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Breast cancer rules rewritten in 'landmark' study
November 5, 2012 12:58 AM   Subscribe

What we currently call breast cancer should be thought of as 10 completely separate diseases, according to an international study which has been described as a "landmark". The categories could improve treatment by tailoring drugs for a patient's exact type of breast cancer and help predict survival more accurately. The study in Nature analysed breast cancers from 2,000 women [Abstract] . It will take at least three years for the findings to be used in hospitals.

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups [Abstract]
The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.
posted by Blasdelb (37 comments total) 31 users marked this as a favorite

 
It would be nice if landmarks were free as opposed to $32 so we all could discuss.
posted by lampshade at 1:23 AM on November 5, 2012 [7 favorites]


Goddamnit, nature plays weird games with what is open access and what isn’t – it was at least open access yesterday. While the paper itself has some really gorgeous figures, it would be pretty opaque to most folks who would not already have institutional access anyhow. Could one of the mods switch the link to the abstract?
posted by Blasdelb at 1:33 AM on November 5, 2012


This is excellent. However, I think it's best seen as a further expansion and refinement of existing knowledge rather than a revolution - it's not news that breast cancer comes in different varieties calling for different treatment - and while the genomic perspective does yield valuable insights is some caution about the clinical implications perhaps appropriate?
posted by Segundus at 1:38 AM on November 5, 2012


nature plays weird games with what is open access

Shame too, because it is something that I really would have liked to read. It does sound like a major shift in the approach.
posted by lampshade at 1:41 AM on November 5, 2012


SO, it's FUCK Cancers now.
Good to know.

I lack any medical knowledge, but I find this sort of thing fascinating and hopefully we can deal with these pressing issues. I wonder how many other cancers might be cancers.

As far as I can tell, all landmarks are belong to us as long as they are abstract, so that's good to know.
posted by Mezentian at 1:49 AM on November 5, 2012


[Okay... I think I've changed it as you want, Blasdelb. If not, let me know. ]
posted by taz at 1:50 AM on November 5, 2012 [2 favorites]


What is really neat about the study is that, while cancer researchers have been trying to use traditional genetic techniques to seperate breast cancers into the diverse catagories we've known they are actually in for a while, until now their efforts haven't really panned out with very clinically significant predictions. The author's methods of looking at the transcriptome of breast cancers (trans-acting aberration hotspots, copy number profiles, cis outlying expression patterns, along with germline and somatic variants) allow them to seperate breast cancers into subgroups, integrating these tecniques, that make clinically significant mortality predictions and may be more clinically significant than the classifications we already use. As more groups look at these kinds of markers we will likely find similarities between cancers of different kinds of cells that also will let us see cancer more clearly by defining it in more meaningful ways - and thus hopefully treat it more effectively. What is really exciting about the work though, is not really the work itself exactly but the fact that work like it is possible if that makes sense.
posted by Blasdelb at 1:58 AM on November 5, 2012 [3 favorites]


"SO, it's FUCK Cancers now.
Good to know.

I lack any medical knowledge, but I find this sort of thing fascinating and hopefully we can deal with these pressing issues. I wonder how many other cancers might be cancers.
"
Well it has really been FUCK Cancers for researchers for a while now, this is a really great explination of how and why in easily accessible comic form. Because cancer isn't really a disease from the outside that invades us exactly, but a function of how evolution continues to act on individual cells in multicellular organisms - and in doing so fucking us over, every cancer is if anything more unique than we are. Over the years we have found patterns that they follow though; they all need to deactivate the inherent controls on cell growth that individual cells all have, circumvent the ways our cells have to kill themselves for the good of the rest, recruit blood vessels to supply nutrients, ignore the body's chemical instructions to slow the fuck down, avoid the immune system getting wise and shutting it down, and optionally spread through the body for maximum damage. They each do these things in ways that are often quite similar that we can take advantage of to shut them down.

What this kind of transcriptomic classification will hopefully do would be kind of like letting mechanics try to fix bikes by seeing the make and model number in addition to the color of the bike. There are some cancers for whom this would be more useful like breast cancer, which we know is really diverse like black bicycles in this analogy, and others for whom it would likely be less useful like 'celeste green' bikes that we know to be less diverse.
posted by Blasdelb at 2:49 AM on November 5, 2012 [9 favorites]


I wonder how many other cancers might be cancers.

If I was your mechanic and you brought your car to me and I immediately chanced the fuel filter every time - hard to start; rough idle; shimmies when you brake; cracked windshield; whatever - would you continue to employ me as you're mechanic or would you maybe look for someone who knows what the hell they're doing?

OK, same question only instead of having to deal with a car that's hard to start, it's your impending demise.

Yeah, some cancers are cancer. Good luck with that understanding.
posted by Kid Charlemagne at 2:59 AM on November 5, 2012


I shouldn't comment, because my comment will be along the 'no shit' lines.

"Cancer"... what a shit thing. You don't catch it when a frog burps, and you don't succumb through being weak.

Micro-systems trump our beloved macro, yeah?
posted by panaceanot at 3:33 AM on November 5, 2012


My step-niece died of breast cancer two years ago, as did her mother and grandmother. She had triple-negative breast cancer, a particularly difficult type to treat. She and her sister were raised by my sister, after meeting and marrying their father after their mother died. Her sister also had breast cancer; she's in remission. They're both in their 30s and black, perfect storms for bad outcomes.

"Cancer"... what a shit thing. You don't catch it when a frog burps, and you don't succumb through being weak. Indeed.
posted by shoesietart at 3:56 AM on November 5, 2012 [3 favorites]


Brain tumors also show an incredible variety of types. In the last ten years before I retired I was working with Oligodendrogliomas . An extraordinarily gifted Chinese Pathologist was interested in studying that small subset of brain tumors, trying to see if it was an homogeneous subset. It turns out that there where lots of variations. Some Oligodendrogliomas had both chromosomes 1 and 19 with small deletions, some just one or the other deletion. In addition a subset of the subset could have some aberration on chromosome 10, another would have a different aberration on chromosome 17.

All these would look exactly alike to most Pathologists studying a tissue section under a scope, but this guy had a sixth sense working for him. He did not want to influence my findings so he would give me a sealed envelope with his guesses. He ended up mostly right, and all the residents would try to pick his brain.

This test is called Fluorescent In Situ Hybridization and has revolutionized the field of Cytogenetics.
posted by francesca too at 4:34 AM on November 5, 2012 [3 favorites]


So what you're saying is we need some new colors of ribbon?
posted by thelonius at 4:38 AM on November 5, 2012


..all the residents would try to pick his brain.
No pun intended?
posted by kisch mokusch at 4:51 AM on November 5, 2012 [1 favorite]


Talking about cancer always kind of bugs me. My mom had breast cancer twice, the first time was caught as early as it could have been and wasn't aggressive at all. She had a lumpectomy a few weeks after finding out and it wasn't a big deal. The second time was a much more aggressive type, she had a bilateral mastectomy and chemo after that. I was worried but mostly because it's some pretty major surgery and I knew the chemo was going to be hard for her but I wasn't every worried that she was going to die from the cancer.

My mom's breast cancer (especially the first time) doesn't feel like it should be in the same category as my cousin's breast cancer that metastasized and killed her before she turned 30.
posted by VTX at 6:10 AM on November 5, 2012


OK, same question only instead of having to deal with a car that's hard to start, it's your impending demise.

I see your car analogy, Slashdotter.
I see it very well. And I weep because my car does not work and needs a mechanic.

I meant that some cancers that are not breast cancer, the less publicised ones, like prostate, might, perhaps, be a variety of cancers. Which would suck even more than they suck now.

I lack the medical knowledge to know if that is even possible, but it would seem to make sense.
posted by Mezentian at 6:33 AM on November 5, 2012 [1 favorite]


> It would be nice if landmarks were free as opposed to $32 so we all could discuss.

Odd, ther full paper shows up just fine on this completely random link I found. It's some very inside baseball biology though, so be forewarned.

Anyway, back to your regularly scheduled episode of Blasdelb's Awesome Science Blog!
posted by Panjandrum at 6:38 AM on November 5, 2012 [5 favorites]


Mezentian, I strongly suspect that prostate cancer can also be subdivided into additional types beyond the tissue-type divisions (adenocarcinoma, small cell carcinoma), histologic grading (Gleason score) and other measures we have now. I'll bet there are some high-powered groups working on this as we speak!
posted by Mister_A at 7:28 AM on November 5, 2012 [1 favorite]


nature plays weird games with what is open access

If you forget about "Nature" and "open access" having narrower meanings in a technical context then this is a really poetic sentiment.
posted by nebulawindphone at 7:40 AM on November 5, 2012 [3 favorites]


No pun intended?

Unfortunately no. It took years living here in the US before I got jokes, and puns are still over my head. (Or should I have said brain?)
posted by francesca too at 7:40 AM on November 5, 2012


I would like to see the specifics of the 10 different diseases. My mom kept a symptom diary which I found after she died of stage IV metastatic breast cancer.

She had unexplained vertigo in '99. I remember this because she and the docs were baffled as to what it was. Naturally they focused on her ears and left it at that.

Then she was writing down things like swollen under the arm and bleeding out of her nipple. They said it was some ductal thing and removed a duct. That was early 2000.

Well in 2005 she was diagnosed with stage IV metastatic---tumors on her adrenal, liver (too numerous to count), spleen, 4 spinal tumors, possible lung tumor (they couldn't reach it to biopsy it). She went through 7 years of hell. She was supposed to die w/in 2 years of her diagnosis.

What I find interesting and I'm far from a doctor are the following: (but worked in pharma advertising on Herceptin and background in sci writing so I do know what I'm reading when I see it)

1. Dizziness unexplained. Beyond basic vitals, why didn't they think possibly of adrenal issues? If she had tumors on her adrenals, that could cause havoc showing symptoms of dizziness, etc. when turning her head. Possibly the spinal tumors too--compression.

2. swollen lymph under the arm and bleeding out of the nipple? Um...that to me, screams breast cancer. Why did they only remove the duct? I know when she had a mammogram, the blood squirted out on the plate. When they removed the duct, did the damn doc send it in for testing? Did they do blood work to show genetic issues pointing to cancer?

All I know is from 1999 to diagnosed in 2005 with stage IV and that far metasisis, I think the doc(s) she went to missed the mark and she could have been diagnosed with perhaps a stage II or even III.

Guess it doesn't matter now. She lived the 7 years past any of their time estimates and was on every single treatment except Herceptin. Better primary care indicators would have been more helpful than treatment modalities at that point.
posted by stormpooper at 7:47 AM on November 5, 2012 [3 favorites]


"Odd, ther full paper shows up just fine on this completely random link I found. It's some very inside baseball biology though, so be forewarned."

Strange, that does seem to be exactly it, what a fortuitous find!

Now that everyone has access to the paper, I'd like to point out how closely all the cancers cluster in Figures Two, Three, and Four (even if what methods exactly they're using to cluster cancers is opaque to you) as well as Figure Five, which is magnificent in its sad callous accuracy.
posted by Blasdelb at 7:49 AM on November 5, 2012


"I would like to see the specifics of the 10 different diseases. My mom kept a symptom diary which I found after she died of stage IV metastatic breast cancer."

If this kind of basic research pans out like the authors hope you should be able to dig out that kind of information, and maybe posit a type though certainly not strongly, in the next few years as further research looks at the relationship that transcriptomically/genomically defined cancer groups have to existing classifications and indicators. The last paragraph of the paper is what you are looking for,
"Finally, because the integrative subgroups occur at different frequencies in the overall population, focusing sequencing efforts on representative numbers from these groups will help to establish a comprehensive breast cancer somatic landscape at sequence-level resolution. For example, a significant number (,17%, n5167 in the discovery cohort) of breast cancers are devoid of somatic CNAs, and are ripe for mutational profiling. Our work provides a definitive framework for understanding how gene copy number aberrations affect gene expression in breast cancer and reveals novel subgroups that should be the target of future investigation."
Thanks for sharing, stories like your mother's are exactly why research like this is so important, regardless of whether this specific strategy turns out or not.
posted by Blasdelb at 8:09 AM on November 5, 2012 [1 favorite]


Massgenomics has a write up of the paper:

These findings demonstrate how useful it is to construct a cohort, not just of many cases, but with long-term follow-up so that researchers can link the genomic architecture of tumors to the eventual death or survival of the patients.

Also at Nature is a recent paper which looked at the exome, methylation status, microRNAs, and gene expression at the mRNA and protein levels of 500 breast tumors. Massgenomics has a write up of this one as well.

I think everyone understands that sequencing combined with targeted therapies are going to completely change how cancers are handled over the next decade. The MD Anderson Cancer Center has just recently started incorporating sequencing into their diagnostic process.

The idea is to do molecular profiling on patients as they come in the door, then to try to match them with the appropriate targeted drugs. Of course people have done this for individual studies, like the ALK inhibitor crizotinib, the investigators and the company looked for ALK rearranged lung cancer patients.The thing that we are doing differently is that we are not looking for one abnormality to match with one drug. We are looking at a panel of abnormalities as patients come in the door and then decide which drug to match them to. So it is a more generalized type of way of doing things and I am sure it is the way things will be done in the community in the future.

The promise of personalized medicine is finally going to be realized, though it will not be soon enough for many.
posted by euphorb at 8:22 AM on November 5, 2012


I think everyone understands that sequencing combined with targeted therapies are going to completely change how cancers are handled over the next decade.

After the Mayo v. Prometheus decision these kinds of discoveries (i.e. making an improved therapeutic decision—such as which drug to use or how much of it—based on a known diagnostic test) will be very difficult to patent. Whether this is a good or bad thing is beyond the scope of this post, but I thought it was worth noting that the decision is likely to affect this kind of research in particular and the entire field of personalized medicine in general.
posted by jedicus at 8:29 AM on November 5, 2012


[Cancer is] a function of how evolution continues to act on individual cells in multicellular organisms...

This reminds me a bit of Lenski's long-running E. coli experiment, recently linked here. Perhaps current humans are like Lenski's generation 31,500, not yet metabolizing citrate (c.f. not yet cancerous) but reliably able to repeat the evolutionary pathway from here to there.

The thing is, Lenski apparently identified several things in way back in the evolutionary history of his bugs that individually are just random mutations, but when you have them all together, you can get to citrate metabolism. (IANAB, this is just my pop-science understanding.)

So, for those of you who understand what's really going on here, is it reasonable to analogize the genetics/cancer search to the search for the group of mutations that are necessary and sufficient for citrate metabolism to arise?
posted by spacewrench at 8:32 AM on November 5, 2012


The thing I learned working in a cell biology lab (which means that ultimately you are working on cancer) was that nothing I worked on would ever cure cancer, but it could be very helpful diagnostically. (Specifically, I was working on a gene that could have played a role in malignant cancers, so detecting its aberrant activity could have affected how harsh a treatment to use. It also seemed to be resistant to one of the most promising treatments, might have been Herceptin?, so detecting its activity could have just skipped what would have been a wasted course of drugs) So I'm pretty excited to see work which not only confirms my own philosophy but looks like it could have real practical implications.

I can't read this now, I'm supposed to be preparing for a meeting and I've a bunch of data entry to do, but I am totally psyched to read the paper this afternoon. I took a quick look at the pdf and it looks like some nice data. I'm always so skeptical of cancer treatment papers, but this looks good.
posted by maryr at 8:53 AM on November 5, 2012


PS: Yo, Broad Institute, shouldn't you be in on this?
posted by maryr at 8:56 AM on November 5, 2012


is it reasonable to analogize the genetics/cancer search to the search for the group of mutations that are necessary and sufficient for citrate metabolism to arise?

Make that "the various groups of mutations."

You're right that these mutations are more or less innocuous on their own, and only cause harm when they come together in the right sorts of combinations.

But it turns out that there are a lot of different combinations that can cause harm. It's not like "For breast cancer, you need mutations A, B and C, each of which is innocuous on its own." It's more like "For breast cancer, you need A1, B1 and C1; or A2, B1 and C2; or A1, B2 and C2; or A1, B2 and D1; or B1, B2 and D1... [fast forward] ...or Y53, Z88 and Z356, each of which is innocuous on its own."

This research says, "Okay, we've got a gazillion different mutation combos that cause breast cancer. We can't study each combo individually: there are too many of them. So what if we sort the combos into a couple of categories, and then study the categories? Would that be a useful approach?" And the result is, more or less, "Yeah, there's reason to believe that would be useful."
posted by nebulawindphone at 8:57 AM on November 5, 2012 [1 favorite]


" So, for those of you who understand what's really going on here, is it reasonable to analogize the genetics/cancer search to the search for the group of mutations that are necessary and sufficient for citrate metabolism to arise?"

Kind of! That is an astute connection. There is a limited sort of natural selection at work on the cells in our bodies where, within this closed environment, cells that circumvent all of the various things that actively and passively prevent cancer are strongly selected for growth. Similarly within the artificial environment of Lenski's long experiment cells that were able to metabolize citrate were strongly selected for. In both systems a large number of mutation events need to happen before the selective pressure is applied. The biggest difference I see is that while Lenski's experiment could theoretically go on forever, at least in humans under natural conditions, cancer always dies with the host - and often actively helps speed it along.
posted by Blasdelb at 9:08 AM on November 5, 2012 [1 favorite]


Yeah, googling a paper is usually the way to get a free PDF. Some labs like to host their better works on a uni/group website.

As for the result, I'm not entirely surprised. Having had to educate people on cancer-as-a-single misconceptions (when not assuring them that, no, just because I'm a biochemist does not mean I'm working on the bird flu) breast cancer being significantly more complicated than was thought doesn't surprise me.
posted by Slackermagee at 9:55 AM on November 5, 2012


I think it's reasonable to wonder whether the window of immune-tolerance we are obligated as placental mammals to make commodius enough for the implanted fetus is one of the big reasons we have so much trouble with cancer.

And recently, it's become clear that window is open wider than we thought:
Three Types of Fetal Cells Can Migrate Into Maternal Organs During Pregnancy: Some Mothers Literally Carry Pieces of Their Children in Their Bodies

Researchers suspect that fetal cells in a mother's blood stream help her immune system tolerate and not attack the fetus. The detection of trophoblasts and immune cells in the maternal lung should aid future studies on this subject, as well as research into pregnancy-related complications like preeclampsia. The presence of fetal mesenchymal stem cells corresponds with previous studies that reported fetal and placental cells differentiating to repair injured maternal organs in both mice and humans. [emphasis added]

Fetal Stem Cells May Help Maternal Heart Recover From Injury

Previous studies have documented a phenomenon in which half of women with a type of heart failure called peripartum cardiomyopathy saw their condition spontaneously recover in the months following pregnancy. Based on this evidence, the Mount Sinai team wanted to determine whether fetal stem cells played a role in maternal recovery.
Breast tissue would seem to be on any shortlist of candidates for this kind of repair or reinforcement, and perhaps breasts could therefore be more accommodating than other organs to cells the immune system would otherwise attack as foreign or cancerous.

Fetal stem cells have been found in maternal tumors, but their role in pathogenesis is unclear:
fetal cells have been found at tumor sites in mothers, but it is unknown whether the cells are helping to destroy the tumor or to speed its growth. [from the first link]
posted by jamjam at 10:30 AM on November 5, 2012


jamjam, pregnancy is actually protective against breast cancer but probably this has more to do with development and hormone levels than anything else.
posted by en forme de poire at 11:53 AM on November 5, 2012


I think you make a good point en forme de poire, but I was imagining in connection with this that after pregnancy (and nursing!), the mother's immune system goes in and cleans up the fetal cells and, almost incidentally, pre-cancerous cells that might be hanging around.

I don't see that as obviating the breast being more accommodating in the first place, however, though it does make the argument more complicated.
posted by jamjam at 12:28 PM on November 5, 2012


Uh, not a Slashdotter, just a research scientist.

As has been said earlier, yeah, I'd bet money that pretty much all cancers are like this and, in fact, some "dissimilar" cancer types are a result of similar issues in the cells themselves.
posted by Kid Charlemagne at 11:55 PM on November 5, 2012






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