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

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

[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

[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.

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

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.

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.