Multiple Myeloma Genomics Initiative Sequences Myeloma Genomes

Myeloma Research Foundation (MMRF) and Multiple Myeloma Research Consortium (MMRC) announced the MMRC Multiple Myeloma Genomics Initiative has completed the sequencing of the first multiple myeloma whole genomes. This is the first time multiple myeloma whole genomes have been sequenced and will be used to identify key targets for new treatments.

“Groundbreaking data from the MMRC Multiple Myeloma Genomics Initiative will play an important role in developing better treatment options for individuals who derive little benefit from existing therapies and may ultimately help provide multiple myeloma patients with the most appropriate treatment for his or her disease,” Louise M. Perkins, PhD, Chief Scientific Officer of the MMRF. “Furthermore, knowledge from this effort could also benefit patients with other types of cancer.”

The critical task of analyzing the data from the project, conducted in collaboration with the Broad Institute of MIT and Harvard, is now underway, and additional genomes are also being sequenced. A portal to facilitate data access is being constructed and these first complete multiple myeloma genomes will be made available to researchers everywhere within the next several months.

“Through its extraordinary generosity and vision, the MMRF is enabling the important work of whole genome sequencing for multiple myeloma, and making the data publicly accessible,” said Todd R. Golub, MD, Director of the Broad Institute’s Cancer Program and co-principal investigator of the MMRC Multiple Myeloma Genomics Initiative. “This is a remarkable beginning.”

The Multiple Myeloma Genomics Initiative is a comprehensive genomic analysis program designed to rapidly accelerate progress made against multiple myeloma by significantly improving the understanding of the biology of the disease.

Spearheaded by the MMRF and conducted in collaboration with the Broad Institute and the Translational Genomics Research Institute (TGen), the Multiple Myeloma Genomics Initiative utilizes tissue samples from the MMRC Tissue Bank to advance cutting-edge research and discovery efforts that span the spectrum of genomic science. Data from the Initiative are placed into the public domain in near-real time via the Multiple Myeloma Genomics Portal, the world's only myeloma-specific repository of genomic data, and can be accessed at www.myelomagenomics.org.

The Multiple Myeloma Genomics Initiative has also just completed two other high resolution genomics profiling studies performed at TGen on the full Reference Collection of 250 patient's multiple myeloma tumor tissue. Jeffrey Trent, PhD, President and Scientific Director of TGen and co-principal investigator on the Multiple Myeloma Genomics Initiative, said, “The Multiple Myeloma Genomics Initiative has created an unprecedented opportunity to examine an extraordinary breadth of genomic information to pinpoint the most important genes and cellular processes driving the disease. Such a remarkable dataset exists for very few other cancers; it will no doubt pave the way toward personalized medicine for multiple myeloma patients.”

Pesticide link to MGUS

(NaturalNews) Just how dangerous are pesticides? No one knows the full answer to that question yet, but research is revealing that exposure to these toxins is clearly a bigger health risk than most people realize.

A new National Cancer Institute (NCI) study just published in Blood, the journal of the American Society of Hematology, has found for the first time that applying pesticides doubles the risk of developing an abnormal blood condition called MGUS (monoclonal gammopathy of undetermined significance). This disorder is characterized by an abnormal level of a plasma protein and requires lifelong monitoring with blood tests. The reason? MGUS can lead to the painful cancer of plasma cells in the bone marrow known as multiple myeloma.

The NCI research involved a study of 678 individuals, culled from a U.S. Agricultural Health Study of over 50,000 farmers who had worked with pesticides. The ages of the study participants ranged from 30 to 94, with an average age of 60. They all lived in either North Carolina or Iowa and were licensed to apply restricted-use pesticides. The research subjects were asked to fill out questionnaires to assess their occupational exposure to a wide range of pesticides and to document how long they had used pesticides. They also answered questions about the pesticide application methods they used, as well as whether they wore protective gear while applying the chemicals.

Information was also obtained about the participants' family history of cancer and their smoking and alcohol usage along with other basic health and medical data. If any research subject had a history of a lymphoproliferative malignancy, such as multiple myeloma or lymphoma, they were excluded from the study. Then, each year for five years the rate of cancer incidence and deaths in the research subject group were documented. At the end of the five year study, interviews were conducted to update the information about participants' occupational exposures, medical histories, and lifestyle factors.

The NCI research team took blood samples from the research subjects and evaluated them for MGUS. No MGUS cases were observed among those who were younger than 50. However, the prevalence of MGUS in those older than 50 was 6.8 percent. And when that figure was compared to a group of men from the general population in Minnesota who did not work with pesticides, the findings showed that the incidence of MGUS was extraordinarily high among those who applied pesticides. Bottom line: the pesticide group had double the risk of having MGUS, placing them at an elevated risk for myeloma.

"Previously, inconclusive evidence has linked agricultural work to an increased multiple myeloma risk. Our study is the first to show an association between pesticide exposure and an excess prevalence of MGUS," said lead author and NCI scientist Ola Landgren, MD, PhD, in a statement to the media. "This finding is particularly important given that we recently found in a large prospective cancer screening study that virtually all multiple myeloma patients experienced a MGUS state prior to developing myeloma.

"What pesticides appear to be the most dangerous? Of the chemicals studied, a significantly increased risk of MGUS was found among the people who used the insecticide dieldrin, the fumigant mixture of carbon tetrachloride and carbon disulfide, and the fungicide chlorothalonil. These pesticides increased the MGUS risk 5.6, 3.9, and 2.4 times, respectively. "As several million Americans use pesticides, it's important that the risks of developing MGUS from the use of pesticides is known," added senior study author and NCI investigator Michael Alavanja, DrPH, in the media statement.

New York Times - Considering Longer Chemotherapy

http://www.nytimes.com/2009/07/21/health/21canc.html?_r=2

A better way to harvest bone marrow

http://www.ted.com/talks/daniel_kraft_invents_a_better_way_to_harvest_bone_marrow.html

Study pinpoints novel cancer gene and biomarker

Research underscores need to combine genomics and basic biology in cancer gene hunt

Dana-Farber Cancer Institute scientists' discovery of a cancer-causing gene — the first in its family to be linked to cancer — demonstrates how the panoramic view of genomics and the close-up perspective of molecular biology are needed to determine which genes are involved in cancer and which are mere bystanders.

The findings are reported in the June 25 issue of the journal Nature.

"In the coming years, we can expect genomic studies [which chart the activity of thousands of cell genes] to generate hundreds or thousands of genetic elements of interest in cancer research," says the study's senior author, Lynda Chin, MD, of Dana-Farber.

"To narrow that group to the genes that actually drive cancer growth and metastasis, it's necessary to do functional studies, which focus on what individual genes do to turn a cell cancerous, and mechanistic studies, which examine how they turn cells cancerous and in what setting. It is a long and intensive effort that will leverage knowledge from different fields and different model systems."

In the study, Chin, lead author Kenneth Scott, PhD, of Dana-Farber, and their colleagues worked their way through a series of experiments — in yeast cells, multiple types of human cancer cells, laboratory cell cultures, and mouse models — to demonstrate that a surplus of a gene known as GOLPH3 can spur cancer cell growth in a variety of tissues.
It is the first gene associated with the Golgi complex, a tiny packaging plant that prepares proteins for their journey within and outside the cell, which has been found to play a role in cancer.

Chin's team also found that the protein made from GOLPH3 may serve as a biomarker for tumors that can be effectively treated with the chemotherapy drug rapamycin: tumors with a high level of the protein are more apt to shrink in response to the drug than those with low levels.

The study began with an observation made years ago that a section of chromosome 5p13 is often duplicated, or amplified, in cancers of the lung, ovary, breast, and prostate gland, as well as melanoma. The presence of this abnormality in so many different types of cancer led Chin and her associates to take a closer look at that stretch of chromosome to see what genes reside there.

Using a method called genomic qPCR that can pick out specific sequences of DNA, they found four genes in the amplified region, two of which, GOLPH3 and SUB1, were expressed at high levels, due to the increase in gene copy. To determine whether both, or either, of these genes are involved in cancer, they conducted "loss of function" tests, in which they lowered each gene's activity in a set of lab-grown tumor cells.

"When we 'knocked down' GOLPH3 expression [or activity] by 95 percent, it significantly inhibited the ability of these cell lines to grow in a semi-solid condition, a cancerous quality that normal cells do not typically share," Chin says. "Knocking down SUB1 to a comparable level had only a minimal effect."

Intriguing as this finding was, it was hardly enough to prove that GOLPH3 is an oncogene — a contributor to cancer when overexpressed within a cell.

Demonstrating that would require several experiments to ensure that GOLPH3 itself, and not a nearby "shadow" gene, is responsible for the effects. Next came gain-of-function studies to see whether revving up GOLPH3 activity can turn a non-cancerous cell cancerous. It did in both mouse and human cells.

"All these results enabled us to build a case that GOLPH3 is an oncogene," Chin states. But there was a problem. "This information wasn't very helpful for achieving our ultimate goal, which is the translation of our findings into a form that is clinically useful for patients."

Despite their discovery that GOLPH3 can promote cancer, researchers didn't know what the gene's role is in normal cells. "There was literally no information on what it does," Chin remarks. The only hint was that the protein it encodes — designated GOLPH3 — is found in the Golgi network.

The team's first attempt to uncover GOLPH3's role — using gene expression profiling to see how protein levels track with various cell functions — was fruitless. So the researchers ran experiments with yeast cells to see which proteins share GOLPH3's cell neighborhood and which proteins it interacts with.

One such partner was found to be VPS35, a component of a structure called the retromer complex. The complex's job is to recycle the antenna-like receptors that dot the cell surface.

From the many genetic screening tests that have been done in yeast, researchers knew that flaws in the retromer complex can cause cells to be vulnerable to rapamycin, just as excess GOLPH3 can. Rapamycin is known to interfere with a protein called TOR, whose job is to control yeast cell size. This suggested that the retromer complex in yeast is important for chemical signals sent to and from TOR.

Chin's team theorized that mammalian GOLPH3 also works with the retromer complex to control the activity of TOR in mammal cells (where it's known at mTOR). To test this idea, the investigators found that knocking down GOLPH3 reduced cell size just as rapamycin did. They followed those experiments with biochemical studies to explore how GOLPH3 affects cell size.

The team next sought to answer whether high GOLPH3 levels cause tumor cells to be more susceptible to rapamycin in animal studies.

They took two sets of human melanoma skin cancer cells — one of which had excess GOLPH3 and the other had normal levels — implanted them in animals, allowed them to grow into tumors, then treated them with rapamycin.

"In the animals where GOLPH3 was overexpressed, the cancer cells grew much faster, but the tumors were much more responsive to rapamycin," Chin notes, "suggesting the tumor-promoting effect of GOLPH3 is dependent on mTOR signaling."

Lastly, the team considered whether the same mechanism might be at work in human cancer cells. An experiment analyzing human tumor tissue for specific proteins suggested yes. The researchers found that non-small cell lung cancer cells with too many copies of the GOLPH3 gene also had abnormally high levels of mTOR activity.

"The mechanistic relationship we'd identified in the mouse system is also at work in human tumors," says Chin, who is also an associate professor at Harvard Medical School.

In addition to identifying GOLPH3 as a bona fide oncogene and an indicator of whether rapamycin is likely to be effective against specific tumors, the study points to the need to follow genomic studies with a rigorous examination of the biological purpose and operation of potential cancer genes, Chin concludes.

"Only then can we turn our intriguing discoveries in the cancer genome into something that is useful to cancer patients."

Co-authors include Omar Kabbarah, Mei-Chih Liang, PhD, Joyce Wu, Sabin Dhakal, Min Wu, PhD, Shujuan Chen, Tamar Feinberg, Joseph Huang, Hans Widlund, PhD, and Kwok-Kin Wong, MD, PhD, Dana-Farber; Elena Ivanova, PhD, Yonghong Xiao, PhD, and Alexei Protopopov, PhD, Dana-Farber and the Broad Institute of Advanced Cancer Science; David E. Fisher, MD, PhD, Massachusetts General Hospital; Valsamo Anagnostou, and David Rimm, MD, PhD,Yale University School of Medicine; Abdel Saci, PhD, Harvard Medical School.

Vegetarian Protection against Multiple Myeloma

I've asked this question in the past and have always been told that there is no scientific evidence of causality between diet and Multiple Myeloma.

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Being a vegetarian cuts the risk of developing cancer, especially cancers of the blood, researchers reported today.
The overall benefit enjoyed by vegetarians over carnivores is a 12 per cent reduction in risk, according to Cancer Research UK.

But researchers were surprised to find that a vegetarian diet offers the most protection against cancers of theblood such as leukemia, multiple myeloma and non-Hodgkin lymphoma.

Vegetarians were 45 per cent less likely than meat-eaters to develop these cancers.

The study involved more than 61,000 people studied over a period of 12 years. During that time some 3,350 developed cancer.

The findings are published today in the British Journal of Cancer.

Experts said they were "surprised" at the massive protection against blood cancers enjoyed by vegetarians.

Sara Hiom, of Cancer Research UK, said: "The relatively low number of vegetarians who developed cancer in this study supports Cancer Research UK's advice that people should eat a healthy, balanced diet high in fibre, fruit and vegetables and low in saturated fat, salt and red and processed meat.

"It's understandable that there's a link between what you eat and cancers of the digestive system. But we are surprised to see an association between leukaemia, non-Hodgkin lymphoma and multiple myeloma."

Researcher Professor Tim Key, of Oxford University, said: "In particular vegetarians were much less likely to develop cancers of the blood which include leukaemia and non-Hodgkin lymphoma. More research is needed to substantiate these results and to look for reasons for the differences."