Jun
04
2016

Genetic Screening For Better Health

Dr. Matt Pratt-Hyatt gave an overview about genetic screening for better health at the 23rd Annual World Congress on Anti-Aging Medicine on Dec. 13, 2015 in Las Vegas. The title of the talk was: ”Genetic Screening: A Tool for Better Health with Age”. He showed that with more sensitive genetic screening techniques minor genetic changes can be detected. These are a lot more common than previously thought of. Matt Pratt-Hyatt, PhD is Associate Laboratory Director for the Great Plains Laboratory in Lenexa, KS.

Specifically, Dr. Pratt-Hyatt explained that single nucleotide polymorphisms, frequently called SNPs (pronounced “snips”) were the most common type of genetic variations among people. These genetic changes in the DNA often cause disease. Different types of genetic testing can identify the gene defects of SNPs. One of the questions is how aging can be better managed when genetic defects are known.

When it comes to our genetic material there are over 3 billion base pairs, all contained in 23 chromosomes. These are home to 20,000-25,000 genes, most of which are normal.

A gene has three regions all of which can have mutations. In the middle there is the coding region; one end is the regulatory region for transcription initiating; at the other end the transcription termination signals are located. Minor mutations in any of these regions can have major implications for the health of the individual or they can stay silent SNPs. SNPs are classified into missense mutation or nonsense mutation. This description just shows how intricate and complex the process of mutations can be!

There are three types of sequencing that are common:

Three types of genetic screening for better health

  1. Sanger sequencing
 utilizes certain dyes that correspond to specific nucleotides of the DNA. The benefits of Sanger sequencing is that it can cover one gene completely. It can find previously unknown mutations. But the disadvantage of Sanger sequencing is that you cannot process a large number of genes.
  2. The Florophore-base detection looks at multiple SNPs in a single run. This method is cheaper than whole genome sequencing. But one of the disadvantages of Florophore-base detection
is that only a limited number of SNPs can be processed per run. It also can miss new mutations.
  3. Benefits of next generation sequencing 
are that it can look at 1000s of SNPs per run. It is much more accurate than previous technologies. A drawback
though is that the equipment is much more expensive.

The physician does not have to order all of these tests, but can make the choice of the appropriate one for the patient. The following are some applications with regard to how genetic screening can be useful for better health.

Detoxification as part of genetic screening for better health

Since the 1970’s and 1980’s it has become clear that there are many steps in the detoxification process in the liver. It involves major enzyme systems that are controlled by the P450 genes. We know several genetic defects that run in different families. These effects are very important for drug detoxification and metabolism.

The P450 detoxification system in the liver

Any mutation in one of the P450 controlling genes will lead to accumulation of the drug that is normally detoxified by this enzyme system. Without discontinuing or lowering the drug there can be toxicity at higher levels. When people age, they often have spontaneous mutations of the P450 detoxification system. The physician who prescribes medications should take this into account. Common drugs that cause problems with the P450 controlled detoxification are antidepressants, the blood thinner Coumadin, the antibiotic erythromycin, the asthma medication Theophylline and many others.

Patient with atrial fibrillation

Here is an example of how important this knowledge is in an elderly patient who was sent to the hospital with an irregular heartbeat. The electrocardiogram allowed a diagnosis of atrial fibrillation. The doctor treated the patient with a cautious loading dose of 0.5 mg of Coumadin in an attempt to thin the blood of the patient. This would prevent a blood clot or a stroke due to the arrhythmia. Normally a small dose like this would not do much in terms of blood thinning. It would take several days of small doses of Coumadin dose like this to achieve blood thinning.

Defect of gene controlling P450 system

Unbeknown to the physician, this patient was different as he had a defect in the Cyp2c9 gene, a subtype of the P450 system. Very quickly the patient developed bleeding gums and bruising of the skin in various locations. When blood tests were taken, the INR, a measure of the clotting system, was 3.7, a value that should not have exceeded a level of 2 to 3. Genetic testing confirmed a homogenous mutation of the Cyp2c9 gene that explained the toxicity of Coumadin in this case, one of the many drugs that is detoxified by the P450 system.

Mental health as part of genetic screening for better health

Many mental illnesses can be caused by defects in various parts of the brain metabolism. This is particularly so when it involves the synthesis of brain hormones. If there are genetic defects, this can lead to the particular brain metabolism that is associated with depression or schizophrenia. Even dementia, Alzheimer’s disease and Parkinson’s disease can be caused by genetic defects. Methylation pathway defects are another source of possible genetic defects, which can affect multiple metabolic pathways. This is the cause of many diverse conditions like autism, diabetes and some hereditary cancers. The reason it is important to be aware of such genetic aberrations is that often vitamin B2, B6, niacin, vitamin B12 and the minerals magnesium and zinc can stabilize a person with methylation defects.

Cholesterol as part of genetic screening for better health

People with obesity have problems with their lipid metabolism, diabetes, high blood pressure and often heart disease and strokes. Changes in cholesterol metabolism are at the center of these problems. Cholesterol is one of the building blocks of cell membranes, and cholesterol is one of the normal components in the blood as long as the subfractions are properly balanced (LDL and the HDL cholesterol). Unfortunately many people have minor or major defects of the biosynthetic pathway of cholesterol. There are 5 genes that control the acetyl CoA biosynthesis. 21 genes involve the main cholesterol biosynthesis pathways. Over 10 genes control cholesterol metabolites. Historically these genes were detected because of various familiar gene defects that caused problems with the biochemical processes surrounding cholesterol. Familial high cholesterol levels (familial hypercholesterolemia) is one of these common conditions.

Patients who have this condition will often have high cholesterol and also often have a family history of gall bladder surgery for gallstones and a history of premature heart attacks or strokes. Early diagnosis and careful clinical intervention can improve the outlook for many patients.

Genetic Screening For Better Health

Genetic Screening For Better Health

Conclusion

Modern medicine cannot help all of the genetic conditions. But you can work around many minor genetic abnormalities. In addition, if the physician knows the genetic defect, it is possible to avoid drug interactions. It is encouraging that newer test methods have now shown success, as they are more affordable than in the past. As time progresses the price of these genetic tests will come down even further. Mental health, detoxification pathways and the metabolic syndrome of obesity are practical applications where genetic tests have significance.

Mar
05
2016

Catch Cancer Early

Cancer of the cervix was the first cancer where physicians practiced early diagnosis (Pap test), so they could catch cancer early. Subsequently this reduced the mortality due cancer of the cervix significantly.

Pap test

When the Pap test was invented and used on a large scale, cervical cancer could be diagnosed at the earliest stage, which is “stage 0” or “cancer in situ” (the earliest local cancer). In 1943 Dr. Papanicolaou published the book “Diagnosis of Uterine Cancer by the Vaginal Smear” where he described in detail how to do the Pap test. This became the norm very quickly and the use of the Pap test spread all around the world following WWII.

This was important, because later physicians detected that cure rates of close to 100% were possible by removing the tiny accumulation of local cancer cells (cancer in situ). This could be achieved by surgical removal (cone biopsy), radiation therapy, and cryotherapy or later also with laser treatment. The key to success in cancer treatment is early detection and early treatment.

Other cancer prevention and early detection

Melanoma

With melanoma, a darkly pigmented skin cancer, the earliest stage, namely stage 0 or carcinoma in situ is treated by surgical excision leaving a wide margin of healthy skin around it. This is the cure, because the physician detected it early and there was no invasion yet into the surrounding tissues.

Breast cancer (ductal carcinoma)

The most common breast cancer type is ductal carcinoma in situ (DCIS), of which 80% are diagnosed by mammography. Treatment for this is usually by local surgical excision, called lumpectomy followed by radiation.

Colon cancer screening with colonoscopy

Colon cancer typically arises out of colonic polyps. A physician typically does a colonoscopy in high-risk patients with a history of colon cancer in a first degree relative.Typically he does this every three years. When he finds a polyp, he removes it during the procedure. My mother died at the age 59 of colon cancer. I had colonoscopies every three years since the age of 40 and on several occasions polyps were removed. Had I not had the colonoscopies, an unnoticed carcinoma in situ would have developed within one of the polyps and subsequently invasive colon cancer could have developed. Colonoscopies are a means of true colorectal cancer prevention.

The newest development: Oncoblot test to detect in situ cancers

At the 23rd Annual World Congress on Anti-Aging Medicine in Las Vegas (Dec. 11-13) Dr. Mark Rosenberg spoke about the universal cancer marker ENOX-2 that is only expressed during embryogenesis (the development of the fetus) and in adulthood only again when cancer develops. A test has been developed to check for the ENOX-2 gene, which becomes positive 5 to 7 years before cancer can be detected clinically. This is called Oncoblot test. Sensitivity of ENOX-2 is high and false positives are negligible, which makes the ENOX-2 marker ideal for cancer screening.

Green tea and capsicum may suppress cancer gene

There are various isoelectric points for various cancer tissues, so the lab physician can tell the treating physician from which tissue a positive cancer test originates. The interesting aspect is that a combination of green tea and capsicum has been able to suppress the expression of the gene, and the cancer gene can be turned off. Corresponding biopsy samples showed that the cancer cells had disappeared. This is an entirely new concept and will have to be further investigated by clinicians for the various cancer types.

25 cancers that can be screened for using the Oncoblot test

Here are the 25 cancers that are screened with the Oncoblot test: Bladder, Breast, Cervical, Colorectal, Endometrial, Esophageal, Gastric, Hepatocellular (liver), Kidney, Leukemia, Non-Small cell (lung), Lung Small cell, Lymphoma, Melanoma, Mesothelioma, Myeloma, Ovarian, Pancreatic, Prostate, Sarcoma, Squamous Cell, Follicular Thyroid, Papillary Thyroid, Testicular Germ Cell, Uterine. Considering that testing for all of these cancers is 1000 USD, this means that each specific cancer test is only 40 USD per test. I suspect that in future the price will come down as mass screening will be done. But the key is that this test is available right now; it is highly specific and highly sensitive.

A specific and sensitive cancer screening test

But the important finding right now is that we have a very sensitive and very specific cancer screening test for over 25 various cancer types that can detect these cancers in the in situ stage (very early).

This has not been the case in the past except with the introduction of the Pap test for cervical cancer.

Change of treatment protocols may be required

The company producing the Oncoblot test states that the results need to be discussed between patient and treating physician. Although the treatment protocol does not change, there will be a lot more early diagnoses of cancer than in the past. In the past stage 1 and 2 stage cancers had the label “early cancers” and physicians developed protocols to treat these early cancers. But with this very sensitive blood test (Oncoblot test) the diagnosis of “in situ cancers” (stage 0) is possible. Mind you, it sets you back about 1000 USD, the cost for processing your blood and the test. Despite the monetary barrier I believe that enough people will go for this test, because with the knowledge that an early cancer diagnosis is possible, it can be treated effectively with high cure rates.

Down side of positive Oncoblot test, when tumor not spotted

The down side may be that those who had the test and are positive for a specific cancer may have to undergo additional tests to locate and treat the tumor.

Suggested future approach to cancer detection and treatment

I envisage four steps to the future of cancer diagnosis and treatment.

Screening for cancer 

To achieve this the Oncoblot test is a useful screening tool. Other similar tests that are in development will do this also in the future. This will give a tissue specific cancer diagnosis at the earliest possible point in time when clinically in most cases no tumor is present clinically for another 5 to 7 years.

Staging of the cancer found

This requires confirmation of the cancer by doing imaging studies and possibly biopsies. An MRI scan of the affected area will likely be very useful, also to rule out early lymph gland metastases. Without being certain about the stage of the cancer the treating physician can not be certain what treatment schedule to follow as treatments differ for various stages of a cancer.

Minimal invasive therapy

Ablative cryotherapy or low-dose laser phototherapy using three different photosensitizers as shown in the example of end stage prostate cancer in this link under the heading “Photodynamic therapy of a group of inoperable prostate cancer patients”. The tragedy in this pilot study was that all of the men presented with end stage prostate cancer, which is difficult to cure. But early prostate cancer is may be easier to cure with the same method, simply because the cancer cells are local (in situ). Every cancer expert knows that cure rates are very high in the early stages of cancer, with the highest cure rates for cancer in situ (stage 0) and somewhat lower success rates for stages 1 and 2.

Poorer long-term survival with more advanced cancers

Stages 3 and 4 have very poor cancer cure rates, as the cancer has already invaded the surrounding area in stage 3 and presents with distant metastases in stage 4. To make an impact in these latter cases requires toxic therapies like chemotherapy, radiotherapy and/or extensive surgery. Having said this, 20% of these end stage prostate cancers still experienced a cure with the triple photosensitizers and low-dose laser therapy (see link above), which conventional therapies would not have achieved.

Retesting for residual cancer using Oncoblot test 

Two months after the completion of the cancer treatment the physician can reorder the Oncoblot test. This will reassure the patient and physician as well that all of the cancer cells have disappeared. As this test is so sensitive, any remaining cancer cells would shed tumor protein into the blood. The Oncoblot test would pick this up immediately. In the few cases that would remain positive this would enable the physician to do further tests. The physician could modify the treatment and hopefully get rid of the last cancer cell.

Examples of two clinical scenarios

Two common cancers are prostate cancer in men and breast cancer in women.

1. Prostate cancer

Prostate cancer is very common in older men. From the age of 50 onwards the risk of getting prostate cancer is higher with every decade.

Another problem is that not every prostate cancer is invasive. Some cancers are low grade and sit around for a long time and may never metastasize. A cancer expert discusses this here.

To attempt to distinguish between the aggressive form of prostate cancer and the slower “wait and see type”, a score has been developed, called the 4K score. This score combines the PSA test and a prostate specific kallikrein marker within one blood sample. Patients with a high 4K score are the ones who have an aggressive prostate cancer that needs urgent treatment. Patients with a low 4K score are the ones where many urologists recommend to wait and observe.

Treat prostate cancer in the early stage

If I were the patient I would lean towards treating any kind of prostate cancer. Cancer can do whatever it wants to.  You do not really know how these cancer cells will behave in the future. The only difference in prostate cancer is that the prostate has a tough capsule. The tumor stays localized for a long time, sometimes for decades. The prostate cancer grows slowly until it breaks out of this shell and metastasizes to the rest of the body. At that point it is often too late to rescue the patient, because it suddenly is a late stage. As stated earlier, late cancer stages lead to poor treatment successes. Knowing this, I would suggest to use a radical prostatectomy in a stage I cancer.

2. Breast cancer

This is common in women. Often the physician detects early cancer on a routine mammography or else with the Oncoblot test. An MRI scan can localize the tumor when it has a certain size. But it may take 5 to 7 years following an Oncoblot test before the cancer can be visualized. This may be a diagnostic dilemma, which has to be worked out in the future. Most breast cancers develop from the epithelium of the breast ducts. Low-dose laser phototherapy with photosensitizers can treat this early cancer stage. If a repeat Oncoblot test 2 months later is negative, the treatment was successful. If it is still positive, surgery, which is more invasive can still be done.

Follow patient closely, if Oncoblot test remains positive following surgery

If not, the clinician will have to closely follow the patient with repeat MRI scans of the breasts. Without utilizing the Oncoblot test this method (the MRI scan) is still superior. Perhaps in the future another way besides the Oncoblot test to localize early cancer becomes available. The fundamental difference between breast cancer and prostate cancer is that breast tissue is very vascular. This encourages any cancer of the breast to metastasize very early. For this reason it is crucial to treat breast cancer very early to have optimal treatment successes.

Catch Cancer Early

Catch Cancer Early

Conclusion

The introduction of the Oncoblot cancer-screening test may revolutionize diagnosis and treatment of 25 or more cancers. A person who has one of these cancers can get screening with this test. I have only highlighted the possibilities with the example of two cancers. I explained what this might mean in practical terms for the diagnosis of prostate cancer and breast cancer. The exciting news is that cancer can now be detected earlier. The confusing part is that it can be diagnosed 5 to 7 years before the cancer is clinically detectable. Many physicians may feel uncomfortable treating cancer that early. I have seen many cancer patients in their end stages in clinical practice. I can only state that it is better to be too early than too late diagnosing cancer.

Cancer that will respond to treatment

Only stage O (cancer in situ) and stage 1 (and sometimes stage 2) can be treated successfully and guarantee a cure. Experience will teach us what the best way is in the future. In the meantime this is an approach to an early diagnosis without taking any risks.