Wednesday, March 2, 2011

Big science: The cancer genome challenge

[Courtesy: NatureNews]
Databases could soon be flooded with genome sequences from 25,000 tumours. Heidi Ledford looks at the obstacles researchers face as they search for meaning in the data.
When it was first discovered, in 2006, in a study of 35 colorectal cancers1, the mutation in the gene IDH1 seemed to have little consequence. It appeared in only one of the tumours sampled, and later analyses of some 300 more have revealed no additional mutations in the gene. The mutation changed only one letter of IDH1, which encodes isocitrate dehydrogenase, a lowly housekeeping enzyme involved in metabolism. And there were plenty of other mutations to study in the 13,000 genes sequenced from each sample. "Nobody would have expected IDH1 to be important in cancer," says Victor Velculescu, a researcher at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, who had contributed to the study.
But as efforts to sequence tumour DNA expanded, the IDH1 mutation surfaced again: in 12% of samples of a type of brain cancer called glioblastoma multiforme2, then in 8% of acute myeloid leukaemia samples3. Structural studies showed that the mutation changed the activity of isocitrate dehydrogenase, causing a cancer-promoting metabolite to accumulate in cells4. And at least one pharmaceutical company — Agios Pharmaceuticals in Cambridge, Massachusetts — is already hunting for a drug to stop the process.
Four years after the initial discovery, ask a researcher in the field why cancer genome projects are worthwhile, and many will probably bring up the IDH1 mutation, the inconspicuous needle pulled from a veritable haystack of cancer-associated mutations thanks to high-powered genome sequencing. In the past two years, labs around the world have teamed up to sequence the DNA from thousands of tumours along with healthy cells from the same individuals. Roughly 75 cancer genomes have been sequenced to some extent and published; researchers expect to have several hundred completed sequences by the end of the year.

The efforts are certainly creating bigger haystacks. Comparing the gene sequence of any tumour to that of a normal cell reveals dozens of single-letter changes, or point mutations, along with repeated, deleted, swapped or inverted sequences (see 'Genomes at a glance'). "The difficulty," says Bert Vogelstein, a cancer researcher at the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, "is going to be figuring out how to use the information to help people rather than to just catalogue lots and lots of mutations". No matter how similar they might look clinically, most tumours seem to differ genetically. This stymies efforts to distinguish the mutations that cause and accelerate cancers — the drivers — from the accidental by-products of a cancer's growth and thwarted DNA-repair mechanisms — the passengers. Researchers can look for mutations that pop up again and again, or they can identify key pathways that are mutated at different points. But the projects are providing more questions than answers. "Once you take the few obvious mutations at the top of the list, how do you make sense of the rest of them?" asks Will Parsons, a paediatric oncologist at Baylor College of Medicine in Houston, Texas. "How do you decide which are worthy of follow up and functional analysis? That's going to be the hard part."

Drivers wanted

Because cancer is a disease so intimately associated with genetic mutation, many thought it would be amenable to genomic exploration through initiatives based on the collaborative model of the Human Genome Project. The International Cancer Genome Consortium (ICGC), formed in 2008, is coordinating efforts to sequence 500 tumours from each of 50 cancers. Together, these projects will cost in the order of US$1 billion. Eleven countries have already signed on to cover more than 20 cancers (see map). The ICGC includes two older, large-scale projects: the Cancer Genome Project, at the Wellcome Trust Sanger Institute near Cambridge, UK, and the US National Institutes of Health's Cancer Genome Atlas (TCGA). The Cancer Genome Project has churned out more than 100 partial genomes and roughly 15 whole genomes in various stages of completion, and intends to tackle 2,000–3,000 more over the next 5–7 years. TCGA, meanwhile, wrapped up a three-year, three-cancer pilot project last year, then launched a full-scale endeavour to sequence up to 500 tumours from each of more than 20 cancers over the next five years.
Although the groups collaborate, TCGA has not yet been able to fully join the ICGC owing to differences in privacy regulations governing access to genome data. For now, members of both consortia are sequencing a subset of tumour samples from each cancer type — around 100 — and will follow this by sequencing promising areas in the remaining 400. That's useful, says Joe Gray, a cancer researcher at Lawrence Berkeley National Laboratory in California, but it's just a start. "In the early days, I thought that doing a few hundred tumours would probably be sufficient," he says. "Even at the level of 1,000 samples, I think we're probably not going to have the statistics we want."
“Even at the level of 1,000 samples, I think we're probably not going to have the statistics we want.”
What bigger numbers could provide is more driver mutations like the one in IDH1. These could, researchers argue, provide the clearest route to developing new cancer therapies. Many scientists have looked for mutations that occur repeatedly in a given type of tumour. "If there are lots and lots of abnormalities of a particular gene, the most likely explanation is often that those mutations have been selected for by the cancers and therefore they are cancer-causing," says Michael Stratton, who co-directs the Cancer Genome Project. This approach has worked well in some cancers. For example, with a frequency of 12%, it is clear that the IDH1 mutation is a driver in glioblastoma. Such searches should be fruitful for cancers that have fewer mutations overall. The full genome sequence of acute myeloid leukaemia cells yielded just ten mutations in protein-coding genes, eight of which had not previously been linked with cancer5.
Other cancers have proved more challenging. IDH1 was overlooked at first, on the basis of the colorectal cancer data alone. It was not until the search was expanded to other cancers that its importance was revealed. Moreover, some mutations shown to be drivers haven't turned up as often as expected. "It's very clear, now that all the genes have been sequenced in this many tumours, you have drivers that are mutated at very low frequency, in less than 1% of the cancers," says Vogelstein. To find these low-frequency drivers, researchers are sampling heavily — sequencing 500 samples per cancer should reveal mutations that are present in as few as 3% of the tumours. Although they may not contribute to the majority of tumours, they may still have important biological lessons, says Stratton. "We need to know about these to understand the overall genomic landscape of cancer."
Another popular approach has been to look for mutations that cluster in a pathway, a group of genes that work together to carry out a specific process, even if the mutations strike it at different points. In an analysis of 24 pancreatic cancers6, for instance, Vogelstein and his colleagues identified 12 signalling pathways that had been altered. Nevertheless, Vogelstein cautions that this approach is not easy to pursue. Many pathways overlap, and their boundaries are unclear. And because many have been defined using data from different animals or cell types, they do not always match what's found in a specific human tissue. "When you layer on top of that the fact that the cancer cell is not wired the same as a normal cell, that raises even further difficulties," says Vogelstein.

How much is enough?

Separating drivers from passengers will become even more difficult as researchers move towards sequencing entire tumour genomes. To date, only a fraction of the existing cancer genomes are complete sequences. To keep costs low, most have covered only the exome, the 1.5% of the genome that directly codes for protein and is therefore the easiest to interpret. Assigning importance to a mutation found in the murky non-protein-coding depths of the genome will be more challenging, especially given that scientists don't yet know what function — if any — most of these regions usually serve. The vast majority of mutations fall here. The full genome sequence of a lung cancer cell line, for example, yielded 22,910 point mutations, only 134 of which were in protein-coding regions (see graphic, right)7. Nevertheless, finding them is worth the cost and effort, argues Stratton. "It could be that none of those mutations pertain to the causation of cancer," he says. "But it equally could be that some do. We'll never find out unless we systematically investigate."
Not everyone agrees. Some researchers argue that the costs of cancer-genome projects currently outweigh the benefits. Prices are poised to drop dramatically in the next few years as a new generation of sequencing machines comes online, says Ari Melnick, a cancer researcher at Weill Cornell Medical College in New York. "Why not wait for that?" he asks. In the meantime there are lower-hanging fruit to pick, says Stephen Elledge, a geneticist at Harvard Medical School in Boston, Massachusetts. Mutations that affect how many copies of a gene are found in a genome, he argues, are cheaper to assess and provide a more intuitive insight into biological processes. "If you delete something, you can turn a pathway off very efficiently," he says. "And if you amplify something, you can increase flow through the pathway. Making point mutations in genes to activate them is a little dicier."
Changes in gene copy number can be detected using fast, relatively inexpensive array-based technologies, but sequencing can provide a higher-resolution snapshot of these regions, says Elaine Mardis, a sequencing specialist at Washington University in St Louis, Missouri. Sequencing can enable researchers to map the boundaries of insertions and duplications with more precision and to catch tiny duplications or deletions that might have gone undetected by an array. Mardis, along with her colleague Richard Wilson and others, used sequencing to detect overlapping deletions in a breast cancer that had spread to other parts of the body (see page 999)8. The deletions spanned the region containing CTNNA1, a gene thought to suppress the spread, or metastasis, of cancer.
Meanwhile, cancer genomics is spreading out from under the large, centralized projects. For example, a $65-million, three-year paediatric-cancer genome project headed by researchers at St Jude Children's Research Hospital in Memphis, Tennessee, and Washington University aims to sequence 600 tumours. And more small projects seem poised to pop up. "Pretty much any cancer centre with any interest in the genomics of cancer is now buying these sequencers and using them," says Sam Aparicio, a cancer researcher at the University of British Columbia in Vancouver, Canada.
Nature Physics Insight: Physics and the Cell

Part of the reason that cancer-genome proponents don't want to wait for sequencing costs to drop is that the real work starts after the sequencing is over. As Velculescu puts it, "Ultimately it's going to take good old-fashioned biology and experimental analyses to really determine what these mutations are doing." With this in mind, the US National Cancer Institute established two 2-year projects in September last year to develop high-throughput methods to test how the mutations identified by the TCGA pilot project affect cell function. The two centres — one at the Dana-Farber Cancer Center in Boston, and another at Cold Spring Harbor Laboratory in New York — aim to systematize the way that researchers pull other needles like the IDH1 mutation from the cancer-genomes haystack and make sense of them. The Boston team will systematically amplify and reduce the expression of genes of interest in cell cultures, and the Cold Spring Harbor centre will study cancer-associated mutations using tumours transplanted into mice.
“It's going to take good old-fashioned biology to really determine what these mutations are doing.”
In addition, large-scale projects are being run in parallel with the cancer-sequencing consortia to assess the effects of deleting each gene in the mouse genome, enabling researchers to learn more about the normal function of genes that are mutated in cancer. Sequencing is all very well, researchers have realized, but it won't be enough. "Some people say statistics should get us all the drivers that are worthwhile," says Lynda Chin, an investigator with TCGA at Harvard Medical School. "I don't agree with that. At the end of the day, we need these functional studies to prioritize the list of potential cancer-relevant candidates." 
See also News and Views, page 989.

Studies spot a gene that allows some cancer cells to evade drugs such as Taxol.

Ovarian cancer cells can survive chemotherapy drugs if they have defects in the FBW7 gene.STEVE GSCHMEISSNER/SCIENCE PHOTO LIBRARY
Potent chemotherapy drugs such as Taxol (paclitaxel) prompt cancer cells to self-destruct — but some tumours stubbornly survive the treatment.
Two studies have now independently pinpointed a gene that lies behind at least part of this resistance1,2. The discovery could help oncologists predict which patients are likely to respond to Taxol and drugs with similar actions, and which may not. It also flags up new targets for cancer therapy.
Taxol belongs to a class of chemotherapy drugs that work by binding to tubulin, a key protein in the network of filaments that maintains a cell's structure. Cells hit with anti-tubulin drugs "try to divide but they can't", says Ingrid Wertz, a molecular biologist at biotechnology company Genentech, headquartered in San Francisco, California.
Cancer cells that respond to Taxol eventually die. But other cells resist the treatment. In 2007, Wertz and her colleagues began asking why. The team found that, in responding cells, levels of one protein in particular, MCL1 – part of a family of proteins already known to affect a cell's life-cycle – were markedly lower immediately after treatment with Taxol (and with another anti-tubulin drug, vincristine). Further experiments showed that a known cancer-fighting protein, FBW7, was destroying MCL1.
Defects in the FBW7 gene had already been linked to a variety of cancers, including breast and colon. Wertz reasoned that its absence might in particular lead to high levels of MCL1, and explain why some cancer cells don't die when treated with anti-tubulin drugs.
Sure enough, the researchers observed that ovary and colon tumour cells with mutations in FBW7 had higher levels of the MCL1 protein and were more resistant to anti-tubulin drugs than cells with working copies of the gene.

Different route, same outcome

Meanwhile, Wenyi Wei, a molecular biologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts, and his colleagues were also studying FBW7's effects. Wei's group was focusing on a particular disease: T-cell acute lymphoblastic leukaemia (T-ALL), in which an estimated 30% of all cases have cells with FBW7 defects. These cells had high levels of other proteins that normally induce cell death, and yet they did not die. Wei's research into why that was led him to the same explanation: without the FBW7 protein, the cells did not break down MCL1, a necessary step for their death. "We went about it in opposite ways but ended up at the same conclusion," Wertz says, "which was really cool."
Wei and his colleagues also found a link to drug resistance. They exposed T-ALL cells to ABT-737, an experimental drug discovered by US healthcare firm Abbott, based in Abbott Park, Illinois (a newer version, ABT-263, is now in phase II clinical trials). This drug does not attack tubulin, but kills by blocking other proteins that promote cell survival. Again, cells with an FBW7 defect, and high levels of MCL1, are less sensitive to the drug. But the researchers found a way to solve this problem: by treating the cells with an agent called sorafenib, which lowered MCL1 levels and restored cells' sensitivity to the experimental drug.
The studies suggest that oncologists may be able to tailor their treatments based on whether or not patients have a defective FBW7 gene in tumour cells. "I think it has potential implications for any cancer in which these anti-microtubule agents are used," Wertz says.
Still, there are other ways to resist Taxol and similar drugs. Cancer cells may contain mutated tubulin, meaning anti-tubulin drugs can't bind to them in the first place. Or they may contain extra protein pumps that enable cells to quickly eliminate chemotherapy drugs. Anthony Letai, an oncologist at the Dana-Farber Cancer Institute in Boston, says that the importance of the MCL1 pathway in conferring drug resistance probably varies depending on the type of cancer.
"As with any study, you don't know how generalizable it is beyond these cell lines that they study," says Letai. "There's probably plenty of cell lines in which these effects are not observable." The trick, he adds, will be to figure out which cancers follow this model.

Bruce Clurman, an oncologist and molecular biologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, says the findings are exciting and provocative, but preliminary. He notes that FBW7 targets a number of proteins for destruction, not just MCL1. "When you disrupt FBW7, it's hard to know which of these downstream targets are playing what role in the development of cancer." These studies focus on FBW7's role in regulating MCL1, but "it's certainly far from the whole story", he says.
Hayley McDaid, a cancer biologist at Albert Einstein College of Medicine in New York, suggests looking at archived specimens from cancer patients treated with Taxol-like drugs. If Wertz's model holds, the researchers should find a correlation between the presence of FBW7 and response to Taxol. "We need to go in and actually do some sequence analysis on those specimens," she says.

Tuesday, November 30, 2010

Tumor for Tumor

A new paper appeared in Clinical Cancer Research on fighting tumor with Tumor derived vaccines from dendrite cells. Dendritic cells are critical to the human body's immune system, helping identify targets, or antigens, and then stimulating the immune system to react against those antigens. The new research grew dendritic cells from a sample of a patient's blood, mixed them with proteins from the patient's tumor, and then injected the mixture into the patient as a vaccine. The vaccine then stimulated an anti-tumor response from T-cells, a kind of white blood cell that protects the body from disease.
Purpose: To determine whether an autologous dendritic cell (DC) vaccine could induce antitumor immune responses in patients after resection of colorectal cancer metastases and whether these responses could be enhanced by activating DCs with CD40L.
Experimental Design: Twenty-six patients who had undergone resection of colorectal metastases were treated with intranodal injections of an autologous tumor lysate– and control protein [keyhole limpet hemocyanin (KLH)]–pulsed DC vaccine. Patients were randomized to receive DCs that had been either activated or not activated with CD40L. All patients were followed for a minimum of 5.5 years.
Results: Immunization induced an autologous tumor-specific T-cell proliferative or IFNγ enzyme-linked immunospot response in 15 of 24 assessable patients (63%) and a tumor-specific DTH response in 61%. Patients with evidence of a vaccine-induced, tumor-specific T-cell proliferative or IFNγ response 1 week after vaccination had a markedly better recurrence-free survival (RFS) at 5 years (63% versus 18%, P = 0.037) than nonresponders. In contrast, no association was observed between induction of KLH-specific immune responses and RFS. CD40L maturation induced CD86 and CD83 expression on DCs but had no effect on immune responses or RFS.
Conclusion: Adjuvant treatment of patients after resection of colorectal metastases with an autologous tumor lysate–pulsed, DC vaccine–induced, tumor-specific immune responses in a high proportion of patients. There was an association between induction of tumor-specific immune responses and RFS. Activation of this DC vaccine with CD40L did not lead to increased immune responses. Clin Cancer Res; 16(22); 5548–56. ©2010 AACR.
Citation: Richard J. Barth, Jr., Dawn A. Fisher, Paul K. Wallace, Jacqueline Y. Channon, Randolph J. Noelle, Jiang Gui, and Marc S. Ernstoff, 'A Randomized Trial of Ex vivo CD40L Activation of a Dendritic Cell Vaccine in Colorectal Cancer Patients: Tumor-Specific Immune Responses Are Associated with Improved Survival', Clin Cancer Res November 15, 2010 doi:10.1158/1078-0432.CCR-10-2138

Thursday, August 5, 2010

Somatic Mutations in Four Human Cancers

[Source : From mass genomics]
In a letter to Nature this week, a group from Genentech presents an elegant analysis of 2,576 somatic mutations across 441 tumors comprised of breast, lung, ovarian, and prostate cancer types and subtypes. Using something called “mismatch repair detection” (MRD) technology, the authors surveyed 1,507 candidate genes spanning some 4 megabases of sequence, largely comprised of known cancer genes and “druggable” genes. MRD apparently uses E. coli to isolate amplicons that contain mutations relative to a reference sequence, which are then assessed for variations by a resequencing tiling array. Matched normal samples were also screened (in pools of five) to eliminate germline events.

I admit to knowing little about MRD or its capabilities, but I’m very familiar with the validation platform (Sequenom), which has proven its value in the HapMap, Cancer Genome Atlas (TCGA), and 1,000 Genomes projects.
Significantly Mutated Genes

Any doubts I had concerning a study from the private sector were quickly swept away, not just by the quality of the journal, but by the analysis that the authors presented. Simply put, I was enchanted. Figure 1, for example, illustrates the significantly mutated gene (SMG) analysis with a grid of eight bubble plots, one per cancer subtype. Significant genes are notable not just by their position on the Y-axis (Mutation q-score), but the size of the bubble, which corresponds to the number of mutations.

The set of SMGs varied across type and subtype, but some patterns immediately jump out. PIK3CA and TP53 were the most significant across three breast cancer subtypes. TP53, in fact, was significant across all eight subtypes, most strikingly in lung and ovarian cancer. KRAS stood out in pancreatic cancer and lung adenocarcinoma, but not squamous lung carcinoma.

On average across all tumors studied here, the authors found 1.8 protein-altering mutations per megabase, with the highest rates seen in lung adenocarcinomas (3.5/Mb) and squamous carcinomas (3.9/Mb). The lowest mutation rate (0.33/Mb) was in prostate tumors, 75% of which harbored the TMPRSS2-ERG gene fusion. These patterns are consistent with Figure 1, where prostate shows a sparse handful of significant genes, while lung cancers have large and diverse sets of them.
Integrated Copy Number and Mutation Analysis

Next, the authors integrated their mutations with Agilent 244K array CGH copy number data to identify genes that were significantly altered, either by mutation, copy number, or both. In Figure 2a, the authors plotted significantly altered genes by their copy number gain or loss, which nicely separated oncogenes and tumor-suppressor genes. The integrated analysis identified 35 additional cancer genes including STK11, EPHB1, and notably GNAS (the G-protein alpha subunit). GNAS proved an important finding, as it was mutated and amplified across several human cancers.
Pathway-based and Recurrency Analyses

The integrated dataset identified two pathways - RTK signaling and RAS/MAPK as the most significantly altered across all tumor types. Furthermore, when the authors compared their dataset with the COSMIC database and the findings of recent cancer sequencing studies, they pinpointed novel recurrent mutations in several genes including HER2, NOTCH4, and PIK3R1.

The authors conclude that their study “represents a substantial expansion of the knowledge base of cancer somatic mutations,” and I tend to agree. They not only generated a rich dataset, but also analyzed and presented it in comprehensive fashion. Furthermore, they (perhaps unsurprisingly) identify numerous cancer genes that are druggable targets, thereby translating these findings into actionable information.


Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty PM, Bourgon R, Zheng J, Moorhead M, Chaudhuri S, Tomsho LP, Peters BA, Pujara K, Cordes S, Davis DP, Carlton VE, Yuan W, Li L, Wang W, Eigenbrot C, Kaminker JS, Eberhard DA, Waring P, Schuster SC, Modrusan Z, Zhang Z, Stokoe D, de Sauvage FJ, Faham M, & Seshagiri S (2010). Diverse somatic mutation patterns and pathway alterations in human cancers. Nature PMID: 20668451

Friday, April 16, 2010

Foundation Medicine: a new genomic approach to cancer diagnosis

[Reposted from Times Online]


On June 25, 2000, Bill Clinton welcomed Francis Collins and Craig Venter to the White House to announce the completion of the first draft of the human genome. Ten years on, scientists have taken many important steps towards understanding what this sequence means for human health, yet most of the medical benefits still lie in the future. Except, that is, in one important disease. Cancer.

Cancer is at root a disease of the genes, caused when mutations trigger uncontrolled cell division. Understanding the genome is thus a highly valuable weapon against tumours, as a knowledge of the molecular defects that drive them can allow doctors to attack them with targeted therapies. In the past decade, several of these smart drugs have hit the market, often transforming the prognosis for patients.

Imatinib (Glivec or Gleevec), for instance, has turned chronic myeloid leukaemia into a controllable disease. Patients with colon cancer can benefit from cetuximab (Erbitux) only if their tumours do not carry a mutation in a gene called KRAS. Trastuzumab (Herceptin) is often highly effective against breast cancers with a HER2 mutation, while gefitinib (Iressa) and erlotinib (Tarceva) work against lung tumours with an EGFR mutation. And most recently,an experimental drug called PLX4032 has had hugely promising results against melanomas with a particular mutation of the BRAF gene, offering hope for treatment of a cancer with a terrible prognosis.

The move towards such targeted therapies is certain to be a dominant theme of oncology over the next decade. But if they are truly to transform patient care, they need to be accompanied by simple diagnostics -- the tests that identify the genetic subtype of a patient's tumour, so that doctors can choose the appropriate therapy. As Sir John Bell has pointed out, access to such tests is currently patchy, particularly on the NHS.

That is where an exciting new company may soon come in. Foundation Medicine, based in Boston, has today announced it has raised $25 million in funding to develop a one-stop-shop service for genomic diagnosis of cancer. It is going to be a while before it has a product to offer doctors -- its executives are currently engaged in a "listening tour" while they develop their services. But its idea is one that has great potential to help patients to benefit from advances in genomic science.

Foundation is advised by several luminaries in this field, including Eric Lander, director of the Broad Institute, a pioneer of the Human Genome Project, and an adviser to President Obama. Other consultants include Levi Garraway, Matthew Meyerson and Todd Golub, of the Dana Farber Cancer Institute and Harvard Medical School.

Its goal is to broaden significantly the scope of genomic cancer diagnosis, so that samples of each patient's tumours can be analysed not just for one or two genes that might be salient to their treatment, as can happen at present, but for dozens.

A few leading-edge cancer centres, such as Dana Farber and Massachusetts General Hospital (which I visited recently), are starting to do this sort of testing already. Foundation, though, will offer an outsourced service that is suitable for any hospital, to widen access to such diagnosis to patients being treated at ordinary centres that lack the facilities or expertise to do such tests themselves.

Alexis Borisy, Foundation's chief executive, described the idea to me as follows:

"The vision that motivates us at Foundation is that we believe more and more cancer patients are going to benefit from an understanding of the core molecular aberrations that are driving their specific tumours. The technology has moved to a point where it's feasible to decipher those in an individual, patient-specific manner, and to do that in day-to-day oncology practice.

"Our aim is to make that technology available to oncologists, to have an off-the-shelf service for oncologists that they can have complete confidence in."

Dr Meyerson told me:

"Through Foundation Medicine, we’re going to make genomic testing available to all cancer patients. It will, if you like, democratise access to this sort of thing. That is our goal. My hope is we will be doing comprehensive testing on every patient’s cancer."

The notion of testing tumours for multiple mutations is important because of the pace at which scientists are unravelling cancer genomics. It is already emerging that some mutations that are common in one cancer type, such as BRAF in melanoma, also occur at lower frequencies in others -- in this case, in lung cancer. That means that a BRAF inhibitor, though designed for melanoma patients, might also work against lung cancers with the same mutation.

The problem is that while testing lung tumours for EGFR mutations alone makes sense, as that gene is commonly defective in that cancer type, it is not cost-effective to perform the BRAF test in isolation to catch perhaps 1 per cent of patients who might carry it. A reasonably-priced "multiplex text" that covers dozens of genes, however, could be applied to every tumour to provide useful diagnostic clues.

As Borisy put it:

"Some mutations might have been validated in one type of tumour, but could also be relevant and actionable in other settings. In the next couple of years, literally tens of thousands of cancer genomes are going to be analysed. We're going to discover actionable genes that are present in maybe 1 per cent, 0.5 per cent of tumours. At this low frequency, we won't be able to find these by testing one aberration at a time."

Many more rare mutations of this sort are going to emerge as projects like the International Cancer Genome Consortium examine the genomic architecture of cancer over the coming years. Standardized tests that look at dozens, hundreds even, of mutations are going to be necessary if we're to make full clinical use of these insights -- and services like Foundation's are likely to make those accessible.
There's another issue here: gene patenting. As I wrote when a US court last month struck down Myriad Genetics' patent on the breast cancer risk genes BRCA1 and BRCA2, broad patent rights over genes have the power to severely restrict multiplex testing of the type Foundation intends to offer. It just isn't practical to pay royalties to dozens of different patent holders over dozens of different mutations for which you might test.

Posted by Mark Henderson on April 15, 2010 in Cancer , Genetics |

Thursday, October 30, 2008

A quick checklist for cancer prevention

An article appeared in Self October 2008 issue. Here is the excerpt:

Slash your cancer risk in minutes a day
Little lifestyle changes can lower your odds of hearing the dreaded diagnosis. Slip them into your routine and sleep better tonight.
By Aviva Patz
From the October 2008 Issue

Slash your cancer risk in minutes a day
More from this package

Stay weight wise

Excess pounds boost cancer risk, a study in The Lancet shows. Build an exercise habit now to head off trouble: The American Cancer Society (ACS) recommends aiming for 30 minutes of activity five days a week. When you hit your 45th birthday, make sure you're also doing 45 minutes of strength training twice weekly to minimize metabolic slowdown. "Beginning in our mid-40s, we lose up to a third of a pound of muscle a year and gain it back as fat, and fat burns fewer calories than muscle," says Miriam Nelson, Ph.D., director of Tufts University John Hancock Center for Physical Activity and Nutrition in Boston.

Practice peace

Say ahhh! High levels of the stress hormone cortisol may inhibit a key gene from suppressing tumor growth, findings in the journal Genes, Chromosomes & Cancer suggest. Tame tension with this formula from the University of Pittsburgh Medical Center Healthy Lifestyle Program: 1. Take deep belly breaths. You slow and elongate brain waves, bringing on calm. 2. Watch your favorite comedy. Enjoying a good laugh activates the areas of the brain that govern humor, in turn suppressing the brain's stress regions. 3. Adopt an uplifting mantra. Try "I love my life!" and repeat it when you're happy. You will train your mind to associate the phrase with being content. Then when you're on edge, chant your mantra and you'll immediately feel at ease.

Bake, don't burn

Grilling beef, poultry and fish until it's charred to a crisp can turn amino acids and other substances in the meat into heterocyclic amines (HCAs), compounds that have been linked to cancer. "HCAs are 10 times more potent than most other environmental carcinogens," says Kenneth Turteltaub, Ph.D., a toxicologist at Lawrence Livermore National Laboratory in California. Try these cookin'-good tips!
Marinate meat before grilling. Soaking chicken breasts in a mixture of cider vinegar, olive oil, lemon juice and spices reduced HCA formation by 92 to 99 percent, notes a study published in Food and Chemical Toxicology. "Marinating creates a barrier between the hot surface and meat, enough to lower the temperature and prevent HCAs from forming," Turteltaub says.
Keep the grill temp below 325 degrees, the point at which HCAs begin to form.
Grill meat or fish in punctured aluminum foil to protect against flare-ups. When fat drips on the hot coals, it forms HCAs, plus other carcinogens called polycyclic aromatic hydrocarbons that rise with the smoke.
Microwave beef burgers for one to three minutes before browning; doing so reduces HCA production by 95 percent, according to a study in Food and Chemical Toxicology. Prior to grilling, discard the juices, which contain the building blocks of HCAs.
Flip burgers often—about once a minute. This action keeps meat juices from getting too hot and activating HCA formation.