Do You Know Alpha-1 Antitrypsin Deficiency?

Let me confess this upfront. Until I met John Walsh at the 2008 Genetic Alliance conference, I was not familiar with the genetic disorder called Alpha-1 Antitrypsin Deficiency (AATD). John is one of the founders and President of AlphaNet. Since then I have learned that AATD, a genetic mutation, reduces the levels of a protective protein in the bloodstream. AAT deficiency can lead to chronic obstructive pulmonary disease (COPD), specifically emphysema, and liver disease.

John had attended a presentation I gave on improving the use of family health history and genetic/genomic data in the electronic health record. Later I was both surprised and honored when he invited me to become a member the AlphaNet board of directors. So when I saw that Alpha-1 Antitrypsin Deficiency was added in April of this year to my 23andMe Carrier Status report, I thought the timing was providential.


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As I have new opportunities to met people with Alpha-1, they would always ask if I have been tested to see if have the mutation. I hadn’t until the 23andMe result appeared. The test most people take is a simple finger-stick test for blood. But you can also get tested by genotyping, which is how I learned of my AAT deficiency carrier status.

23andMe told me that an estimated one out of every 5,000 - 7,000 North Americans has AAT deficiency. Interestingly, in Scandinavia the numbers are higher. One in every 1,500 to 3,000 people there is affected. These numbers go higher when you take into account the people who have AAT deficiency, but have not been diagnosed.


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The main versions of the gene that encodes AATD are PI*M (the normal version), PI*S, and PI*Z. A person inherits a copy of the gene from each parent, producing six possible combinations: MM, MS, MZ, SS, SZ, and ZZ. Something I learned from 23andme - In addition to the PI*M, PI*S, and PI*Z versions of the gene for AAT, there are more than 20 known rare mutations that can lead to AAT deficiency.

The PI*Z form of the gene is the most severe mutation; the ZZ genotype accounts for 95% of AAT deficiency. People with the SZ genotype are at an increased risk for COPD, particularly if they smoke. The MZ genotype causes only mild reduction in AAT protein levels, but may lead to decreased lung function in smokers.

Difficult Diagnosis

The AlphaNet website tells us that Alpha-1 patients experience difficulty and delay in getting properly diagnosed. Clinical research studies have shown that once a patient develops symptoms, it takes an average of seven years and visits to five different doctors before the diagnosis of Alpha-1 is correctly made. I have met Alpha’s that confirm this. Many non-smoking Alpha’s are of accused of smoking by their doctor. About 3% of all people diagnosed with COPD may have undetected Alpha-1.

For treatment of lung disease caused by AAT deficiency, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. Both end-stage lung and liver disease can be treated by organ transplantation. In AATD patients with cirrhosis of the liver, the prognosis is generally grave.

The AlphaNet Community

I began working with AlphaNet a year ago. I learned that one of the many things AlphaNet does is provide disease care coordinators for more than 7,000 people with Alpha-1. Their website further explains that “AlphaNet Coordinators are spread across the United States and subscribers to AlphaNet are assigned to a specific AlphaNet Coordinator based upon geographical location. Each AlphaNet subscriber is contacted at least monthly by his or her AlphaNet Coordinator. The AlphaNet Coordinator provides support, education and assistance with augmentation therapy infusion issues and supplies.” Since 1997, AlphaNet has donated $25 million to the Alpha-1 Foundation, which performs research to cure AAT deficiency.

More information I learn from 23andMe includes -

· Not everyone with AAT deficiency will have symptoms, leading some researchers to suggest that additional genetic factors other than mutations in the gene that encodes AAT may be involved.
· Between 15% and 19% of adults with AAT deficiency develops cirrhosis of the liver after age 50.
· The donor liver following liver transplantation will make normal AAT protein and actually cure the deficiency in the rest of the body.


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Family History

A paper on Alpha-1 antitrypsin deficiency was published this summer in the New England Journal of Medicine. One of the authors, Dr. Robert A. Sandhaus, is also a board member and Medical Director of AlphaNet. The article states that “AAT deficiency is recognized in less than 10% of persons in whom a diagnosis would be expected on the basis of screening studies in the general population. The diagnosis of AAT deficiency is generally made after the identification of COPD or liver disease or after the deficiency has been diagnosed in a family member”.

The authors recommend that a family testing discussion be held in the initial evaluation of the newly diagnosed patient. A diagnosis of Alpha-1 could impact family including brothers, sisters, children, grandchildren, and possibly extended family members.

To assist in finding those who are still undiagnosed, Intermountain Healthcare’s Clinical Genetics Institute is designing a study using an internet-based, patient-entered family health history program. Both the software program and the research study are under development, but we hope to find that computerized family health history tools can be effective screening methods to identify and treat those families that might be at risk for an inherited, familial disease for which they are not aware. The earlier the detection, the less damage the disease will have done.

Perspective from a medical geneticist



Traditional vs. Predisposition Genetic Testing

The two results from testing discussed this month, BRCA and alpha-1 antitrypsin (AAT), represent much more traditional types of genetic testing than the predisposition testing we’ve written about in most of the posts. In contrast to the BRCA testing which was limited to only three mutations (or the Cystic Fibrosis gene CFTR where only one mutation is tested), the AAT test results report all of the recommended clinically important mutations in this gene. Grant does an excellent job of describing the disease and its implications.

From my perspective, the challenge that hasn’t been adequately met in practice is testing of individuals who are symptomatic. As Grant points out, we are not doing a very good job of identifying the disease in symptomatic individuals. In 2008, Hogarth and Rachelefsky published a review in the journal Chest that looked at testing and screening for AAT deficiency. (reference below) They highlight 4 interventions that could be used if the disease was identified early. These include: smoking prevention/cessation; minimizing the hazards of occupational respiratory pollutants; the opportunities to receive augmentation therapy; and the potential for family planning and guided genetic counseling/testing. Thus we have a situation where we can definitively characterize the results of the mutation testing; we can identify individuals at risk; we can initiate preventive measures in those at risk and start treatment in symptomatic patients. This in some ways represents an ideal genetic test.

Genetic Testing for Symptomatic Patients

While there have been some suggestions that population screening (at least in Caucasians) for AAT mutations would be beneficial, the consensus has been that this approach would be too expensive. In addition, there are many individuals who carry disease causing mutations who never develop symptoms. That said, we’re doing a very poor job testing individuals who are symptomatic, despite professional guidelines supported by strong evidence that recommend testing all individuals with emphysema, COPD, or asthma with airflow obstruction not completely reversible with the use of bronchodilators; all individuals with unexplained liver disease; asymptomatic subjects with persistent obstruction found on pulmonary function test findings and with identifiable risk factors; and adults with necrotizing panniculitis.

Informed Consumers

So it certainly appears that there would be a role for informed consumers to be able to access testing given that health care professionals are not doing an adequate job. Interestingly this has been studied in AAT, including testing of minors. (see references below). These tests seem to be well accepted. Nearly 80% of current smokers indicated that they were highly likely to stop smoking if they were ZZ. Most individuals (but not all) said they would share the results of testing with their physician, however a small number would not want the result placed in their medical record because of concerns about privacy.

The U.S. Center for AIR is performing testing under a research protocol to learn more about the risks and benefits of direct-to-consumer testing for AAT deficiency. This type of research is extremely important to better understand the role of consumer directed genetic testing. Kudos to the groups that are sponsoring this important research. Testing is also available outside of a research protocol through the AAT Deficiency Testing Center. In contrast to 23andMe that provides results, but no other support, AAT testing is sponsored by AAT organizations that can provide support for newly diagnosed patients.

It should be noted that one can also measure the level of alpha 1 antitrypsin activity in the blood stream, obviating the need for a genetic test. So, if you’re interested in being tested for AAT deficiency, probably better to use one of these services than 23andMe. However, if you have been identified as carrying a mutation through the 23andMe testing, contact one of the advocacy organizations for more information. It could save your life!

References:

Hogarth DK, Rachelefsky G. Screening and familial testing of patients for alpha 1-antitrypsin deficiency. Chest. 2008 Apr;133(4):981-8

Strange, C, Moseley, MA, Jones, Y, et al Genetic testing of minors for α1-antitrypsin deficiency. Arch Pediatr Adolesc Med 2006;160,531-534

Gitter AC, Jones Y, Schwartz L, et al. Confidential home α1-antitrypsin testing: specialty center support for rare diseases. Presented at: the American Thoracic Society Annual Meeting; May 18–23, 2007; San Francisco, CA; poster A988

Strange, C, Dickson, R, Carter, C, et al Genetic testing for alpha1-antitrypsin deficiency. Genet Med 2004;6,204-210

Can Men Understand BRCA?

I was surprised when 23andMe added selected BRCA cancer mutations to the Carrier Status list in February of 2009, especially since everybody knows that Myriad Genetics holds a controversial patent to the BRCA1 and BRCA2 genes. Because Myriad is a Salt Lake City-based company, we watch them closely. And more importantly, I have a personal story with Myriad BRCA testing and a family member - which I will share at the end of this post.

The UPDB

Myriad originated in 1991 as a gene discovery company. Their researchers were able to access and link important genealogical and medical databases, which resulted in discovering the BRCA genes. The new database was named The Utah Population Database (UPDB). It originally contained information on 200,000 Mormon family groups and most of the1.6 million descendants of the initial 10,000 Utah settlers. This database was linked to the Utah Cancer Registry (which contains more than 100,000 entries), in which generated 40,000 cross-linked entries. Since then, the database has expanded with updated genealogical and public health records, and Intermountain Healthcare has linked its clinical data with the UPDB to offer an even more powerful research tool.

Anything Here for Me?

My 23andMe report cautions me to remember that the BRCA mutations covered by the report are only three of hundreds in the BRCA1 and BRCA2 genes that can cause cancer. The absence of these mutations does however not rule out the possibility that I may carry another cancer-causing variation in one of the other genes.


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Population Risk

It seems like a small number when one reads that only 5 to 10 percent of breast cancers occur in women with a genetic predisposition for the disease. The incidence in men only accounts for 1% of all breast cancer. In addition, I learn that these mutations greatly increase not only the risk for breast cancer in women, but also the risk for ovarian cancer in women as well as prostate cancer among men. Additionally, 23andMe provides data for only three specific cancer-associated mutations that are found mainly in people with Ashkenazi Jewish ancestry.

Since I am not a woman, nor an Ashkenazi Jew (100% European according to my 23andme ancestry painting), is any of this information important to me? I think so. Because I am not a carrier, the children I may have will be at reduced risk of breast cancer. But my interest at this moment is not for me, but rather for affected family members, for whom I care deeply.

October is Breast Cancer Awareness Month

The National Breast Cancer Awareness Month (NBCAM) program is dedicated to promoting the importance of early screening and detection of breast cancer through a nationwide campaign held during the month of October. They are celebrating their 25th anniversary. Whenever I hear about a NBCAM activity, I think about what my sister-in-law (SIL) went through. She is a breast cancer survivor.

A Personal Story

Her story starts with her maternal Grandma, who was diagnosed with breast cancer at age 45. After several surgeries failed to “hack it out”, Grandma died at 49.

My SIL’s mother was first diagnosed with breast cancer at age 29. She had surgery to remove her breasts, followed by chemotherapy, but that didn’t stop the cancer from spreading to her spine, and finally her lungs. Even after complaining about respiratory difficulties, the lung cancer was not discovered until the autopsy. Mom also fought for 4 years before dying. My sister-in-law was seven years old.

Thinking It Was Inevitable

While growing up, my SIL always thought that at some point she would die of breast cancer herself. In 2001 when she was 25 years old, she heard about the Myriad BRCA test and wanted to take it. The test came back negative for any of the BRCA mutations, so she started to think she had dodged a bullet. She did have genetic counseling, which would have told her some risk still existed. She saw an oncologist, but did not have a mammogram since she was nursing a newborn at the time.

Three years after the negative Myriad test, my SIL was pregnant once again, and for the first time ever, found a lump in her breast. She had an ultrasound and was told that the lump was benign and would disappear after the pregnancy. Two weeks later she visited her Obstetrician and told the doctor she thought the lump was getting bigger. A needle biopsy by a breast surgeon revealed she had cancer.

A Prayer Is Answered

A small miracle followed. She began chemotherapy while pregnant with her fourth child. Her daughter was born as beautiful and healthy as her other children. After the birth she had a radical bi-lateral mastectomy, reconstruction, and radiation therapy.

I asked her if she felt modern medicine had let her down. She said no, because – she explained - she had always felt that it was her responsibility to follow through with the accurate diagnosis and treatment of her healthcare. However, she did feel that she should have asked an aunt to take the BRCA test to help interpret her results. Today, she is still interested in learning about new genetic testing for breast cancer that might help her three young daughters.

As their Uncle, these three beautiful little angels give me sweet hugs and a lot of love. As I thought about their future and possible inherited risk, I found myself feeling sad thinking about what they might face in the future. I can’t imagine how I would feel if I were their mother or father.



Perspective from a Certified Genetic Counselor




BRCA Mutations and Inherited Risk for Breast Cancer









Women who talk with me about inherited risk for breast cancer often ask about “the breast cancer gene”. I think it comes as a surprise to many of these women (and their husbands) that everyone, men and women, have BRCA genes. In fact, every person has two copies each of BRCA1 and BRCA2. One of each came via the egg cell from their mother, and one came in the sperm cell donated by their father that resulted in their personal conception; talk about personalized health! So although Grant does not carry one of the three common Ashkenazi (or Eastern European) Jewish BRCA mutations, he does carry BRCA genes in which hundreds of mutations are possible. Cheery thought!

Grant shared the story of his sister-in-law and her family’s experience with relentless breast cancer. Breast cancer at ages 45, 29, and 28 are the hallmark of hereditary breast cancer caused by a BRCA mutation. How could it be that Grant’s sister-in-law tested negative for BRCA mutations and then she was diagnosed with breast cancer? Her story helps to illustrate the promise and the pitfalls of genetic and genomic testing, and it is a good example of how genetic test results may be only part of the story of risk. I appreciate her willingness to have her brother-in-law share her story. (I hope he told her he was sharing the story!)

Mutation: A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome.

The genomic test result that Grant received as part of 23andMe represents the mutations tested for during initial testing usually offered to individuals with Eastern European Jewish ancestry who have a family history of breast or ovarian cancer. I am not sure what led the designers of the 23andMe to select and report on BRCA mutations despite the fact that another company owns the patent for those genes. I suspect it may be because other labs have been licensed to conduct screening for the three mutations in certain specific populations.

Promise and Pitfall

I have the sense that Grant was not surprised to learn he is not a carrier of a BRCA mutation. I have not heard him mention or write about cancer in his biologic family. That is little consolation for the fact that his sister-in-law has developed breast cancer and his nieces (grandnieces, etc.) could develop breast cancer. The promise with genetic testing is the possibility that knowing if you are at risk, it may offer the opportunity to prevent cancer. The pitfall is the false hope that testing that is negative (no mutation detected) has ruled out risk for the disease.

As Grant’ s sister-in-law mentioned in her reflection, she wished that her aunt had been tested for BRCA mutations to help to interpret her results. If her aunt (her mother’s sister) had breast cancer and tested negative, then her negative result would have been meaningless. It would have indicated the fact that the cause of early breast cancer in the family had not yet been linked to a BRCA mutation. In the study of families with inherited breast and ovarian cancer, we know that BRCA is not the only reason for cancer in every family. There must be other hereditary factors besides BRCA that cause breast cancer. Researchers have not been able to identify another familial breast and ovarian cancer gene with the same dramatic impact of BRCA1 and BRCA2, but others or combinations of others must exist.

The Story Is Not Over

In the same way that 23andMe updates risk assessments as new SNPS are linked to diseases and reported back to Grant, new ways to evaluate BRCA genes have been added to the analysis in high risk families. The story of Grant’s sister-in-law and her genetic testing is not over. In 2001 - and again in 2007 - Myriad Genetics updated their analysis of BRCA genes to include evaluation for large gene rearrangements.

While rearrangements are also called mutations, the original testing for mutations involved sequence analysis of the genes and did not reveal that chunks of DNA could be missing (deleted) or copied more than once (duplicated). Several families, in whom a BRCA mutation was not originally detected, have since been found to have a duplication, or - more likely - a deletion. Grant’s sister-in-law could visit with a genetic counselor about this new testing option. The original result would inform the genetic counselor of the testing completed at the time of the test in 2001. There would not be a need to repeat the sequence test that was performed, but new analysis to look for a large rearrangement of BRCA1 or BRCA2 may provide the genetic key that would allow identification of at risk family members.

The promise of genetic testing is realized in the identification of those at increased risk. Individuals and their family members may use this information to attend carefully to the possibility of the development of cancer at younger than expected ages. It may also allow for early intervention in those at risk when preventive interventions are available.

Good resources for breast cancer information:

American Cancer Society: http://www.cancer.org/
Susan G. Komen: http://www.komen.org/
Facing Our Risk of Cancer Empowered: http://www.facingourrisk.org/
National Cancer Institute: http://www.cancer.gov/

Prostate cancer - Part 2

This is a follow-up from our August 10th post. If you missed it, start here.

Normally Grant writes about a topic from his 23andMe report, followed by commentary from two healthcare providers, Marc Williams and Janet Williams (who happened to be related by marriage - to each other). For this post we reverse the order.



Perspective from a Certified Genetic Counselor




As someone who works with individuals who are seeking risk assessment for familial cancer, Grant’s result is really frustrating. What in the world does he do with this information?

He can remain nonchalant, nonplussed, implacable: “don’t worry, be happy”. He can go to his doctor and discuss this result. The provider may or may not think this information merits consideration in decisions about screening. Should it merit consideration? He can be screened with an exam and a PSA.

Grant is now in the position of “waiting” for prostate cancer.

PSA Screening + Genomic data = Prostate Biopsy

It doesn’t help that the most publicized story about genomics and prostate cancer (Jerry Gulcher) involves a fellow who is intimately involved with genomic testing. He saved his life by insisting on a prostate biopsy despite a normal PSA. It is difficult to keep any perspective when a story comes out that is so compelling! There is probably much more to his story, but it the short version that gets referenced.

The 23andMe result information that Grant now knows may provoke him to seek screening. However, he has no assurances that screening will be anymore sensitive because he is known to have markers found in men with prostate cancer. As recently demonstrated, PSA levels are not consistently sensitive to the presence of prostate cancer. PSA levels can be normal in individuals with advanced prostate cancer. High PSA levels are not caused solely by prostate cancer. Digital rectal exam can reveal nodules or an enlarged prostate, but either can be a benign finding. The presence of the risk markers cannot predict if a high PSA is more likely to be prostate cancer. The markers do not imply reassurance that a normal PSA level rules out prostate cancer. The high-risk markers are not correlated with aggressiveness of prostate cancer or its ability to metastasize.

The Clinical Decision Conundrum

The nightmare situation that Grant may not have considered is how this information now shapes the decisions he makes from here on out. For Grant, not acknowledging the risk information would be ironic. He is in the business of incorporating genomic information into medical records and medical care. He believes in the future of genomics and personalized medicine. The current reality is that the evidence to use the information gained in genomic testing does not facilitate the ability to take specific action. In addition, the screening we currently use to detect prostate cancer is itself flawed in its ability to adequately identify men with prostate cancer. We use the test because it is all we have at the current time.

Grant is caught between a rock and hard place. He can use his genomic result to direct screening tests with results that are “fuzzy”. The screening tests may indicate risk or suspicion of prostate cancer, but not disease. Prostate cancer can only be diagnosed with biopsy. What is Grant’s threshold for prostate biopsy at this time? How will his provider be able to discuss sound options when there is no evidence to guide a decision (not that that has stopped medicine in the past). I am angry that he now has information that indicates an association with increased risk for cancer, but with no way to apply the information in a way that can prevent or alter the development of prostate cancer. What decisions will Grant make differently because he and his provider now know that he is at increased risk?

Job Security

Finally, I am concerned about those who do not have Grant’s laissez-faire attitude about increased risk and cancer. Perception of risk and communicating risk with some perspective is tricky business. I think 23andMe has worked hard to provide ways to visualize and explain the quantity of risk. The complexity of risk and personal reaction to risk - really an “incorporation” of risk into one’s concept of self - is not explored. The upshot is that it may mean job security for me and other genetic counselors.



Grant's Comments




This is great. I’m getting free genetic counseling to help interpret my 23andMe report. Not having a medical professional guide a patient through genetic test results is a common criticism of direct-to-consumer (DTC) testing services. I’m lucky. With Janet, I have that issue covered.

Here Comes My Excuses

At this point, I haven’t approached any clinician with my 23andMe information. This includes not talking with a doctor about my prostate cancer risk. Janet has certainly given me a lot to think about. In contemplating my reaction (or lack thereof), I think it comes down to the fact that, from the information I have now (my current and possibly changing genetic risk, my lack of family history, and my age), I don’t have any alarm bells going off in my head.

I have learned a lot about PSA screening – and how it is not always useful – both from Janet and from my own research on the Web. One of the arguments against DTC testing is that its clinical utility has not been proven. I find this very ironic in light of a critical point Janet made in her post. “The current reality is that the evidence to use the information gained in genomic testing does not facilitate the ability to take specific action. In addition, the screening we currently use to detect prostate cancer is itself flawed in its ability to adequately identify men with prostate cancer. We use the test because it is all we have at the current time.”

Warning. Editorial comment to follow. Sometimes the anti-DTC voices do not use the same standard for personal genomics that they do for currently accepted medical practices which also have limited proven utility. In other words, we should not ban DTC testing because of its early stage and many questions concerning its clinical value, just as we will not stop using other sanctioned but vulnerable clinical tests. Interestingly though, results of a survey on awareness of personal genomic testing that I refer to in a following paragraph show some evidence of limited clinical utility. (End of editorial comment.)

A Link Between Prostate and Colorectal Cancer

I learned from the 23andMe website that “three SNPs in the same area of the genome have recently been found to be independently associated with prostate cancer risk. This region is called 8q24, because it lies within band 24 on the long arm (named the "q" arm) of chromosome 8. The three SNPs are not close to known genes (although there are others located farther away).” I then discovered this week from the website that both prostate and colorectal cancer have suspected risk-causing SNPs in the 8q24 region. 23andMe tells me about a published study on this subject titled “A common genetic risk factor for colorectal and prostate cancer.”

Although not ready for primetime, 23andMe does include data targeted at my risk for colorectal cancer. This information is listed under their Research Report section in the ‘Elevated Risk’ category. As stated by 23andMe, “Research Reports give you information from research that has not yet gained enough scientific consensus to be included in our Clinical Reports.”


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The Issue of Risk

One of Janet's main concerns with DTC personal genomic services is the communication with and understanding of risk by the consumer. She states that “the complexity of risk and personal reaction to risk - really an “incorporation” of risk into one’s concept of self - is not explored.” An excellent discussion of this topic can be found on the UK’s PHG Foundation website. They have an article titled "Understanding DTC genetic risk prediction services" that points out that "because the calculated risk is updated every time a new association is discovered, the prediction for an individual can change from being above average risk to below average risk overnight. This is particularly problematic where it might result in opposing recommendations". The article concludes by saying "companies offering genome-wide risk prediction services should ensure that their customers understand that, whilst the measurement of the DNA sequence itself (the assay) will remain constant, the interpretation of the result (the test) is likely to change as the science develops".

Let me quote Janet one last time. She writes "the presence of the risk markers cannot predict if a high PSA is more likely to be prostate cancer. The markers do not imply reassurance that a normal PSA level rules out prostate cancer. The high-risk markers are not correlated with aggressiveness of prostate cancer or its ability to metastasize". I found these three sentences made the most impact on me.

Wow. We sure have a lot more research to do.

Awareness of Personal Genomic Tests

Also from the PHG Foundation website is an article on a study surveying both consumer and healthcare provider knowledge of personal genomics during the year 2008. On the consumer side, of 5,399 respondents, 22% were aware of personal genomic (or direct-to-consumer) tests, 0.3% had used these tests, and two-thirds of these users had shared the test results with a healthcare provider. That would be 2 out of every 1000 patients - certainly not enough for doctors to complain about yet.

I found the medical professional survey results really surprising. The 1,880 physician respondents (mostly family physicians, internists, pediatricians, and obstetrician/gynecologists), only 42% were aware of personal genomic tests. Among those aware, 42% had at least one patient who asked questions in the past year about having such a test, and 15% had at least one patient who brought the results of a personal genomic test to them for discussion in the past year. The biggest discovery according to the study was, “among the latter group, which is composed primarily of internists and family physicians, 75% indicated that the personal genomic test results changed some aspect of the patient’s care, such as screening tests offered, medications or dosages prescribed, lifestyle changes recommended, frequency of follow-up appointments, or diagnoses made.” (Emphasis added of course.)

Getting back to me

Janet is right. It would be a bit embarrassing if I couldn’t make wise decisions related to how I use my 23andMe report since I work in the clinical genomics industry. Should I schedule a prostate cancer screening? The pressure is on.

Read the next post - I Want A New Drug - One That Matches My Genotype

The Big PC – What Men Fear Most

Although my relative risk for Prostate Cancer came in third behind Crohn’s Disease and Type 1 Diabetes, the absolute risk of 24% certainly got my attention. It was the second item I clicked on after looking at Crohn’s. At my age I am supposed to be paying more attention to prostate screening guidelines, but I haven’t been. This risk score may provide a good incentive to do so. Let's read further to see if that’s true.

A quick Google search on recent prostate cancer announcements returned several links for radio host Don Imus and Senator Chris Dodd going public with their diagnoses. This is evidence that this disease is cheerfully bipartisan. At age 48, deCODE Genetics co-founder Jeffrey Gulcher reviewed his deCODEme data, which indicated he had a doubled lifetime risk for prostate cancer. Even though his PSA levels were fairly normal, Gulcher ended up getting a biopsy that revealed a grade 6 (Gleason scale) prostate carcinoma, which was successfully resected. “This test may have saved his life,” deCODE CEO Kari Stefansson said.



As a test for our blog readers - did you notice my risk scores for Crohn’s had been updated since our post on that subject back on July 13th? My absolute risk for Crohn’s increased from 1.5% to 1.6%. The change is because the new score is now gender specific.

Worse Than Death

The digital exam and the threat of impotence are what men seem to fear more than death from the disease, even though almost 30,000 men die each year from prostate cancer in the United States. More than 185,000 US men develop prostate cancer annually. Among men of all races in the US, prostate cancer is the most common cancer. It is also the leading cause of cancer related death among men of all races.

If I develop prostate cancer, I would get to chose from hormonal therapy, brachytherapy, radical prostatectomy, cryotherapy, or just watchful waiting. Sounds like a fun treatment menu.



My Risk and Family History

The heritability of prostate cancer is estimated to be 42-57%. This means that genetic and environmental factors contribute nearly equally to differences in risk for this condition. The MD Perspective section made strong references to family history and prostate cancer risk.

23andMe: What are the other major risk factors for prostate cancer, besides age?
Dr. Marc A. Shuman, M.D. (Professor of Medicine and Urology; Director of the Prostate Cancer Specialized Program of Research Excellence, University of California, San Francisco): Genetics and ethnic background are the main risk factors, other than age, for prostate cancer. A family history of prostate cancer also significantly increases the risk of developing prostate cancer. In addition, African-American men have a significant increase in prostate cancer compared to men of European ancestry. Asian-American men are at a significantly decreased risk of disease.
23andMe: How does heredity influence the risk of prostate cancer?
Dr. Shuman: Family history is one of the most significant risk factors for developing prostate cancer. Men whose first-degree male relatives—fathers or brothers—have had prostate cancer are at increased risk. The risk is doubled in men who have had two first-degree relatives with the disease. Heredity is believed to contribute as much as 40% of the total risk of getting the disease.

No grandfathers, father, or uncles have had prostate cancer in my family. Besides my father, I am not aware if they have had any screenings done.

Community Comment 1

The 23andMe website has a community section that allows for people to post questions and comments. One person said he was surprised by his 23andMe result on prostate cancer. He said –

“My father and his two brothers had prostate cancer when they were in their 60's. My older brother had prostate cancer in his mid 40's. I guess this suggests a strong hereditary link. Surprisingly to me, my results say I have slightly lower probability of developing prostate cancer than the average European guy (15.2% versus 17.8%). Maybe there is still a lot to learn about genetic propensity for prostate cancer.”

I guess it is possible to have a strong family history, but not have inherited the risk-effecting genetic variants like other family members.

Odds Calculator Shows its Age

The default age range in the odds calculator shows that my lifetime risk from 35 to 79 years of age is 24.4 out of 100. This is the absolute risk that appears on my elevated risk screen. However, when I change the range for my current age, the absolute risk reduces significantly to .26 out of 100, that is nearly 100 times less! I also learn as I age every five years, the risk goes up quickly to.95 out of 100,
then 2.3 out of 100,
then 4.1 out of 100,
then 6.2 out of 100,
and then 7 out of 100 at 70 years old.

This tells me that age by itself is a big risk factor.



My Five Marker Effects (with number six to come later)

23andMe analyzes 5 SNPs associated with Prostate Cancer: rs1447295, rs6983267, rs10505483, rs1859962, and rs4430796. Based on these markers, estimates of a person's lifetime odds of getting Prostate Cancer can range from 17% to 46%. 23andMe’s estimate is applicable to people of European and African ethnicity, based on available published scientific research (for which the website lists cites of those published studies).



New Paper Points to Another SNP for Prostate Cancer – Then I Point it to Me

In the Proceedings of the National Academy of Sciences published in April 2009 two recent genome-wide association studies have independently identified a prostate cancer susceptibility locus on chromosome 10q11.2. In summary, they say that if you have the C variant for the SNP rs10993994 (tested in the 23andMe V2-chip), your odds for getting prostate cancer later in life are increased.

So I go to the Browse Raw Data section of the 23andMe website and enter in the SNP to see what I have. My 23andMe report allows me to search the more than 500,000 SNPs its microarray chip sequences, even though all of the SNPs may not be currently used in my risk assessment. I find that I have the C variant, which adds 1.47–1.82 to my current cumulative relative risk of 1.37. It will be interesting to track how quickly 23andMe updates my risk estimate.



Of course, the healthcare IT person in me thinks that this data should be in my EHR (electronic health record), and when a new variant is found to affect risk, this search should be automated and should send a message to me and my healthcare providers. (In fact, Intermountain Healthcare’s Clinical Genetics Institute is collaborating with the Partners HealthCare Center for Personalized Genetic Medicine to develop such a solution).

Community Comment 2

Another post in the community section asks a question about prostate cancer prevention. A 23andMe representative has answered by sharing a link to the Mayo Clinic website that seems to provide a comprehensive guess. Yet another community post suggests tomato paste may be the secret.

With no family history of prostate cancer, a current absolute risk of one-quarter of 1% (which may be updated soon), and a diet heavy on pomegranate juice and tomato paste (OK, maybe not), I’m not sure that I am fully motivated yet to get that first screen done. Who wants to be the first to scold me?



Perspective from a Certified Genetic Counselor




Prostate Cancer Serious Business

Prostate cancer is the poster boy for men’s health. Sometimes in screening circles you can hear whispers like “breasts get all the money and attention!” No duh. Hmmm. Breasts versus walnut-sized internal organs… So the marketing and money battle may have been lost, but the screening banner should not sag. Prostate cancer is serious business and can be deadly serious.

Yet, Grant talks about the screening process as being half the battle in this fate worse than death—the indignity and discomfort of the exam. The 23andMe test result may provide the reason for him to seek screening. (The other tidbit offered up in screening circles: “if men had to do mammography to screen their prostates or other appendages, there would be a better machine.”)

Markers and Prostate Cancer

Once Grant read about Crohn’s disease and realized that it didn’t apply to him, he focused on the prostate cancer risk. The 24% risk, as well as the relatively long bars next to the risk percentage, got his attention. He mentions that the risk range offered by the testing is between 17% and 46%. The graph showing Grant’s markers illustrates that three of the five markers were associated with lower risk of prostate cancer. Two markers were associated with increased risk for prostate cancer. Several studies show an association between certain markers and a risk for prostate cancer. The studies do not tell us that the markers cause prostate cancer.

Some of the markers are located in places along the genome in which a known gene resides. In a few instances the product of the gene is linked to the prostate. In these circumstances, it makes sense that a change in the gene might affect the prostate. For other markers there is no nearby resident gene and so the biologic role of the marker is unknown. Knowing how and why the markers are associated with the development of cancer might allow for targeted intervention to decrease the risk or prevent prostate cancer.

As Grant indicates, new markers and their relative contribution to risk will continue to be found. He looked up a new marker just reported and found that he has it. It will be interesting to see how the additional marker changes his risk. I notice that he didn’t look or didn’t find any markers associated with decreased risk for prostate cancer. None of the markers tell him whether or not he will develop prostate cancer, and if yes, when it will develop or how aggressive it might be.

What’s a Man to Do? Do I Feel Lucky?

Grant talked about his lack of attention to screening. Unfortunately that is a typical failure in men in Grant’s age group. Technically, Grant isn’t yet of the magic prostate cancer screening age, so he really shouldn’t feel badly. But, because of this result should he start screening now anyway? What should he do? The dread digital? Or perhaps the even more dreaded biopsy?

(Just a parenthetical reminder of the recommendation agreed to in testing: Do not use these test results in making management decisions about your healthcare.)

Risk Factors Associated with Prostate Cancer

The weight of the research so far indicates that family history, ethnicity and age are well known to be associated with determining risk. Having one or more close relatives with prostate cancer (your father, brother, or son) will increase your risk. Being African or African American will increase your risk, being of Asian background reduces the risk. All men have increasing risk as they get older. The fact that Grant does not have a family history of prostate cancer is reassuring.

Most studies found the greatest risk in those individuals who had the high risk markers AND family history. Grant’s heritage is white northern European, so higher risk, but not the highest risk ethnicity. Grant is nearing the at risk age group. With the start of screening for prostate cancer should come a discussion about the limitations of the process. However, like it or not, imperfect as it is, it is what we have. At least now there is a reason (perhaps more compelling than age alone) to get the screening done. When to start? Talk to your healthcare provider.

Janet is a cancer genetic counselor and has very strong feelings about this which she will share in the subsequent blog post. In a bit of a role-reversal, Grant will react.




Perspective from a medical geneticist



An Alternative View

Jeffrey Gulcher Chief Scientific Officer of deCODE genetics (a company that offers a direct-to-consumer genomic test service called deCODEme) had a less ambivalent response than Grant to his increased risk of prostate cancer. He opted to visit his physician and had a blood test to measure his prostate-specific antigen (PSA). The test was normal, albeit in the high end of the normal range. Despite the normal result he pursued a prostate biopsy which revealed the presence of aggressive prostate cancer that fortunately had not metastasized.

Still, several questions are raised: How should a PSA test be interpreted if one has increased risk based on genotyping? (Answer we don't know.) How should a PSA test be interpreted based on the presence or absence of a family history of prostate cancer? (Answer we don't know.) Does evidence support population screening with PSA? (Answer - not according to either the United States Preventive Services Task Force and the American College of Preventive Medicine both of which in 2008 concluded that there is insufficient evidence to recommend routine population screening with PSA.)

While not denying the likelihood that these choices were likely life saving for Dr. Gulcher, if a large number of men pursued this course of action what benefits and harms would they experience? Would the situation be analogous to full-body CT scanning where 9 out of the 10 findings are incidental and have no health impact? Pursuit of these "incidentalomas" consumes scarce health care resources and, in some cases, leads to invasive procedures with attendant morbidity and occasionally mortality. I would find counseling a patient presenting to me with a test result extremely challenging.

Read the next post - Prostate cancer - Part 2