What kinds of genetic tests are available?

There are around 1000 genetic tests currently available; a few of these are marketed directly to consumers. In general, these consumer genetic tests fall into four categories: Paternity, Lineage/Ethnicity, Disease, and Nutrigenomic.

Paternity tests can determine whether one person is related to another person. The most common application of this test is in a paternity dispute. Paternity tests are the most common genetic test sold by online companies. The reason this test is the most popular is because the test itself only costs the customer around $199, and the results are 99.9% accurate. From the perspective of the laboratory, the test is easy to perform, which means they can offer it at a low price. One important aspect of this test is that it does not sequence the customer's DNA directly. It analyzes regions of DNA that do not code for proteins, and thus no medical information can be gleaned from the results of a paternity test.

Lineage and Ethnicity tests are also sold by online companies. These tests trace the ancestry of the customer by analyzing specific genes that have been traced to specific lines of human ancestry. As with paternity tests, no medical information is contained in the results.

Disease tests, on the other hand, are designed to identify specific mutations which are known to cause a certain disease. Several disease tests are available online, which can screen for diseases such as breast cancer, alpha1-antitrypsin disorder, and Hemochromatosis. One important question with these tests is whether they accurately predict the incidence of disease.

Nutrigenomic tests look at genes involved in the everyday operation of the body. Mutations in these genes can result in proteins which function less effectively than normal. In some cases, dietary changes can counteract these defects. For example, a person might have an enzyme that doesn't break down glucose fast enough, leading to high blood sugar level. This information might enable the person to better manage their intake of sugar. There are testing packages for many physiological functions such as bone health, glucose utilization, and stress. The usefulness of nutrigenomic testing depends on whether the effects of the mutations possessed by the individual can actually be reversed through diet or lifestyle changes.

Genetic tests are very accurate if properly administered. However, accuracy is not the only important factor to consider. A highly accurate disease test can show the incidence of a particular mutation, but the predictive value of a test result varies depending on many factors. For example, if a person receives a positive result for a mutation on the BRCA1 gene, this does not necessarily mean that the person has breast cancer. It merely signifies an increased risk of developing breast cancer. Other factors such as ethnicity, lifestyle, and hormone balance, may also play a role in determining whether or not the gene actually leads to the disease state. Although the test may accurately show the presence of mutations, these mutations are usually not the sole determinants of disease. Some disease tests are like this, while others have a higher predictive value. It depends on the disease and the person. Nutrigenomic tests must be interpreted in the same manner. Paternity and lineage tests, on the other hand, are highly accurate simply because there are no other factors. Their predictive value is 99.9%.

A genetic test that can detect whether heart transplant patients are rejecting their donated heart

HealthDay News reported about a simple blood test that can detect whether heart transplant patients are rejecting their donated heart. These patients have an average risk of 3 percent to 5 percent for moderate/severe rejection, and must be monitored for rejection for the rest of their lives. For decades, the heart-muscle biopsy was the most reliable method for detecting rejection. This test may reduce the need for invasive heart-muscle biopsies.

The study by New York-Presbyterian Hospital and Columbia University Medical Center analyzed data from patients in the four-year Cardiac Allograft Rejection Gene Expression Observational Study (CARGO), conducted at eight U.S. transplant centers.

The study looked at a gene expression test called AlloMapT molecular expression testing, which provides information about 20 genes representing molecular pathways in white blood cells found to be associated with heart transplant rejection, as well as information about control genes.

The researchers found that the AlloMap test appeared able to distinguish heart transplant patients who were rejecting their new heart from patients who weren't. The study found that patients with a low AlloMap score had less than 1 percent chance of rejection.

New York-Presbyterian/Columbia will begin offering AlloMap testing to patients on Jan. 1, 2006.

Marie Godfrey, PhD

 

Breast cancer and tamoxifen

A number of genetic tests are available for breast cancer-related genes, and recent news suggests another test could predict responses to tamoxifen. More than 210,000 women in the United States will develop breast cancer. Approximately 70 percent of these cancers are fueled by estrogen, many of which are treated with tamoxifen, a drug designed to block the effects of estrogen in breast tissue. Some women take tamoxifen as a preventative measure against breast cancer.

An enzyme known as CYP2D6 is “responsible for activating tamoxifen to a metabolite called endoxifen that is nearly 100 times more potent as an anti-estrogen than tamoxifen itself,” says James Rae, PhD, research assistant professor of internal medicine at the University of Michigan Medical School. A study of 256 women with breast cancer “suggests that women who inherit a genetic variant in the CYP2D6 gene appear to be at higher risk of relapse when treated with five years of tamoxifen.” Women with this genetic variant (about 10 percent of women) were almost twice as likely to see their breast cancer return.

As always, further studies are needed, but researchers hope this finding may lead to a genetic test--not currently offered clinically. Research is being conducted by the members of the Pharmacogenetics Research Network to confirm whether genetic testing can be used to identify patients likely to respond to endocrine therapy, including tamoxifen. This group is led by David A Flockhart, MD, PhD at Indiana University School of Medicine.

One interesting sidenote in the study was that researchers also found that women with the CYP2D6 variant were less likely to have hot flashes. Any hot flashes among this group tended to be less severe, suggesting that this side effect could predict the gene variation. Ironically, Paxil--a selective serotonin reuptake inhibitors or SSRI used to treat hot flashes--can prevent tamoxifen from being activated. Effexor, another SSRI, does not interfere with tamoxifen’s activation. So, women with breast cancer and hot flashes or depression (SSRIs are also used to treat depression) might be well-advised to confer with their physician on possible drug interactions.

Their findings are published in the Dec. 20 issue of The Journal of Clinical Oncology and were reported by Breast Cancer News online (31 Dec 2005).

Marie Godfrey, PhD

Does ovary removal prevent cancer in women with a BRCA1 or BRCA2 mutation?

The numbers and statistics in the following blog entry are almost guaranteed to confuse you.

The article under discussion here, in the Journal of the American Medical Association, is titled: "Salpingo-oophorectomy and the Risk of Ovarian, Fallopian Tube, and Peritoneal Cancers in Women With a BRCA1 or BRCA2 Mutation." It appears in volume 296, pages 185-192. The original article is available only by subscription or from the authors. Information here comes from the abstract. Definitions are at the end of this entry if you need them.

The authors conclude:

Oophorectomy is associated with reduced risk of ovarian and fallopian tube cancer in high-risk women, although there is a substantial residual risk for peritoneal cancer in BRCA1 and BRCA2 mutation carriers following prophylactic salpingo-oophorectomy.

They also state, in the results:

The overall (adjusted) reduction in cancer risk associated with bilateral oophorectomy is 80% (multivariate hazard ratio = 0.20; 95% confidence interval, 0.07-0.58; P = .003).

O.K., so, according to this article, if you have one of the BRCA mutations, and you have your ovaries and fallopian tubes removed, you can still get ovarian or fallopian tube cancer [???]. You are also still at risk for peritoneal cancer. The 80% reduction in cancer risk sounds pretty good, though. If I hadn't already had my ovaries removed (they didn't tell me whether they removed the fallopian tubes), I'd probably consider this surgery if I were found to have the BRCA1 or BRCA2 mutation.

But what do the study numbers tell us?

1. The study was retrospective--1828 patients with BRCA1 BRCA2 gene were identified from an international registry between 1992 and 2003. Because it is only 2006, it is possible that women identified for the study will develop cancer (or die) in the future--only these occurrences in the past were considered in the analysis of the results. We do not know what will happen to the current "survivors". Also, the abstract doesn't identify how many women were "lost to follow-up" (that is, have data only for part of the study period).

[By the way, those of you worried about genetic privacy, do you wonder what this international registry is and where it gets its data? I certainly do.]

2. The data for the women were first split into those who had no oophorectomy 783/1828 (43%) and those who did: 555 (30%) prior to the study period and 490 (27%) during the study period. O.K. 43 + 30 + 37 = 100%; so far, so good.

3. By the end of the study period, 32 of the 783 women who had not undergone surgery developed cancers [the abstract doesn't say what type, but ovarian, fallopian tube, or peritoneal is implied]. This is reported, not as 32/783 (4.1%), but as 1015/100 000 per year.

4. Of the women who had undergone surgery, eleven cancer cases were identified at the time of prophylactic oophorectomy and 7 were diagnosed following prophylactic oophorectomy. This is reported in the abstract as 217/100 000 per year. The fraction 18/1045 (11 + 7 = 18 and 555 + 490 = 1045) is 1.7%.

5. If you compared 4.1% with 1.7% (over the short course of the study), you might say that among women with a BRCA1 or BRCA2 mutation, those who had no surgery (oophorectomy) were 2.4 times as likely to develop cancer compared with women who had prophylactic (pre-emptive) surgery (4.1 divided by 1.7). [Note that the wording is "as likely", not "more likely".]

6. If you compared the per-year numbers 1015 vs. 217, you could say 5 times as likely (1015 divided by 217).

7. If you did a "survival analysis" [as the authors did], you would find "The overall (adjusted) reduction in cancer risk associated with bilateral oophorectomy is 80% (multivariate hazard ratio = 0.20; 95% confidence interval, 0.07-0.58; P = .003)."

So, which is the "real" number?

Just one more set of numbers: Only about 5-8% of women have a mutation in the BRCA1 or BRCA2 genes. Many sources report that mutations of the BRCA1 and BRCA2 genes give women a higher risk of developing ovarian cancer (15 percent to 54 percent), than women without the mutation.

So . . . do you have a test for BRCA1 and BRCA2? . If you find out you have one or more mutations in these genes, do you have the removal surgery? If so, have you now eliminated your chances of having ovarian, fallopian tube, or peritoneal cancer? The answer is, No.

The purpose of spouting all these numbers is to help you understand that news articles select the numbers that seem simplest to them; the deeper you dig, the more likely you are to wonder about the validity and practicality of those numbers.

Marie Godfrey, PhD

Definitions: Salpingo-oophorectomy--removal of ovaries and fallopian tubes. Peritoneal-- the peritoneum is a membrane that forms a sort of envelope around your abdominal organs and also lines your abdominal cavity

Genetic testing and breast cancer

Many other women who are related are learning, thanks to genetic testing, that they share a strong potential for being hit with breast or ovarian cancer in their future. Some of these women are choosing mastectomies, ovarectomies, and hysterectomies to remove the potentially susceptible tissue and dramatically reduce their chances of having cancer of the breast, ovary, or uterus.

One recent story from the Associated Press, published at http://kvoa.com/Global/story.asp?S=4776478, described Mindy Diamond-Rivera, a 47-year -old woman in Arizona who had her breasts removed and "is ready to get rid of her ovaries and uterus." Last September, she learned that her chances of breast cancer were 87%--a striking confirmation of the family history she's been afraid of since her mother, grandmother, and great-grandmother all died of breast cancer before 43. Taking no further chances, she had her breasts removed last November. Because having the BRCA-1 gene also predicts that her chances of having ovarian cancer are 60%, she intends to have her ovaries removed--and her uterus. "Everything's coming out", she says. According to the article, "Her insurance has covered almost everything so far. Most insurance companies cover about 80 percent of the genetic testing, said genetic counselor Jessica Ray [of the High-Risk Breast and Ovarian Cancer Clinic at the Arizona Cancer Center]. The cost of the test without insurance is $2,975."

New test available for sensitivity to a colon cancer treatment

According to news from The Mayo Clinic, a genetic screening test that can determine which patients are likely to have a serious adverse reaction to Camptosar® (irinotecan hydrochloride), a key component of standard first-line therapy for advanced colon and rectal cancers. An article at http://www.emaxhealth.com/51/4752.html describes the details.

According to Mayo Clinic medical oncologist Matthew Goetz, M.D. who was quoted in the article, "Irinotecan is an important treatment approved by the FDA for patients with colon and rectal cancers, but its side effects can be dangerous or even lethal in up to 30 percent of the population." The UGT1A1 test--which looks for a mutation in the gene that helps a patient metabolize irinotecan, was approved by the FDA in August; licensing agreements have just been finalized. If a patient has the mutated gene, dosing of irinotecan would have to be reduced or even eliminated to avoid serious side effects.



According to the article, "This kind of customized dosing approach based on a person's genetic makeup is known as pharmacogenomics and is the newest frontier of 21st century medicine." Dr. Goetz adds that the application of this test for patients with colon and rectal cancer may only be the beginning. "Irinotecan also is being tested and used for other cancers, such as cancers of the GI tract, as well as lung and breast carcinoma,"

Because the UGT1A1 pathway is also important in the metabolism of other drugs, the test may be useful for managing potentially serious side effects of some other drugs also. The test kits are available from the Mayo Clinic, through your physician or other healthcare provider. The test is not being sold directly to consumers.

Marie Godfrey, PhD


 

 

 

Predictive genetic testing and cancer

Predictive genetic testing may help identify people who are at an increased risk for developing certain types of cancer. While this type of testing may indicate the absence or presence of a gene thought to be associated with a specific cancer (for example, the BRCA1 gene and one form of breast cancer), testing also carries many limitations and risks. Before undergoing genetic testing, you need to fully understand the process and its implications. here are some items to consider.

An accurate test may produce a positive, negative, or ambiguous result, but it cannot guarantee that a person will or will not develop cancer. As thorough a knowledge as possible of family history is perhaps the most important part of any genetic test. However, people with no information on their potential cancer ancestry can still learn some things from genetic testing. In the latter case, a person's pertinent genetic makeup can be compared to others in the general population or with similar ethnic ancestry.

Many experts recommend undergoing genetic testing only when a pedigree analysis suggests the presence of an inherited cancer syndrome for which a specific mutation has been identified. Other guidelines suggest that genetic testing should be pursued only when the test will impact future medical care and decisions.

Besides family history, another important element of genetic testing is the assistance of a genetic counselor. Generally, your family doctor has neither the knowledge nor the time to provide all the assistance you may need. Your doctor may, however, be able to help you find a counselor and arrange for testing and support.

Marie Godfrey, PhD 

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Tests related to colon cancer

There are three basic tests that I know of, in addition to at least three types of examinations.

1. Hemoccult test--this one has been around for a while. It is a take-home test, sometimes availale from your pharmacist or the American Cancer Society. The test is free. The test kit consists of three pieces of filter paper, on which you smear three small stool samples, taken at different times. You send the kit in for analysis and receive results by mail. The test looks for occult (hidden) blood, which may have come from a cancer in the colon. Since there are a number of other reasons to have blood in your stool (hemorroids for example). A positive test result simply means there is more testing to do.

2. The test I described a couple of days ago is a genetic test for the existance of cancer. Some colon cancers are associated with one or more of three genetic mutations. The test, which you can purchase over the Internet, looks for these mutations in cells within a stool sample. I believe the test is quite expensive. If you think you'd like to try this test, I would recommend consulting a physician. Insurance is more likely to cover the test that way.

3. Another test is a predictive test: do you have the genetic mutation that results in more frequent polyp formation in the colon? Approximately 5-10 percent of colon cancers are associated with this mutation and as many as 80 percent of people with this mutation may develop colon cancer. This test is also available over the Internet, but I recommend a physician's support is here also.

Then, there are the "physical" exams: sigmoidoscopy and colonoscopy. In both cases, the preparation for the exams is worse than the exam itself. If you are over 50, you should have the colonoscopy at least every 10 years, more often if you have a tendency to form polyps or a family history of forming polyps. A sigmoidoscopy is generally less extensive than a colonoscopy; to me there's no logical reason to do the lesser of the exams. I believe it was more popular when exams were done without a sedative and were often painful. The colonoscopy is performed when you are sedated and the physician performing the exam can take photographs/videos for comparison with later tests. If polyps are found during the exam, they can be removed and tested for malignancy. The prep? You have to clean out the colon for the examination. This means drinking a fluid to stimulate evacuation and staying near a bathroom.

The third test is a "virtual" colonoscopy. I believe it involves getting a miniature camera into the colon--by swallowing a gelatin-coated pill--and then picking up the transmissions from the camera. I'll have to check this one out further, because I haven't heard much about it lately, and don't know if it's still being used, and if it is, how the whole process works.

To learn more about any of these tests, check out the American Cancer Society's site. Remember that the organization is somewhat conservative and generaly recommends only the most tested exams, not listing newly developed tests or exams until they have been clearly shown to benefit people.

If you have a specific question about a test or exam, or about the genetics of colon cancer, please use the comment mode to ask your question. You do not have to give your name.

Marie Godfrey, PhD