Scientists Crack 'Entire Genetic Code' of Cancer

Entropy98 writes "Scientists have unlocked the entire genetic code of skin and lung cancer. From the article: 'Not only will the cancer maps pave the way for blood tests to spot tumors far earlier, they will also yield new drug targets, say the Wellcome Trust team. The scientists found the DNA code for a skin cancer called melanoma contained more than 30,000 errors almost entirely caused by too much sun exposure. The lung cancer DNA code had more than 23,000 errors largely triggered by cigarette smoke exposure. From this, the experts estimate a typical smoker acquires one new mutation for every 15 cigarettes they smoke. Although many of these mutations will be harmless, some will trigger cancer.' Yet another step towards curing cancer. Though it will probably take many years to study so many mutations."

Comments

Benign

[Smivs]

I didn't use to like skin cancer, but it grows on you

Powers

[sakdoctor]

Although many of these mutations will be harmless, some will trigger cancer

And some will give you super powers.

Sadly, the article makes no sense

[Thagg]

What does it mean that melanoma has 30,000 errors in the DNA? Is it that the one melanoma they looked at had 30,000 differences from the other cells in the patient's body? It appears that, far from finding the needle in the haystack, they've found 30,000 haystacks.

Re:Sadly, the article makes no sense

[ColdWetDog]

Is it that the one melanoma they looked at had 30,000 differences from the other cells in the patient's body? It appears that, far from finding the needle in the haystack, they've found 30,000 haystacks.

Not quite. It's more like they ** think ** they've found a map to the 30,000 needles in a single haystack and they hope that the haystacks (individual humans) are similar enough that they can generalize a bit on how to find the other needles in other haystacks.

FTFAbstract:

All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.

The researchers state (and I haven't really had time to look at the article) that they have identified all, or at least the vast majority, of mutations from a single cancer and furthermore have managed to characterize (see above) the mutations. Other researchers have done similar research for other cancers. The idea is that, after all of this information is digested, somebody can use this knowledge to figure out better treatments for cancers. Of course, this remains to be seen. It's reasonable but by no means certain. The babble at the end of the BBC article is typical hyperbole.

Re:Sadly, the article makes no sense

[sevennus]

Remember, it takes three events for a cell to become cancerous. 1. It must mutate to be able to express appreciable amounts of telomerase. 2. It must mutate in such a way that it circumvents its apoptosis (self-destruction) checkpoints. 3. It must mutate in such a way to allow constitutive, amplified replication. True, there are probably a gazillion different combinations of different mutations that can cause allow all of these things to happen, but I'm pretty sure it can't be caused by ONE mutation. But it's just my first post, so don't take my word for it.

Re:Sadly, the article makes no sense

[izomiac]

That's pretty much on target. UV light is absorbed by DNA, and it causes changes like Thymine-Thymine dimers (ATCG are DNA bases, a T-T dimer is when two adjacent T's on the same strand bind to each other). Cells have DNA repair mechanisms, some of which are accurate, others of which are not. If the repair is inaccurate you have a mutation in a semi-random location (needs something like two adjacent thymines, and it probably needs to not be in it's condensed storage form). A mutation in each of about 8 genes that control the cell cycle will lead to uncontrolled replication and further mutation. Certain types of cells are vulnerable to different things, and require certain genes to be knocked out (or overexpressed) to form certain types of cancer. It's all very random, but there are trends within each type of cancer (hence its behavior).

Re:Sadly, the article makes no sense

[ppanon]

The test for cancer is to... swallow a bunch of radioactive isotopes and then get zapped by large doses of radiation that cause the swallowed isotopes to show up in a way that an image can be constructed?

Well, I'm assuming you're talking about CT/CAT scanning and that's one way to find cancer early when it's still small. Not all imaging techniques involve ingesting radioactives, though. MRIs use very powerful magnets to interact with hydrogen to detect fine structures in the body. Some cancers are more easily detectable with one imaging approach vs. the other. Another way involves waiting until the cancer has progressed and grown so much that it's easy to notice but very likely to kill you.

Anyways, it's all about risk trade-offs. Dentists also regularly bombard you with low doses of ionizing X-rays to take a picture of your teeth to detect cavities. Not treating those cavities could lead to needing root canals, pulling the tooth, or even bad gum disease that can affect your immune system and heart health.

The problem with MRI is that it needs very strong magnetic fields and the rapid drop off of magnetic field strength currently make it impractical for use on a torso, as opposed to a head or a limb. Maybe that will change eventually. However even some radiation from a CATScan is a good trade-off if they suspect some types of cancer and it allows them to detect and treat it early.

Re:Sadly, the article makes no sense

[nacturation]

But 30,000 errors in the DNA doesn't mean those cells were exposed to 30,000 mutating events (the 1 for every 15 cigarettes or whatever).

Enough of your logic. You're upsetting the smokers who want to believe that as long as they smoke less than 450,000 cigarettes they won't get cancer.

Re:Sadly, the article makes no sense

[RDW]

It's true that each patient is extremely likely to have a unique 'cancer genome', a specific combination of mutations found only in their tumour. But the vast majority of these will be 'passenger' mutations that aren't relevant to the progress of the tumour. The trick, as you suggest, is to home in on the 'driver' mutations that are really causing the disease. One way to get at these is to look first at the mutations in the coding sequences of known genes (and because of the human genome project and all the work that's followed it, we pretty much know where all the protein-coding genes are located).

I just had a quick look at both papers, and it turns out that in the lung cancer case, fewer than 100 of the tens of thousands of mutations actually cause an amino acid change in a protein sequence (for the melanoma, the figure is less than 200). This doesn't mean that there aren't other interesting needles to find in the haystack of mutations (e.g. changes in regulatory sequences), but they might as well go after the 'low hanging fruit' first. With current technology, it's very easy to sequence 100-200 genes in a pretty large set of samples from different patients. Any of these genes that turn out to be mutated in multiple tumours immediately become subjects for further study.

As the technology starts to ramp up and gets cheaper every year, we can begin to go after the less obvious changes. Each of these studies is in effect an entire human genome project (they haven't just done a low resolution map, they've completely sequenced the genomes). Pretty soon we're going to have a large collection of sequenced tumour samples to compare and use to find common alterations.

Re:Sadly, the article makes no sense

[DebateG]

So I work in biological sciences, and I have the special privilege of having the guy who sequenced the first cancer genome working down the hall from me (he's also my thesis committee).

There is now technology to sequence entire genomes very quickly using massive parallel sequencing. Ideally, if you were sequencing a tumor from a single person, you would get tissue from the tumor and also from the non-tumor (usually skin) and sequence them at the same time. Then you compare the two to distinguish what is simply variation in each person's genetics and what is acquired by the tumor. In my opinion, that's the best way to do things and probably the most informative because you're looking a tumor in a real person that is subject to all the selective evolutionary pressures that occur in people.

These groups didn't take that approach for reasons unclear to me. Instead, they sequenced cancer cell lines. If you cut out a person's tumor and stick it in a test tube with various growth factors, it will almost certainly die within a week or so. However, you occasionally get some cells that can grow in this situation because they've acquired some mutation that lets them grow in tissue culture. You then expand and passage these cells until they grow rapidly in culture. The problem here is that you're no longer dealing with a normal human tumor; you're selecting for tumor cells that grow in the artificial tissue culture environment. The second problem is that you're not sure what to compare the tumor sequence with. Due to privacy concerns, you almost never know who actually gave the tumor that was made into a cell line (as an aside, look up the HeLa cell line and its sordid history) so you have to compare to the human genome project. The problem here is that there are differences between people and you can't tell whether the "mutation" you see is just a normal variation or actually something in the tumor.

These are the important limitations you have to consider when evaluating these papers.

Now, on to your question. They have 30,000 changes in the DNA compared to their reference "normal" genome. Nearly all of those are in "junk" DNA: as far as we know, they don't code any genes or anything else that regulates genes. Of the ones that are in interesting regions, the vast majority of them are called synonymous mutations which means the DNA is changed but due to the way it is interpreted, the protein that it makes is identical (to use a computer analogy, imagine that an the opcode for JMP was changed from 01 to 02 but both 01 and 02 are translated by the computer as JMP).

Now, a certain number of mutations aren't like that. They either lead to truncated proteins, alter the amino acid sequence of proteins, alter mRNA splicing, etc. There are also other genetic changes such as duplications where the gene sequence is unchanged but may be copied several times to increase the gene dose. These are really the interesting things because they alter protein function or gene dose. From a brief reading, it looks like there are around 100 of these.

Now, it's really difficult to tell whether these mutations are really relevant to cancer progression. Some of them might just happen due to tumors just mutating really fast and not really affect the cancer progression one way or another; they are so called "passenger" mutations that just come along for the ride. You can introduce these mutations into cells in lab to see if they do anything, but the real test is to sequence a bunch of human cancers and see if certain mutations are recurrent. This work is currently underway and will prove very informative about how genetically heterogeneous tumors really are.

So, in short, there are about 100 haystacks. Further sequencing of other tumors will show if these are relevant to cancer in general. In my personal opinion, I think that further sequencing will identify very few common mutations and everyone's cancer will be essentially unique in the mutations it acquires. That will force us to completely rethink how we view cancer on a broader scale as not a single disease but a collection of highly related diseases that need to be treated individually.

Patent?

[innocent_white_lamb]

I wonder if they will patent this so everyone who develops a treatment using techniques discovered here must cough up a royalty?
 
Why are patents allowed on naturally occurring phenomena like genes anyway?

Re:Patent?

[AdmiralXyz]

Why are patents allowed on naturally occurring phenomena like genes anyway?

I've read interviews with multiple government and legal officials, whose basic point seems to be that patents on genes are a "necessary evil", because research into genomics is really, really, really expensive, and without patents + licensing fees giving biotech firms some way to recover some of their investment now (as opposed to ten years down, when drugs based on their discoveries could conceivably come to market), no businessperson would even think of throwing his money at that kind of research. According to them, without patents, there would be no research and progress in this field whatsoever.

I'm not saying whether or not I agree with that, but that's the way it is.

Re:Patent?

[BiggerIsBetter]

This sort of thing should probably be done by academia or government then. Progress for the greater good doesn't have to be commercially driven.

Re:Cold turkey

[schon]

the 1 in 15 smokes stat is a real motivator!

Maybe, but if you only smoke the other 14, you should be OK.

Unless the 15th one isn't labeled, then it's harder.
 
/me ducks

How real is this?

[Anonymous Coward]

Do these guys promise to come back in 2 years and report on their progress?

The extrapolation for lung cancer is badly flawed

[WhiskerBiscuit]

Cancer cells start accumulating mutations as a consequence of rapid cell division and poor quality control on DNA replication; they also have problems keeping their chromosomes intact. This is called "genomic instability" and it is a hallmark of cancer.

The critical point here is that most of these mutations are acquired *after* the cancer gets going, regardless of whether the mutagen in question is still being administered.

Therefore, it's not proper to infer a linear relationship between the dose of mutagen and the number of mutations.

Beyond that, the numbers involved in that extrapolation seem to have been pulled out of thin air, and I question whether they knew the smoking history of the individual who donated the material that created that cell line. (The lung cancer in question had 30,000 mutations, so by their logic the smoker must have smoked 345,000 cigarettes, or 17,250 packs of 20. That's a pack a day for 47 years, which is admittedly within the bounds of possibility, but still an awful lot of smoking.)

Whatever. Smoking is still awful for you, but this kind of nonsensical extrapolation without regard to detail is terribly annoying.

In other news...

[thetoadwarrior]

Cancer will be issuing a DMCA take-down notice and sue the pants off the scientists for cracking its code.

Might be okay, might not.

[Valdrax]

So, since it's cigarette smoke that's the problem... Everyone switch to pot?

I know you're joking, but there's no conclusive evidence that nicotine itself causes cancer. It's particulate matter and other smoke residues that seem to drive lung cancer, and we know that there are just as many carcinogens in pot smoke as tobacco smoke.

Weirdly, however, large studies seem to indicate that there isn't an increased cancer risk from heavy pot smoking. Other research suggests that THC reduced lung cancer growth. However, pot smokers are at elevated risk for other lung diseases that come purely from breathing hot smoke all the time.

So, if you're going to switch from tobacco to marijuana, consider going with methods other than smoking. You may not get cancer from smoking, but it's still not good for you, and there are much safer ways to get high. (They are also ways that do not force other people in your presence to participate through second-hand smoke, which will bother others regardless of the long-term health risks or lack thereof.)

Re:Population and cancer

[n0tWorthy]

Nope. There's been a large reduction in cancer deaths due to research and treatment advances (I'm a two time cancer survivor, 1 a stage 4 of the neck) so cancer is having a much smaller reduction on population than it used to. Also, since cancer occurs after the reproductive years in the vast majority of cases there is no breeding it out of the system. If cancer killed people before they reproduced then the genetic causes of cancer would be eliminated pretty quickly.

You can support your family and get support at the American Cancer Society Cancer Support Network (http://csn.cancer.org/). A lot of people there going through the same things you and your friends are.

Tell That to Monsanto

[Telephone Sanitizer]

> The genes aren't patentable.

Tell that to Monsanto. If the genes from their GE plants turn up in a farmer's soy crop, he's in for hell even if they just drifted over as pollen from neighboring fields.

In the United States, patents protect not just the device or technique, but also the product of it. Thus, those who patent techniques for isolating genes also have patent-protection for the genes, themselves. Patents do not ordinarily cover "products of nature," but when something exists in a lab in "purified" form, it's exempted from this limitation. http://www.ornl.gov/sci/techresources/Human_Genome/elsi/patents.shtml

Here's what Monsanto does with their patents:
http://www.commondreams.org/headlines05/0115-04.htm

Under U.S. patent law, a farmer commits an offense even if they unknowingly plant Monsanto's seeds without purchasing them from the company. Other countries have similar laws.

In the well-known case of Canadian farmer Percy Schmeiser, pollen from a neighbor's GE canola fields and seeds that blew off trucks on their way to a processing plant ended up contaminating his fields with Monsanto's genetics.

The trial court ruled that no matter how the GE plants got there, Schmeiser had infringed on Monsanto's legal rights when he harvested and sold his crop. After a six-year legal battle, Canada's Supreme Court ruled that while Schmeiser had technically infringed on Monsanto's patent, he did not have to pay any penalties.

Schmeiser, who spoke at last year's World Social Forum in India, says it cost 400,000 dollars to defend himself.

"Monsanto should held legally responsible for the contamination," he said.

Another North Dakota farmer, Tom Wiley, explains the situation this way: "Farmers are being sued for having GMOs on their property that they did not buy, do not want, will not use and cannot sell."

Misleading title...

[hahn]

Saying they've "cracked" the code to these two cancers (skin and lung) is not really as big a step as the title implies. They've found the genetic mutations associated with the cancers. That's probably the easy part (and it wasn't so easy). The problem in studying cancer is that the function of genes is often dynamic and interdependent. Think of a room with 30,000 light switches. Sometimes light switch #5 will turn on the light bulb, but sometimes it won't. It depends on whether light switch # 7, 100, and 10542 are all on simultaneously or not. And if switch #2742 is on, the light, if it's on, will be very dim. This why even though we give a cancer a single name - e.g. "melanoma" - there are often very different mutations present, any one or multiple ones which can affect the person's survival, but not necessarily all the time. There are cancers which reliably result from single mutations, but the most common ones are due to mutations in many many different genes. To the point that most cases of cancer can or should be considered unique.

IMHO, where I think the results of these studies may be most helpful with regards to treating people successfully is figuring out which mutations cause the cancer to spontaneously regress, whether it's by self-destruction or immune mechanisms. Even then, maybe it's not even because of a cancer mutation. Maybe some people possess some genetic trait in their immune system that allows them to destroy cancers. In which case, too many people would be looking in the wrong haystack for a needle.

Common damage

[AlpineR]

If you fire a rifle at a running car, it might survive several shots and still keep running. Some of the shots go through the windows, some through the doors, and some just bounce off the pillars. But some shots could poke holes in the body and leave underlying parts exposed. Then further shots might puncture the gas tank or the radiator. A little less likely, shots might break the fuel pump or electric distributor. And just maybe a shot will interrupt the ignition circuit.

Even though any particular car's damage will be unique, the damage that made cars stop running will be common. Most will involve the gas tank or radiator. And a few will involve smaller parts.

A study like this is looking for those major parts which are likely to be damaged in cancer cells. It might also reveal common patterns of damage which disabled protective mechanisms and left those key part vulnerable. Then you might have an idea of how to detect critical damage, how to repair subcritical damage, how to armor critical areas, and how to completely disable malfunctioning cells.