News from the Front in War on Cancer--Mission Not Accomplished

Scientific American

Janet Rowley noticed something odd about the glowing chromosomes revealed by her microscope. It was the early 1970s, the first years of the so-called "war on cancer," and she was using a new staining technique to examine cells from patients with chronic myelogenous leukemia (CML), a cancer of the blood that was almost always fatal. The technique highlighted bands within the chromosomes, and she could see an extra piece on the end of chromosome 9. That fragment was nearly the same size as a "missing" chunk of chromosome 22 that other researchers had detected a decade earlier. To Rowley, it looked as if the tips of these two chromosomes had swapped places, or translocated. During the next few years she found two other cases of chromosomal translocation in different forms of leukemia. The finds forever changed the way scientists thought about cancer.

Shuffled chromosomes in leukemia established that broken, scrambled and messed-up genes cause cancer. The genetic code details when cells should grow, divide and eventually die. Cancer is a disease of misinformation—cells ignore the rules, growing despite multiple molecular signals telling them to stop and invading other tissues because they no longer respond to biological messages to stay put or even destroy themselves. In the past four decades scientists have identified thousands of genetic mistakes that either cause cancer or boost the risk of developing it. The effects of these typos are sometimes dramatic—the gene variants BRCA1 and BRCA2 can boost women's lifetime risk of developing breast cancer from 12 percent to 60 percent. Some errors are found only in cancer cells themselves; other changes can be passed from generation to generation. The latter are the mistakes that may be passed down and boost the risk of developing cancer—this is the inherited genetic risk, or the reason that people with a familial history of a disease may want to get tested earlier or more often.

As researchers uncover more genetic mistakes and delve deeper into the human genome, it may be possible to pin down the exact probabilities conferred by inherited genetic risk. If clinicians could scan a healthy person's genes for variations that explain their probability of developing cancer, perhaps they could prevent or catch the disease before it became a problem: Spit into this vial and the doctor will tell you what will ail you in 20 years.

Despite the plummeting cost of DNA sequencing technology, much of the information is a jumble of alphabet soup. Science can figure out what gene variants and markers a person has, but they can't tell exactly what it means for his or her health. It will take researchers years to untangle the genetics of cancer. Even large steps, heralded as a major advances, answer few questions and pose many more.

This spring, a massive international collaboration doubled the number of known genetic regions associated with the risk of breast, prostate or ovarian cancers. The genetic markers are signpost that researchers can follow to better understand the biology of these cancers. Only a few of the 74 newly identified markers are shared by more than one type of cancer, underscoring cancer's complexity. Yet exactly how the findings can inform public health recommendations remains to be discovered. Each marker is associated with small modifications of risk, but the effects add up. The findings could lead to more accurate cancer screening and hint at ways cancers could be caught before the disease becomes aggressive. Only further study, however, will show where to draw the lines between risk percentages that tell patients "not to worry" or "get tested now."

Reams of data

The impressive number of hits in the new work stems from the size of the research effort: 160 institutions around the world analyzed a pool of more than 200,000 individuals' genetic sequences. The international project is called the Collaborative Oncological Gene-environment Study (COGS). To find the dozens of new cancer risk regions, researchers combed the pooled genetic information for variations called single-nucleotide polymorphisms (SNPs). A SNP is change in a single letter of the DNA code, likely introduced as a "typo" during gene replication. If such a change happens within a gene, it can affect the structure of proteins. If it falls within a stretch of DNA that regulates genes, it can affect the amount of protein a cell produces.

The COGS researchers put 211,000 SNPs of interest, which were previously identified in other studies, on a custom-made DNA array that looks a bit like a computer chip. Then they used the chip to scan the pooled genetic information to look for differences between people who had cancer and those who did not. If a particular SNP popped up more often in the group of people who had cancer, that SNP could be linked to increased risk for that cancer.

Most of the SNPs the cancer teams identified are specific to one of the three cancers, but 17 are shared risk factors for all three. The new SNPs, combined with 75 previously known markers, explain a proportion of inherited genetic risk for these cancers: 28 percent for breast, 4 percent for ovarian and 30 percent for prostate cancer. The research was published as a collection of 13 papers in April in Nature Genetics, Nature Communications, PLoS Genetics, The American Journal of Human Genetics, and Human Molecular Genetics (Scientific American is part of Nature Publishing Group).

Comparing genomes to uncover SNPs of interest is one way that researchers dig down to find the genetic basis of complex diseases. "We get little bits that we put together," says Stephen Chanock, chief of the Laboratory of Translation Genomics at the National Cancer Institute. Chanock was involved in several of the new studies. Complex diseases such as cancer spring from many gene variants that all contribute to the disease. These studies are helping researchers fill in the list of risky genetic markers. "What is emerging is the complicated genetic architecture of different diseases," he says.

Following the signs

Rowley's swapped chromosomes eventually led researchers to find a way to treat CML. Now patients can take a pill that jams a monkey wrench into a process vital to the cancer's development. The drug, called imatinib (first marketed as Gleevec in the U.S.), often grants patients a normal life expectancy with minimal side effects. Few cancer treatments have met this high bar, but researchers still comb the genome for cancer's fingerprints and clues to what might stop the disease.

Indeed, the COGS findings provide signposts for future research. For example, a handful of SNPs associated with prostate cancer risk fall within genes important for the binding of a cell to a surface. That surface could be another cell to facilitate communication or create a barrier through which pathogens cannot pass. Cell–cell adhesion is important for immune response and is also involved in tumor metastasis—tumor cells use cell adhesion to stick to a new location in the body. Understanding the mechanisms for cell–cell adhesion may offer insights for new treatments.

In a number of regions the SNPs are involved in more than one type of cancer cluster. "In some cases we are beginning to understand why that is," said Doug Easton, a professor at the University of Cambridge and the lead author of the main breast cancer paper at a press conference before the papers were published. One of the COGS papers honed in on a genetic region that helps control the length of telomeres, which are protective caps on the end of DNA strands. The so-called TERT locus harbors SNPs relevant to both breast and ovarian cancer risk, making it a prime candidate for further study.

The next step for the international cancer teams is an even larger study with a new chip called OncoChip, made by Signature Genomics. They plan to screen 600,000 SNPs of interest to see if they are involved five malignancies—ovarian, breast and prostate as well as colorectal and lung cancers. The larger numbers will give the researchers more statistical power to uncover less common gene variants. In addition researchers will map the already discovered variants to figure out which genes and biochemical pathways are involved. Studies of gene function are critical to characterize cancer biology, says Mathieu Lupien, a scientist at the Ontario Cancer Institute and assistant professor at the University of Toronto who was not involved in COGS. "Now we can move forward and understand why it is those genetic defects promote cancer," he says.

Weighing the risks

Genetic markers may lead to better treatments, but researchers also hope to catch cancer before it starts.

Clinicians already use cancer-risk calculators to group people into high- and low-risk categories based on lifestyle choices, environment and family history. The new SNPs could be additional indicators that make the stratification more accurate and efficient. High-risk groups could get targeted recommendations for avoiding risky behaviors or whether to get screened for a type of cancer.

Currently, cancer screening is saddled with a lot of false positives, which means people who do not have cancer are told they are positive. Such results lead to unnecessary and even dangerous procedures—not to mention the anxiety felt by those who believe they have a potentially life-threatening disease. For example, screening for prostate, lung, colorectal and ovarian cancers in 68,436 people over a period of three years led to a least one false positive for 60 percent of men and 49 percent of women. Another study found that follow-up procedures (such as a biopsy) after a false positive cost an average of $1,024 for women and $1,171 for men. The challenge is figuring out where to draw the line for high-risk, says Ros Eeles, a professor of oncogenetics at the Institute of Cancer Research in London and one of the principal investigators involved in the main prostate cancer paper. "We could do the test and give a risk profile, but we don't know what you should do when you have the information," she says. Studies that retroactively profile genetic risk markers in patients could reveal where the lines should fall and what interventions are most effective.

"We're not to the point of being able to predict an individual's risk," says Joe Gray, a professor at Oregon Health & Science University's Knight Cancer Institute and not involved in the COGS studies. A more thorough understanding of risk factors and better cancer screening could lead to a future where doctors can "prevent people from having cancer we don't know how to treat," he says.

More information about how different genetic variants contribute to risk of disease could help refine the definition of high-risk groups. A well-tested SNP profile could sort out individuals at the top of the spectrum, where the benefits of screening would outweigh the risks. Once the genetic risk is understood, public health professionals can employ the same communication strategies used to counsel people about heart disease risk. "We do [stratified screening] all the time with cardiovascular risk," says Hilary Burton, director of the PHG Foundation based in England. Right now the evidence on breast cancer screening is "finely balanced between benefits and harm," she says. The newly identified SNPs can help tip the balance for some carefully identified individuals.

The vision the researchers outline could be in the not-too-distant future. People in their 40s today might see safer, stratified risk screening for some cancers within their lifetimes, Cambridge’s Easton said in a press conference. Still, before all patients can receive the benefits of safe screening, researchers will need to address a gap common to current genome-based discoveries: The 200,000 people in the COGS pool are largely of European descent and live Australia, North America and Europe. Whereas the consortium did find some risk markers specific to people of Asian descent, other genetic groups such as African and indigenous populations in the Americas and Australia are underrepresented.

"We are still very much in the discovery mode," Chanock says. Decades after uncovering the genetic basis of cancer, that is a sobering statement.

Follow Scientific American on Twitter @SciAm and @SciamBlogs.

Visit ScientificAmerican.com for the latest in science, health and technology news.

© 2013 ScientificAmerican.com. All rights reserved.

Sorry you didn't like this comment. Please provide a reason below.

Are you sure?
Rating failed. Try again.
Request failed. Try again.
We will promote constructive and witty comments to the top, so everyone sees them!
Sorry, we can’t load comments right now. Try again.

    Recommended for You

    • Melania Trump stuns in first lady fashion stakes

      First Lady Melania Trump stunned fashion watchers by donning a sleek, off-the-shoulder cream dress with a daring thigh-high slit to dance with President Donald Trump at the inaugural balls. The new first lady's sartorial picks for the inauguration went some way to silencing critics who have complained in the past that she favored high-end European clothes rather than American creations.

      AFP
    • ESPN drops commentator over Venus Williams 'gorilla' remark

      US broadcaster ESPN has dropped commentator Doug Adler after he compared Venus Williams to a "gorilla" at the Australian Open -- although he insisted the word he used was "guerrilla". ESPN said Adler should have been more careful during his coverage of the seven-time Grand Slam-winner's win over Stefanie Voegele. "During an Australian Open stream on ESPN3, Doug Adler should have been more careful in his word selection," an ESPN statement said.

      AFP
    • Charges: Cop left out gun that girl, 8, used to kill herself

      STRATFORD, N.J. (AP) — A police officer left his personal .357-caliber revolver loaded and unsecured on a shelf before his 8-year-old daughter fatally shot herself, prosecutors said Friday as they announced criminal charges against him.

      Associated Press
    • Grown-up Paris Jackson hits her namesake city for Givenchy

      PARIS (AP) — Colorful fall-winter menswear shows in Paris mixed high culture, androgyny and streetwear, as Paris Jackson, the daughter of the late pop icon Michael Jackson, stepped out for the cameras at Givenchy's library show— fittingly in the City of Light.

      Associated Press
    • Israel Plays its Trump Card

      Right-wingers in Jerusalem are ecstatic; Palestinian leaders are apoplectic. Welcome to a new era of the Arab-Israeli conflict.

      Foreign Policy Magazine
    • 'NCIS: Los Angeles' star Miguel Ferrer dies at 61

      NEW YORK (AP) — Miguel Ferrer, who brought stern authority to his featured role on CBS' hit "NCIS: Los Angeles" and, before that, to NBC crime drama "Crossing Jordan," has died.

      Associated Press
    • One of the largest icebergs ever seen is even closer to breaking off Antarctica

      Just 6.4 miles of ice are holding an iceberg the size of Delaware onto the floating Larsen C Ice Shelf in Antarctica, and scientists warn it could cleave off the ice-bound continent at any time. Researchers who closely monitor the crack cutting across this particular Antarctic ice shelf reported on Thursday that it continued to make rapid progress, expanding another six miles in just the past two weeks.  SEE ALSO: An iceberg the size of Delaware is about to break off Antarctica This means that a collapse may be imminent, at which point, one of the top 10 largest icebergs ever observed will break away into the turbulent seas off the coast of the Antarctic Peninsula.  Scientists affiliated with a group that has been tracking the ice melt in this area, known as Project MIDAS, say the iceberg could measure 5,000 square kilometers, or 1,930 square miles. The rift in the Larsen C Ice Shelf, including the 6-mile extension in the past two weeks. Image: Project midas/nasa Scientists are worried that the calving event — which refers to the breaking off of the iceberg from the ice shelf — could speed up the disintegration of the broader shelf and land-based ice that lies behind it. "When it calves, the Larsen C Ice Shelf will lose more than 10 percent of its area to leave the ice front at its most retreated position ever recorded; this event will fundamentally change the landscape of the Antarctic Peninsula," researcher Adrian Luckman wrote in a blog post.  "We have previously shown that the new configuration will be less stable than it was prior to the rift, and that Larsen C may eventually follow the example of its neighbor Larsen B, which disintegrated in 2002 following a similar rift-induced calving event," Luckman wrote. Larsen B Ice Shelf prior to the breakup in 2002. Image: NASA Larsen B Ice Shelf after its breakup in 2002. Image: nasa The researchers found that the rift which had been progressing episodically across the floating ice shelf suddenly grew by 11.2 miles, or 18 kilometers, during the second half of December, leaving only 12.4 miles left connecting the iceberg to its parent ice shelf.  On Thursday, that length declined to 6.4 miles of ice remaining fully intact, which puts the ice shelf in an even more tenuous position.  Scientists are not sure exactly when the iceberg will break free, but they think it will occur soon.  The length and width of the crack in the Larsen C Ice Shelf over time. Image: Project midas "We expect that the iceberg will break free within the next few months, although it's hard to be certain about timing," Martin O'Leary, a researcher at Swansea University in the U.K. who studies the Larsen C Ice Shelf as part of the MIDAS team, told Mashable in an email on Jan. 6. Rifts like this are a natural phenomenon, but such large ones are rare, scientists say. They can destabilize larger parts of ice shelves and land-based ice sheets by exposing more ice to mild ocean waters and air temperatures. This has been happening in parts of the West Antarctic Ice Sheet, but it is not guaranteed to happen with Larsen C. The Larsen C Ice Shelf is the most northerly of the remaining major Antarctic Peninsula ice shelves. This part of Antarctica has been warming rapidly in recent years, and the shelf is being undermined from below by warming ocean waters, as well as from above by increasing air temperatures.  View is of a rift in the Antarctic Peninsula's Larsen C ice shelf from our airborne survey of polar ice: https://t.co/VgjxopHHLI @NASA_ICE pic.twitter.com/gt5mpHqbxn — NASA (@NASA) December 3, 2016 In 2002, Larsen C's neighbor, known as the Larsen B Ice Shelf, disintegrated entirely after a series of similar rift-induced calving events. The Larsen B calving event was featured in the opening scenes of the sci-fi climate change-related disaster film, The Day After Tomorrow . Sea level rise implications Floating ice shelves don't raise sea levels when they disintegrate or lose large icebergs. This is because their ice is already resting in the ocean, like an ice cube in a glass.  However, because they act like doorstops to the land-based ice behind them, when the shelves give way, the land-based glaciers can start sliding into the sea in a process that's difficult (if not impossible) to stop, long-term. It adds new water to the ocean — therefore, increasing sea levels.  The entire West Antarctic Ice Sheet contains enough ice to raise global sea levels by another 10 to 15 feet if it were all to melt. This process would likely take centuries, however, though sea level rise is already accelerating worldwide as glaciers melt and ocean temperatures increase. BONUS: 2016 was Earth's warmest year on record, continuing a three-year streak

      Mashable
    • Prosecutor: 'Dance Mom' should be imprisoned for fraud

      PITTSBURGH (AP) — A prosecutor on Friday urged a federal judge to sentence "Dance Moms" star Abby Lee Miller to prison instead of probation for bankruptcy fraud.

      Associated Press
    • Women’s March on Washington, D.C. (91 photos)

      A day after President Trump was sworn in to office, women in as many as 200 cities around the world took to the streets in sympathy with the protest march in Washington. Yahoo News is providing continuous coverage of the marches around the world. Follow throughout the day on the Yahoo News live blog . See more news-related photo galleries , and follow us on Yahoo News Photo Tumblr.

      Yahoo News Photo Staff
    • LGBT Page Removed From WhiteHouse.Gov

      In the coming administration quickly got rid of a page that helped LGBT rights.

      International Business Times
    • Is There a Hidden Meaning Behind Melania Trump's Tiffany & Co. Inauguration Gift?

      On Friday morning during the traditional welcoming to the White House of the incoming president and first lady by the outgoing president and first lady before the inauguration, Melania Trump presented Michelle Obama with a gift from Tiffany & Co.

      Yahoo Style
    • Texas court grants appeal after 35 years without conviction

      DALLAS (AP) — A Texas inmate who was imprisoned for 35 years while waiting for a new trial after a court overturned his murder conviction should be set free, an appellate court ruled.

      Associated Press
    • Bin Laden documents: worry over IS tactics, 'aging' Al-Qaeda

      Months before his death, Osama bin Laden fretted about the Islamic State group's impatient, violent tactics and the fading of Al-Qaeda, documents released by the CIA Thursday showed. The latest release from the trove of documents found when Navy Seals stormed the Al-Qaeda chief's secret Pakistan compound and killed him in 2011 show bin Laden trying to keep his jihadist followers around the world aligned in his war against the United States. One letter to AQAP founder Nasir al-Wuhayshi warns not to move too fast against the government because conditions were not yet right anywhere to form an Islamic state that could govern effectively and resist attacks from outside.

      AFP
    • Geraldo Rivera: Inaugural address was 'too harsh'

      Fox News correspondent says the speech didn't 'match' the Trump he knows

      FOX News Videos
    • Hawaii bill compels mediation for Zuckerberg-type land deals

      HONOLULU (AP) — A Hawaii lawmaker said Friday he plans to introduce legislation that could force Facebook CEO Mark Zuckerberg into mediation before he is allowed to buy real estate on Kauai island.

      Associated Press
    • Roger Federer floors Berdych in 90 minutes at Australian Open

      Swiss marvel Roger Federer blitzed long-time rival Tomas Berdych in straight sets to storm into the fourth round with a vintage performance at the Australian Open on Friday. The 17-time Grand Slam champion, seeded 17th after an injury-hit 2016, downed the 10th-seeded Czech 6-2, 6-4, 6-4, in just 90 minutes. Federer reached the round of 16 in Melbourne for the 15th time where he will face Japanese fifth seed Kei Nishikori.

      AFP
    • Alleged NYC Bucket of Gold Thief Arrested In Ecuador

      Julio Nivelo took authorities on a months-long search that spanned two continents.

      Inside Edition
    • Trump signs first executive order, targeting Obamacare with few specifics

      President Trump signed his first executive order in his redecorated Oval Office late Friday, targeting Obamacare, as his administration ordered an immediate freeze on new regulations just hours after his inauguration. Seated behind the iconic Resolute Desk, made from the timbers of a British exploration ship in the late 19th century, Trump also signed the commissions for his first two Cabinet nominees to win Senate confirmation: Defense Secretary James Mattis and Homeland Security Secretary John Kelly. Trump was surrounded by senior aides and advisers, including his son-in-law Jared Kushner, Chief of Staff Reince Priebus, Kellyanne Conway, Hope Hicks, National Security Adviser Mike Flynn, Stephen Miller and Marc Short.

      Yahoo News
    • Trump's inaugural ball cake looked suspiciously like Obama's from 2013

      Looks like we have a copy-cake on our hands. Baker and Food Network personality Duff Goldman created a cake for President Obama's "Commander-in-Chief" inaugural ball in 2013. On Friday, however, he noticed a very similar cake in the news — the cake at one of Donald Trump's inaugural balls. SEE ALSO: How Trump's inauguration concert compared to Obama's The cake on the left is the one I made for President Obama's inauguration 4 years ago. The one on the right is Trumps. I didn't make it. 樂 pic.twitter.com/qJXpCfPhii — Duff Goldman (@Duff_Goldman) January 21, 2017 Turns out, the resemblance wasn't a coincidence. According to Tiffany MacIsaac of Buttercream Bakeshop, the order she received from Trump's team requested an exact replica of Goldman's 2013 creation.  "Duff Goldman originally created this for Obama's inauguration 4 years ago," she wrote on Instagram, "and this years committee commissioned us to re-create it." But — hold up — the D.C. bakeshop isn't keeping the profits from the commission. "Best part is all the profits are being donated to @humanrightscampaign, one of our favorite charities who we have loved working with over the years," she continued. A photo posted by Buttercream Bakeshop (@bttrcrmbakeshop) on Jan 21, 2017 at 7:35am PST FYI, the Trump cake is mostly made of Styrofoam — it's intended primarily to be a display item. But it's a good lookin' cake nonetheless. That Obama team had great taste, huh? Remembering a fantastic cake I made is awesome and the chef that re-created it for @POTUS Trump did a fantastic job. Group hug, y'all.  — Duff Goldman (@Duff_Goldman) January 21, 2017 BONUS: Obama 'Hope' artist has a new set of powerful posters

      Mashable
    • Analysis: Trump speech shows America getting what it ordered

      WASHINGTON (AP) — America is getting what it ordered on Election Day.

      Associated Press