Highlight HEALTH

Welcome to the 7th edition of the Cancer Research Carnival, a blog carnival devoted to cancer research. This edition includes some great articles on cancer research ethics, cancer therapeutics, cancer stem cells, cancer genetics and cancer biology.

I believe it’s important to maintain perspective on the significance of cancer research and the impact it has on patients. As such, this months edition of the Cancer Research Carnival includes narratives from some people affected by the disease. I think their stories will inspire us all with their determination and courage, and serve as motivation to continue searching for therapies to combat cancer.

How is research progressing on the battle against cancer?

The latest American Cancer Society (ACS) annual cancer statistics report finds that cancer deaths have decreased by 18.4% in men and 10.5% in women since mortality rates began to decline in the early 1990s [1]. However, despite a declining death rate, there was an increase in the number of cancer deaths in 2005 compared to 2004. The ACS says that it’s [2]:

… important to understand that for the number of cancer deaths to decrease, the decline in the overall cancer mortality rate must be large enough to offset the increasing numbers due to growth and aging of the population.

Over the last 15 years, researchers have been making progress. Although the rate of decline in cancer deaths in 2005 wasn’t enough to exceed population factors, cancer mortality rates continue to decrease. Indeed, between 1990/1991 and 2004, over a half million deaths from cancer were averted [2].

With these statistics in mind, let’s get to the research highlighted in this months edition of the Cancer Research Carnival.

Cancer Research Carnival #7

Adventures in Ethics and Science

A recent New York Times essay by Andrew Vickers ponders why cancer researchers are so reluctant to share their data [3]. Dr. Janet Stemwedel discusses the essay, asking Should Researchers Share Data?.

Bayblab

Autophagy, the self-removal of cellular components, is frequently observed in tumor cells following radiotherapy. Researchers have found that inhibition of genes associated with autophagy results in enhanced cytotoxicity of radiotherapy to otherwise resistant carcinoma cells [4]. Kamel talks about Autophagy and Radiation Resistance.

Mark’s Daily Apple

Increased body-mass index (BMI) is associated with the risk of some types of cancer. A systematic review and meta-analysis published in the Lancet journal last month assess the strength of associations between BMI and different sites of cancer [5]. Mark’s Daily Apple reports there’s a Higher Cancer Risk if You’re Fat and questions whether public education on the risks of obesity is truly enough.

The Pink Tee Shirt

Beep Beep - Emmy describes what it’s like to be living with breast cancer.

Stage 4 cancer is like a hungry coyote out there, watching, setting traps.
I wonder when he will catch me.

Cancer and Your Genes

Two papers in the February 28th issue of Nature provide understanding into a subset of breast and ovarian cancers, the action of drugs used to treat them and a novel mechanism of drug resistance to chemotherapy [6-7]. Dr. Matt Mealiffe reviews the articles and their significance, describing the Mechanism of Cisplatin-Resistance in BRCA2-Related Ovarian Cancers.

Cancer Genetics

SNPs (pronounced “snips”) are DNA sequence variations that occur when a single nucleotide in the genome is altered, producing different alleles (meaning sequences that code for the same gene). Two papers in the March issue of Nature Genetics identify multiple new SNPs associated with prostate cancer [8-9]. Ramunas breaks it down, describing Prostate Cancer — Old & New SNPs and deCODEPrCa.

Eye on DNA

As research identifies more disease-associated SNPs, new genetic tests allow consumers to test themselves for disease susceptibility. Dr. Hsien-Hsien Lei discusses this competitive market, reporting that deCODE Launches PrCa Prostate Cancer DNA Test.

Mystery Rays from Outer Space

Although it’s widely accepted that metastasis is a late event in cancer progress, a recent study demonstrated that tumor cells can spread systemically from early alterations in breast cancer [10]. Dr. Ian York deliberates Early Metastasis.

Z-Mail 101

David’s daughter Beth presents her thoughts on the situation her Aunt Wendy is in as she battles colon cancer.

You have to live life day by day and for each moment. Enjoy what you have in front of you and not take for granted the little things. We’re all going to die at some point; cancer patients just have more information.

Terra Sigillata

The internet is increasing used as a source of health information. A current study of quality criteria for online content, specifically for breast cancer information, finds that most resources are accurate [11]. However, websites that contain information on complementary and alternative medicine (CAM) were likely to contain inaccurate statements. Abel Pharmboy suggests we Beware of Alternative Medicine Sites Offering Breast Cancer Advice.

Doctor David’s Blog

An investigation examining the role of BRCA1 in human mammary stem cell fate found that BRCA1 plays a critical role in the differentiation of ER-negative stem/progenitor cells to ER-positive luminal cells [12]. Dr. David Loeb reviews study and discusses Cancer Stem Cells and Familial Cancer Risk for Breast Cancer.

Gene Sherpas: Personalized Medicine and You

Men with a family history of prostate cancer have a much greater risk of developing the disease than men with no family history. A systematic review and meta-analysis demonstrated that the risks are greatest for relatives of those diagnosed when they were young and those with more than one affected relative
[13]. The Dr. Steve Murphy evaluates the study and its shortcomings, discussing the New England Journal, Prostate Cancer and Babel.

Britannica Blog

The World Health Organization’s International Agency for Research on Cancer (IARC) has been conducting research on the increased risk of cancer in night-shift workers as well as the increased cancer risk in painters and firefighters [14]. Kara Rogers reviews the biology of melatonin secretion and disruption of circadian rhythm, writing about Cancer on the Night Shift: Why Night Workers Are at Risk.

Chrysalis Angel

Chrysalis Angel worries when she hears the word “cured” and reminds us all to Remain Vigilant.

Stay on top of your check ups, follow the recommendations of your doctors, do your own breast self exams. Take back your life and your health. You can only do that by remaining vigilant. Then, get out, enjoy your life and loved ones. Make your life as much of what you want it to be as you can, and maybe someday soon – there will be an absolute cure for cancer.

Conclusion

Thanks to everyone that contributed articles — it’s been a pleasure to host this months edition of the Cancer Research Carnival. Be sure to take a moment and let your fellow bloggers know this issue is available so that everyone’s hard work can be appreciated and enjoyed by all. You can find more information about the carnival as well as the hosting schedule and past editions at the Cancer Research Blog Carnival.

References

1. Cancer Facts & Figures 2008. American Cancer Society. Atlanta, Ga. 2008.
2. Report Says Half a Million Cancer Deaths Have Been Averted Since Death Rate Drop. American Cancer Society Press Release. 2008 Feb 20.
3. Vickers A. Cancer Data? Sorry, Can’t Have It. The New York Times. 2008 Jan 22.
4. Apel et al. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. 2008 Mar 1;68(5):1485-94.
   View abstract
5. Renehan et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008 Feb 16;371(9612):569-78.
   View abstract
6. Edwards et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008 Feb 28;451(7182):1111-5. Epub 2008 Feb 10.
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7. Sakai et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008 Feb 28;451(7182):1116-20. Epub 2008 Feb 10.
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8. Eeles et al. Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet. 2008 Mar;40(3):316-21. Epub 2008 Feb 10.
   View abstract
9. Thomas et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet. 2008 Mar;40(3):310-5. Epub 2008 Feb 10.
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10. Hüsemann et al. Systemic spread is an early step in breast cancer. Cancer Cell. 2008 Jan;13(1):58-68.
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11. Bernstam et al. Commonly cited website quality criteria are not effective at identifying inaccurate online information about breast cancer. Cancer. 2008 Feb 11;112(6):1206-1213 [Epub ahead of print].
    View abstract
12. Liu et al. BRCA1 regulates human mammary stem/progenitor cell fate. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1680-5. Epub 2008 Jan 29.
    View abstract
13. Johns and Houlston. A systematic review and meta-analysis of familial prostate cancer risk. BJU Int. 2003 Jun;91(9):789-94.
    View abstract
14. Straif et al. Carcinogenicity of shift-work, painting, and fire-fighting. Policy Watch, The Lancet Oncology. 2007 Dec;8(12):1065-1066.

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The International Serious Adverse Events Consortium (SAEC) officially announced its formation this morning. The new global, non-profit partnership between leading pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and academic institutions plans to identify and validate genetic markers that may help predict which individuals are at risk for serious adverse drug events. The goal of the consortium is to publish a set of predictive SNPs for all drug-related serious adverse events (SAEs), reducing significant patient and economic costs as well as improving the flow of safe and effective medical advances by addressing safety issues of new drugs before they reach the market.

Dr. Janet Woodcock, deputy commissioner for operations at the FDA, which has been under pressure to ensure drug safety, especially following Merck’s withdrawal of Vioxx from the market three years ago, said today [1]:

This is what personalized medicine is really about, finding out for the individual, not just the general population … what their risks are. Up until now we’ve been kind of helpless [in dealing with adverse effects].

Indeed, a recent study found that the incidence of serious adverse drug events reported to the FDA doubled between 1998 and 2005; painkillers and immune-system boosters were responsible for the majority of occurrences [2].

Pharmacogenetics and SNPs

Not all people respond similarly to the same medication. Pharmacogenetics is the study of genetic variation that gives rise to diverse response to medication with a particular emphasis on improving drug efficacy and safety. One type of difference in DNA between people are single nucleotide polymorphisms (SNPs). I’ve written about SNPs previously. SNPs (pronounced “snips”) are DNA sequence variations that occur when a single nucleotide - A, T, C or G - in the genome is changed, producing different alleles (meaning sequences that code for the same gene). Common SNPs only have two alleles. For example, ATCGATCG and ATCAATCG represent two alleles: G and A. These small variations in DNA sequence make up approximately 90% of all human genetic variation and occur every 100 to 300 bases along the 3-billion-base human genome [3]. SNPs occurring in genes that code for drug-metabolizing enzymes (meaning enzymes that break down drugs in the body for elimination) may affect the amount of drug in an individual’s body at a given time and thus elicit variable responses to the drug [4].

Serious adverse drug events

Identifying and validating SNPs that affect drug metabolism is a crucial first step toward constructing a set of predictive SNPs for all SAEs. According to the FDA, a serious adverse drug event is a negative event that results in death, a birth defect, disability, hospitalization, was life-threatening or required intervention to prevent harm. PricewaterhouseCoopers, which provides industry-focused assurance and advisory services, reports that blockbuster drugs are typically efficacious in only 40% to 60% of the patient population [5]. Serious adverse drug events in patient subpopulations result in that drug being removed from the market (think Vioxx) at a huge financial and public relations cost to the manufacturer. The identification of genetic variations linked with SAEs is believed to be essential for the development of safer drugs while also identifying patients for whom a medicine will have the greatest probability of providing medical benefits with the fewest risks.

Initial studies

The SAEC is conducting two studies that will address drug-related liver toxicity, the leading cause of acute liver failure [6], and Stevens-Johnson Syndrome (SJS), a severe and life-threatening adverse reaction to medication that afflicts many children as well as adults and is associated with over 200 different medicines. Researchers will use data from The SNP Consortium and Hap Map Project, which mapped SNPs in conjunction with the Human Genome Project, to identify genetic variations linked with SAEs.

Three SAEC partners are conducting clinical studies and analyzing data: Newcastle University, currently conducting the Diligen study, which is investigating the genetics of drug-induced liver injury relating to the antimicrobial agents flucloxacillin (Flopen/Floxapen), a narrow spectrum bata-lactam antibiotic of the penicillin class, co-amoxiclav (Augmentin), a combination antibiotic containing amoxicillin and clavulanic acid, and the standard anti-TB drugs; EUDRAGENE, a European academic consortium to establish a case-control DNA collection for studying the genetic basis of adverse drug reactions, currently studying liver injury caused by non-steroidal anti-inflammatory drugs; and Illumina, a leading developer, manufacturer and marketer of next-generation life-science tools and integrated systems for the analysis of genetic variation and biological function. Columbia University is hosting the Consortium’s data analysis and coordinating center. The pharmaceutical companies Abbott, GlaxoSmithKline, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Pfizer, Roche, sanofi-aventis and Wyeth have been closely involved with the consortium launch and development of its scientific model, and are contributing data and underwriting costs.

SAEC chairman and CEO Arthur Holden said [7] in the announcement:

The traditional research model only provides one piece of the puzzle in understanding the genetic variations that could lead to an increased risk of an adverse event. Because of the number of patients needed to tie a genetic variant to an SAE, and the resulting cost of doing these studies, no one company, research center, or agency can efficiently conduct this research on its own. The most efficient way to study drug-related SAEs is to create a global, publicly available ‘knowledge base’ that will help identify the genetic variations that may predict SAEs.

SAEC research study results will be made available to the research community within 12 months of completion of the group’s genotyping for validation and further investigation. If initial studies are successful, the SAEC plans to examine every major drug-related serious adverse drug event to determine it’s underlying genetic cause.

References

1. Drug Makers, FDA Partner on Drug Safety. Associated Press. 2007 Sep 27.
2. Moore et al. Serious adverse drug events reported to the food and drug administration, 1998-2005. Arch Intern Med. 2007 Sep 10;167(16):1752-9.
   View abstract
3. SNP Fact Sheet. Human Genome Project Information.
4. Roden et al. Pharmacogenomics: challenges and opportunities. Ann Intern Med. 2006 Nov 21;145(10):749-57.
   View abstract
5. Personalized Medicine - The Emerging Pharmacogenomics Revolution. PricewaterhouseCoopers Global Technology Centre, Health Research Institute. 2005 Feb.
6. Drug-Induced Liver Toxicity. U.S. Food and Drug Administration. Created August 3rd, 2005. Updated March 9th, 2007.
7. FDA, Leading Pharma Companies Launch Global Collaboration to Research Genetic Markers Linked to Drug Safety. PharmaLive. 2007 Sep 27.

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In 2004, Korean investigators lead by Woo Suk Hwang at Seoul National University announced the creation of the world’s first human embryonic stem cell line generated by somatic cell nuclear transfer (SCNT), which involves the transfer of DNA, usually from a skin cell, into an egg cell that has had its DNA-containing nucleus removed. The work, published in the prominent journal Science, was retracted in 2006 amidst evidence that the researchers had falsified their data.

However, a study published online August 2nd, 2007, by the journal Cell Stem Cell reports that the Koreans unintentionally created the world’s first human embryonic stem cell derived by parthenogenesis, or virgin birth. Development is triggered spontaneously from the egg alone without the need for sperm fertilization.

Parthenogenesis is a natural phenomena that occurs in some insects, including aphids, honeybees and formicine ants, as well as some reptiles, including geckos, rock lizards and Komodo dragons. The process also occurs, though more rarely, in plants. There are no known cases of naturally occurring parthenogenesis in mammals because of imprinted genes. Imprinted genes are genes whose expression is determined by the parent that contributed them instead of following the usual rule of inheritance in which both copies of an inherited gene (one from the mother and one from the father) are equally expressed. In 1899, Jacques Loeb documented the first case of artificial parthenogenesis, treating sea urchin eggs with inorganic salt solutions to initiate embryonic development instead of the sperm of the male urchin [1].

In January 2007, researchers from the Harvard Stem Cell Institute analyzed patterns of genetic recombination in parthenogenetically derived mouse embryonic stem (ES) cell lines [2]. What they found was surprising: in contrast to ES cells produced by nuclear transfer, which are homozygous at most loci (meaning they contain two copies of the same form of a given gene at a specific location on a chromosome, referred to as an allele), parthenogenetically derived ES cells show predominant heterozygosity (meaning they have different alleles at a number of chromosomal locations) as a result of meiotic recombination. Meiosis is the process of cell division in sexually reproducing organisms that results in a reduction in the number of chromosomes in reproductive cells and leads to the production of gametes in animals (male gametes are sperm and female gametes are eggs) and spores in plants. Meiotic recombination, also known as crossing over, is a process of physical rearrangement occurring between two strands of DNA. A common event during meiosis, recombination leads to offspring that has different combinations of genes from their parents.

Researchers examined Hwang’s cell line using genome-wide single nucleotide polymorphism (SNP) analysis and found recombination patterns that are consistent with its derivation from a parthenogenetically derived embryo. SNP (pronounced “snip”) analysis identifies DNA sequence variations that occur when a single nucleotide - A, T, C, or G - in the genome is changed, producing different alleles. Common SNPs only have two alleles. For example, ATCGATCG and ATCAATCG represent two alleles: G and A. SNPs make up about 90% of all human genetic variation and occur every 100 to 300 bases along the 3-billion-base human genome [3]. These small variations in DNA sequence can have a significant impact on how individuals respond to disease, drugs and other therapies.

Parthenogenesis may provide a method for the generation of stem cells that are therapeutically valuable for women. Stem cells created by parthenogenesis don’t require cloning and won’t be rejected by the host immune system. However, concerns regarding safety and differentaion efficiency exist, as mouse parthenogenetic embryos are unable to complete full development due to the absense of paternally expressed imprinted genes, and tissues derived from parthenogenetic embryonic stem cells appear to have growth defects [4]. Further study is required to characterize the stem cells generated in the study. Nevertheless, parthenogenetically derived stem cells are another step closer to patient-specific, personalized medicine.

References

1. Jacques Loeb. On the nature of the process of fertilization and the artificial production of normal larvae (plutei) from the unfertilized eggs of the sea urchin. Am J Physiol 1899 3:135-138. Reprinted in Studies in General Physiology. Chicago: The University of Chicago Press, 1905. pp. 539-543.
2. Kim et al. Histocompatible embryonic stem cells by parthenogenesis. Science 2007 315, 482–486.
   View abstract
3. SNP Fact Sheet. Human Genome Project Information.
4. Hernandez et al. Paternal and maternal genomes confer opposite effects on proliferation, cell-cycle length, senescence, and tumor formation. Proc. Natl. Acad. Sci. U. S. A. 2003 100, 13344–13349.
   View abstract

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