chemicals. In the event that these efforts fail and DNA damage does occur, cells also have their own DNA repair systems. Not surprisingly, mutations in the genes that encode these DNA-fixers can leave cells vulnerable and increase the chances that a cancer will develop. Bloom’s syndrome, Fanconi anemia and hereditary breast cancers caused by BRCA mutations are all examples of cancer syndromes caused by relatively rare functional mutations in DNA repair genes.
Research from the University of Texas M.D. Anderson Cancer Center in Houston published online today in <a href="https://dx.doi.org/10.1158/1078-0432.ccr-08-1607" target="_blank" rel="noopener noreferrer">Clinical Cancer Research</a> shows that common variations, not just rare mutations, in DNA repair genes can increase the risk for pancreatic cancer.
Pancreatic cancer is the fourth leading cause of cancer death for both men and women in the United States. Environmental factors such as smoking, obesity, diabetes, chronic pancreatitis and dietary factors are known to play a part in determining the risk of pancreatic cancer, but about 10% of patients have a family history of the disease, suggesting that there are also genetic risk factors.
Donghui Lie and colleagues examined variations in several DNA repair genes among 734 non-Hispanic white pancreatic cancer patients and 780 people without the disease. They found that having two copies of the A version of rs1801516 in the ATM gene increased the odds of pancreatic cancer 2.76 times compared to two Gs. Having just one copy of the A version did not significantly increase risk.
SNPs in the ATM gene have also been associated with an increased risk of developing breast cancer. The protein encoded by ATM is known to be crucial for the cellular response to DNA damage.
The researchers also found a significant association between having two copies of the A version of rs2074522 in the LIG3 gene (also involved in DNA repair) and risk for pancreatic cancer. 23andMe does not currently provide data on this SNP.
“Pancreatic cancer is a highly fatal disease because most of the cases are diagnosed at late stage and the tumors are resistant to most therapies. Early detection for pancreatic cancer is crucial to reduce the mortality,” the authors write.
“However, there is no screening method available to identify the high-risk individuals among those at risk,” they write &#8212; referring to people such as smokers, people with diabetes, and those with a family history of pancreatic cancer.
The authors suggest that in addition to aiding in the development of screening tests for pancreatic cancer, finding and understanding variants such as those identified in their study will help aid in developing new treatments.

Variation in DNA Repair Genes May Increase Risk for Pancreatic Cancer

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People sometimes think of ancestry as the &#8220;fun&#8221; part of the 23andMe Personal Genome Serviceâ„¢, an intriguing glimpse at the past that is completely unrelated to our more serious Health and Traits features.
But a new paper shows how ancestry can actually reveal quite a bit about the genetics of disease. In the December issue of <a href="http://cancerres.aacrjournals.org/cgi/content/abstract/68/23/9723" target="_blank" rel="noopener noreferrer">Cancer Research</a>, Laura Fejerman of the University of California San Francisco and several colleagues show that among Latinas, a woman&#8217;s breast cancer risk increases with her proportion of European ancestry.

Most Latinos are descended from mix of Native American ancestors and European immigrants. In countries such as Brazil, where slavery was practiced until the late 19th century, many people have substantial African ancestry as well.
Fejerman and her colleagues used 106 <a href="https://en.wikipedia.org/wiki/Ancestry-informative_marker" target="_blank" rel="noopener noreferrer">ancestry informative markers</a> (AIMs) to estimate the relative European and Native American ancestry of 440 Latina women from the San Francisco Bay area with breast cancer and 597 control subjects without the disease. With every 25 percent increase in European ancestry, the researchers found, a woman&#8217;s chances of having breast cancer rose 79 percent.
The finding is no surprise – Latinas have lower breast cancer rates compared to European women, as do Native Americans. But the study does demonstrate that ancestry and population history can be valuable tools for understanding the genetics of disease.
And researchers still have a lot more to learn about population differences in rates of breast cancer. Though environmental factors are known to play a role, the new study strongly suggests that genetics is worth investigating as well.
There&#8217;s also an intriguing puzzle in breast cancer mortality differences among different populations. Though Latinas, Native Americans and African Americans are less likely to develop the disease, when they do their chances of dying from it are greater. Researchers would like to know whether those differences are due to genetics, differences in access to health care, or other factors.
Image: Peruvian &#8220;<a href="http://www.artnet.com/magazine_pre2000/features/ramirez/ramirez12-02-96.asp" target="_blank" rel="noopener noreferrer">casta</a>&#8221; painting, late 18th c.

Study of Breast Cancer among Latinas

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23andMe is marking the 23rd anniversary of National Breast Cancer Awareness Month this October with an initiative to build a web-based forum dedicated to helping women who face the disease.
Co-founders Linda Avey and Anne Wojcicki told science and business leaders at Fortune&#8217;s Most Powerful Women Summit today that we will be creating a specific breast cancer network within 23andWe, the research division of 23andMe.
&#8220;Great strides have been made in targeting treatment for breast cancer,&#8221; said Linda Avey. &#8220;We&#8217;d like to build on this progress, and we believe that by creating a web-based forum that enables women to share their experiences, the entire community could benefit and more personalized treatments may ultimately be an outcome.&#8221;
Women whose lives have been touched by breast cancer will be able to come together, share their knowledge and offer advice. They will also have the opportunity to participate in surveys that will be used to drive genome-wide association studies aimed at finding out more about the genetic factors that contribute to breast cancer.
&#8220;Women who have been recently diagnosed with breast cancer can learn a tremendous amount from women who have already been treated,&#8221; said Anne Wojcicki. &#8220;By combining the ability to participate in research with the ability to learn from each other, 23andMe hopes to make a significant contribution to this community.&#8221; 

Breast cancer can affect both sexes, but it is mainly a concern for women–one in eight will face the disease at some point in her lifetime. The National Cancer Institute estimates that in 2008 about 182,500 women will be diagnosed with breast cancer, and close to 40,500 will succumb to the disease.
<ul>
<li>To learn more about breast cancer: 
<a href="http://www.cancer.gov/cancertopics/types/breast" target="_blank" rel="noopener noreferrer">National Cancer Institute </a> 
Susan G. Komen For the Cure</li>
<li>To learn more about 23andWe, click <a href="https://www.23andme.com/research/" target="_blank" rel="noopener noreferrer">here</a>.</li>
</ul>

breast cancer — Page 4

Confusion Over Utility of Common Genetic Variations in Breast Cancer Risk Prediction

Researchers Link Common Genetic Variations To Those Changes A Woman’s Body Goes Through

BRCA1/2 Mutations May Decrease Lifespan Even In The Absence of Cancer

Variation in DNA Repair Genes May Increase Risk for Pancreatic Cancer

Study of Breast Cancer among Latinas

23andMe Co-founders Announce Breast Cancer Initiative

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