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Neurofibromatosis (NF) is a set of genetic disorders that can cause tumors to develop and grow along various types of nerves. The tumors may also affect the development of non-nervous system tissues such as skin and bone.

There are three types of NF tumors that result from mutation or loss of different tumor suppressor genes:

• Neurofibromatosis type 1 (NF1) is the most frequent inherited cause of brain and nerve tumors. One in every 3,000 children is born with NF1, making it also one of the most common inherited human diseases worldwide. Enlargement and deformation of bones may also occur. Approximately 50% of people with NF1 also have learning disabilities. NF1 is caused by a mutation or loss of the tumor suppressor gene NF1.

• Neurofibromatosis type 2 (NF2) is much rarer, occurring in one in 25,000 births. NF2 is characterized by the development of multiple tumors on the cranial and spinal nerves. The hallmark of NF2 is the formation of tumors that affect auditory nerves. Hearing loss beginning in the teens or early twenties is typically the first symptom of NF2. NF2 is caused by a mutation or loss of the tumor suppressor gene NF2.

• Schwannomatosis is even rarer than NF2, affecting one in 40,000 individuals. SImilar to NF1 and NF2, Schwannomatosis tumors can develop on cranial, spinal and/or peripheral nerves. Although patients with Schwannomatosis do not have learning disabilities, they experience chronic pain and occasionally numbness, tingling and weakness. The candidate Schwannomatosis tumor suppressor gene is named INI1.

The National Institutes of Health (NIH) is the primary source of federal funding for biomedical research. However, other agencies also support research initiatives. In 1996, Congress added Neurofibromatosis to the Congressionally Directed Medical Research Program (CDMRP-NFRP). This program has been responsible for many advances in NF research, including NF mouse models, learning disabilities and nerve signaling pathways. In 2005, the Neurofibromatosis Research Program (NFRP) established the NF Clinical Trials Consortium, which is comprised of 10 major hospitals nationwide. The Consortium was established, not for drug discovery, but as a pipeline to test drugs repurposed to treat NF, including rapamycin (a relatively new immunosuppressant drug) and lovastatin (a statin used for lowering cholesterol). The Consortium will initially focus on NF1 for proof of concept. Once established, it will have the option of expanding to encompass NF2 and Schwannomatosis studies.

NF research program funding in jeopardy

The U.S. House and Senate included an $8 million appropriation for the CDMRP-NFRP in the FY2008 Defense Bill. This is a decrease of $2 million from 2007 and is over a 66% decrease from the high-water mark of $25 million in FY2005. Recently, I wrote about Flat Funding of Biomedical Research and The Threat to America’s Health. Separate from the NIH, the CDMRP is another funding source that supports research initiatives. The drastic funding cuts in the CDMRP-NFRP, specific to NF studies, endanger the research investment made to date, particularly with the NF Clinical Trials Consortium described above.

The Children’s Tumor Foundation (CTF), a non-profit medical foundation dedicated to improving the health and well being of individuals and families affected by the neurofibromatoses, is the largest non-government funder of NF research in the world. In 1991, the CTF began a formal advocacy and lobbying program for federal funding of NF research. Recently, the CTF announced an advocacy campaign to increase federal funding of the CDMRP-NFRP [1]:

We are all aware of the budget pressures our country faces, and understand that the $25 million funded in 2005 is not realistic in the current environement. However, this small program has accomplished so much, and as we enter what we believe will be a period of rapidly increasing clinical trials, this is a particularly important time for continued support of this funding. We are asking all of you to contact your Congressman and Senators to seek their support. There is much discussion of earmark reform in Washington. It is important to note that this funding is not an earmark. It is not directed to any one institution, state or district. It is a long standing program that makes grants solely on a peer review basis. Further, this is not a partisan issue - this funding has benefited over the years from strong support from both Democrats and Republicans. The accomplishments and return on investment from the CDMRP are a shining example of what the federal government can achieve when legislators work with the scientific community and non-profit organizations.

Indeed, the CDMRP-NFRP is a small program. Congressional appropriations for NF from 1996 to 2008 totaled just $190.3 million. By comparison, CDMRP funding for breast cancer totaled $2222.7 million, for prostate cancer, $890 million [2]. Nevertheless, CDMRP funding for NF research in 2008 is critically important to address the needs of translational research (meaning to connect basic research to patient care), complications of NF with high morbidity and mortality, and refinement and standardization of imaging techniques and biomarkers for use in future clinical trials.

You can read more on the Children’s Tumor Foundation and Neurofibromatosis here at Highlight HEALTH. Additional non-profit organization resources are listed in the Highlight HEALTH Web Directory.

I’m actively involved in neuro-oncology, specifically NF research, and can attest to the importance of CDMRP-NFRP funding. I encourage you to take a moment and email your Senator and Representative and urge them to support increased Neurofibromatosis research funding through the CDMRP. You can find your legislators contact information by visiting the House and Senate websites. For the House website, simply enter your zip code in the box in the upper left corner; for the Senate website, select your state from the pulldown menu in the upper right corner. Use the contact information provided to email, fax or mail your request for support.

UPDATE: April 1st, 2008

Sample letters are now available (in MS Word format) for download, making it that much easier to email, fax or mail your Senator and Representative.

References

1. The Children’s Tumor Foundation: Advocacy. Accessed 2008 Mar 30.
2. Congressionally Directed Medical Research Programs: Funding History. Accessed 2008 Mar 30.

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We’ve talked previously about the health benefits of coffee and the antioxidant compounds responsible for it’s bitterness. To add to the “perks” of coffee consumption, a recent report in the Journal of Cancer Epidemiology Biomarkers & Prevention suggests that caffeine protects against breast cancer in women that have a BRCA1 gene mutation [1].

What is BRCA1? The acronym stands for breast cancer 1, early onset. The BRCA1 gene encodes a protein that plays a role in maintaining genomic stability and acts as a tumor suppressor. Approximately 5%-10% of breast cancer and ovarian cancer is hereditary and 30%-50% of these are due to DNA mutations in the genes BRCA1 and BRCA2 [2]. Women age 35-40 that carry the BRCA1 mutation are particularly susceptible with a risk between 45%-60% of developing breast cancer [2]. The absolute risk of cancer by age 70 is reported to be between 45% and 87% [3-4].

The authors of the report had previously evaluated the association between coffee consumption and the risk of breast cancer among women who had detrimental mutations in either BRCA1 or BRCA2. They observed a statistically significant reduction in the risk of breast cancer among women who consumed six or more cups of coffee per day compared to those who never drank coffee [5]. The association was only observed for BRCA1 and for caffeinated coffee.

Ninety-five percent of caffeine is metabolized in the human body by a member of the cytochrome P450 family of enzymes, CYP1A2, which stands for cytochrome P450, family 1, subfamily A, polypeptide 2. The cytochrome P450 proteins catalyze many reactions involved in drug metabolism and the synthesis of cholesterol, steroids and other lipids. CYP1A2 also metabolizes acetaminophen (Tylenol) and caffeine. Decreased enzyme activation and impaired caffeine metabolism is associated with a common A to C polymorphism in the CYP1A2 gene (meaning a genetic variation in an individual’s DNA sequence, in this case a specific A to C basepair substitution that alters the function of CYP1A2) [6].

In the present study, the authors examined whether the CYP1A2 genotype (meaning a person’s genetic makeup, in this case the difference in the CYP1A2 DNA sequence between individuals) modifies the association between a history of coffee consumption and the risk of breast cancer. A total of 411 BRCA1 mutation carriers (170 cases and 241 controls) and their coffee consumption habits were evaluated. The CYP1A2 genotype did not affect breast cancer risk. However, among women with at least one variant C allele (meaning an alternative DNA coding sequence) in CYP1A2, specifically the CYP1A2*1F allele (an A to C basebair substitution at a specific location in one or both copies of the DNA coding sequence for CYP1A2), those who drank coffee had nearly a 3-fold decrease in the risk of breast cancer compared with women who never drank coffee.

The authors suggest that mechanisms other than induction of CYP1A2 may account for the influence of caffeine on breast cancer risk. Coffee contains a number of biochemically active compounds including caffeine, phytoestrogens (including flavonoids) and other phytonutrients (including tocopherols). However, caffeine is the only major compound in coffee known to be metabolized by CYP1A2. Thus the authors attribute the decrease in breast cancer risk to prolonged caffeine exposure among individuals that are “slow metabolizers”.

Coffee is a major contributor to the total in vitro antioxidant capacity of the diet. An investigation of the quality of vitamin and polyphenolic antioxidants in beverages found that black tea contained the highest concentration of high-quality antioxidants, followed by coffee [7]. Here’s the breakdown:

This may be particularly relevant for women who carry the BRCA1 mutation as a decrease in the expression of genes involved in the antioxidant response has been shown for BRCA1-deficient cells [8].

A separate hospital-based, case-control study done last year evaluating the role of coffee in breast cancer etiology found among premenopausal women that consumption of caffeinated coffee was associated with a decrease in breast cancer risk [9]. The study included 1,932 women with primary, incident breast cancer and 1,895 controls. Women who consumed four or more cups of coffee per day experienced a 40% reduction in breast cancer risk. Although this study didn’t examine individual genetics, it is one of many demonstrating coffee’s protective effects against breast cancer.

It’s fascinating that impairment of caffeine metabolism coupled with high coffee consumption can result in a reduction in breast cancer risk for women who have an otherwise increased risk due to a BRCA1 gene mutation. The BRCA1 variant C allele isn’t common; in their previous study, the authors indicate that >95% of the mutations identified weren’t pathogenic [5]. Nevertheless, these results underscore the importance of addressing individual genetic variability in the metabolism when evaluating diet-disease associations.

References

1. Kotsopoulos et al. The CYP1A2 genotype modifies the association between coffee consumption and breast cancer risk among BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev. 2007 May;16(5):912-6.
   View abstract
2. Ferla et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007 Jun;18 Suppl 6:vi93-8.
   View abstract
3. Antoniou et al. Risk models for familial ovarian and breast cancer. Genet Epidemiol. 2000 Feb;18(2):173-90.
   View abstract
4. Ford et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994 Mar 19;343(8899):692-5.
   View abstract
5. Nkondjock et al. Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Int J Cancer. 2006 Jan 1;118(1):103-7.
   View abstract
6. Sachse et al. Functional significance of a C–>A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. 1999 Apr;47(4):445-9.
   View abstract
7. Vinson et al. Vitamins and especially flavonoids in common beverages are powerful in vitro antioxidants which enrich lower density lipoproteins and increase their oxidative resistance after ex vivo spiking in human plasma. J Agric Food Chem. 1999 Jul;47(7):2502-4.
   View abstract
8. Bae et al. BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res. 2004 Nov 1;64(21):7893-909.
   View abstract
9. Baker et al. Associations between black tea and coffee consumption and risk of lung cancer among current and former smokers. Nutr Cancer. 2005;52(1):15-21.
   View abstract

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