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Cancer genomics researcher here. I agree wholeheartedly about getting sequencing done if you have cancer - it's what I would do for myself or my family. Two min

Cancer genomics researcher here. I agree wholeheartedly about getting sequencing done if you have cancer - it's what I would do for myself or my family. Two minor quibbles about your thoughts: 1) Exome sequencing is below $1000, but analyzing that data adds a non-negligible cost. Still, even 2 or 3 grand is way cheaper than wasting time on treatments that won't work. Whole-genome sequencing is even better (for a little more cost) because of the extra types of information it adds about structural variants and copy number changes. 2) We're reasonably sure that most cancer causing variants are in the coding space, but there are undoubtedly some in non-coding regions (and classes of large structural events like duplications or deletions that affect both). It's the best time in the history of the world to have cancer, and it is only getting better. Survival curves are slowly bending, and new classes of treatments like immunotherapies are helping to bend them even more. The bottom line is, If you get cancer, fight like hell to get your tumor sequenced. Most insurers cover at least some kind of genomic test for cancer these days.

jfarlow 10y ago
I would add to that that because most cancer causing (single mutation) variants are in the coding space, it ultimately seems reasonable to be able to revert the mutations back to wild type with genome editing tools such as Cas9 in the (decade-ish future?). Using small molecules to fight against cancer as the article speaks to really seems like the last vestiges of a 20th century technology, while designing novel genetic tools like immunotherapies are today's superweapon - tomorrow's is just to fix the mutation. All the more reason to pour money into the DNA side of things (sequencing, synthesis, analysis) over the small molecule side of things ('drug development'.
- nonbel 10y ago
  >"it ultimately seems reasonable to be able to revert the mutations back to wild type with genome editing tools such as Cas9 in the (decade-ish future?)" What are you basing this on? Have you seen a study where they report "modification" in a living organism using this tech? I highly doubt it, due to toxicity. Also see my post above regarding the presence of aneuploidy and chromosomal instability in cancer cells. How is crispr/cas9 going to fix that?
  - jfarlow 10y ago
    >What are you basing this on? Logical extension of how the strategies for technologies like Car-T therapies are being developed and delivered. By first targeting an ex-vivo tissue (like T-cells that can be harvested and then re-implanted), you first develop the tools to use genome editing techniques effectively, without significant off-target effects. It's essentially practice for much more useful therapies that can be done in-vivo. Further, the design of the biological 'sensors' in the T-cells are precisely the kinds of sensors you'd need to deliver a payload to and only to a mutation-containing cell. So you would neither need to target an entire organism (rather a tissue, or even a particular cell type), and off target effects from genomic insertion would be curtailed by advances in the technologies surrounding Cas9 itself. For many cancers you wouldn't need to repair the mutation in the entire organism as the cancer is tissue- or cell-specific. You are correct that you would, however, likely need to repair the prior to significant metastasis or loss of stability of the chromosome. At that point fixing a point mutation is not going to help much. All the more reason screening and baselines should start being established now - so that we can even detect a mutation prior to it becoming 'cancerous'. If you know you have a stop codon mutation in your Her2 gene when you're born, it will not be too far off when that stop codon, in particularly sensitive tissues, could be reverted with reasonable safety prior to the development of an (inevitable) cancer. And ultimately that actually cures the the cancer in a way a small molecule can never, from first principles, hope to do.
    - nonbel 10y ago
      This editing procedure is extremely toxic, and I do not believe this is all due to off-target effects. I found this one quickly, where the paper claimed 80% viability when their data showed something more than half of them "go missing" (impossible to tell more from the chart): https://news.ycombinator.com/item?id=12971533 https://news.ycombinator.com/item?id=12971533 Here is actually one where they injected into Drosophila embryos. It looks like to get 10% success rate, they had to kill 50% of the "subjects" (table 1): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714591/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714591/ Here is another where you see the more cas9 you inject, the more animals (C. elegans) die (table S1): https://www.ncbi.nlm.nih.gov/pubmed/23979586 https://www.ncbi.nlm.nih.gov/pubmed/23979586
JangoSteve 10y ago
> 1) Exome sequencing is below $1000, but analyzing that data adds a non-negligible cost. That is by and large the most significant factor that we've seen which slows adoption of more widespread whole-exome or whole-genome sequencing. It takes less than a day and costs less than $1000 to sequence your exome (and even your whole genome), but the backlog for analysis of the sequencing results in labs can be 9 months or more. There are patients that could be treated from the analysis of their genome that aren't even considered if their prognosis is shorter than the amount of time it will take to get clinically actionable results from the lab, which is the really sad part. This problem is actually what led us to create our company, Genomenon, to help make the analysis much faster and alleviate the bioinformatics bottleneck at the sequencing labs.
- bozoUser 10y ago
  > It takes less than a day and costs less than $1000 to sequence your exome (and even your whole genome), but the backlog for analysis of the sequencing results in labs can be 9 months or more. Layman qs. what is stopping the labs to quickly analyze the genome? Computational power or few labs doing this kind of work?
  - jfarlow 10y ago
    In general it's a (computationally) hard problem to restitch a genome together. Even today, when you 'get your genome sequenced' you are not getting a full read-through of your entire genome's data. Imagine you want to reconstruct the data on two RAIDs that are mostly, but importantly not exactly, mirrors of each other. Each RAID has 23 drives. Each drive has ~1Gb or so of data. And much of the data is not only mirrored between the two RAIDs, but is also mirrored between the 23 drives - and many of that mirrored data is 'off by 1' in very important ways (both 'must', and 'must not' scenarios). Further some of the data contains very long sections of highly repetitive data. And some of the data is mechanically biased to be harder to read than others. You must now reconstruct those two RAIDs with single-bit accuracy - as a single bit-flip in certain sections determines whether or not you get cancer. The data you are given to do the reconstruction is a 200Gb single column CSV file with each row being 12 bytes of data. Go.
bradleyjg 10y ago
> The bottom line is, If you get cancer, fight like hell to get your tumor sequenced. Most insurers cover at least some kind of genomic test for cancer these days. Is this something that has to go through your oncologist or can you drive the process independently?

jfarlow 10y ago

I would add to that that because most cancer causing (single mutation) variants are in the coding space, it ultimately seems reasonable to be able to revert the mutations back to wild type with genome editing tools such as Cas9 in the (decade-ish future?). Using small molecules to fight against cancer as the article speaks to really seems like the last vestiges of a 20th century technology, while designing novel genetic tools like immunotherapies are today's superweapon - tomorrow's is just to fix the mutation. All the more reason to pour money into the DNA side of things (sequencing, synthesis, analysis) over the small molecule side of things ('drug development'.

nonbel 10y ago
>"it ultimately seems reasonable to be able to revert the mutations back to wild type with genome editing tools such as Cas9 in the (decade-ish future?)" What are you basing this on? Have you seen a study where they report "modification" in a living organism using this tech? I highly doubt it, due to toxicity. Also see my post above regarding the presence of aneuploidy and chromosomal instability in cancer cells. How is crispr/cas9 going to fix that?
- jfarlow 10y ago
  >What are you basing this on? Logical extension of how the strategies for technologies like Car-T therapies are being developed and delivered. By first targeting an ex-vivo tissue (like T-cells that can be harvested and then re-implanted), you first develop the tools to use genome editing techniques effectively, without significant off-target effects. It's essentially practice for much more useful therapies that can be done in-vivo. Further, the design of the biological 'sensors' in the T-cells are precisely the kinds of sensors you'd need to deliver a payload to and only to a mutation-containing cell. So you would neither need to target an entire organism (rather a tissue, or even a particular cell type), and off target effects from genomic insertion would be curtailed by advances in the technologies surrounding Cas9 itself. For many cancers you wouldn't need to repair the mutation in the entire organism as the cancer is tissue- or cell-specific. You are correct that you would, however, likely need to repair the prior to significant metastasis or loss of stability of the chromosome. At that point fixing a point mutation is not going to help much. All the more reason screening and baselines should start being established now - so that we can even detect a mutation prior to it becoming 'cancerous'. If you know you have a stop codon mutation in your Her2 gene when you're born, it will not be too far off when that stop codon, in particularly sensitive tissues, could be reverted with reasonable safety prior to the development of an (inevitable) cancer. And ultimately that actually cures the the cancer in a way a small molecule can never, from first principles, hope to do.
  - nonbel 10y ago
    This editing procedure is extremely toxic, and I do not believe this is all due to off-target effects. I found this one quickly, where the paper claimed 80% viability when their data showed something more than half of them "go missing" (impossible to tell more from the chart): https://news.ycombinator.com/item?id=12971533 https://news.ycombinator.com/item?id=12971533 Here is actually one where they injected into Drosophila embryos. It looks like to get 10% success rate, they had to kill 50% of the "subjects" (table 1): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714591/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714591/ Here is another where you see the more cas9 you inject, the more animals (C. elegans) die (table S1): https://www.ncbi.nlm.nih.gov/pubmed/23979586 https://www.ncbi.nlm.nih.gov/pubmed/23979586

JangoSteve 10y ago

> 1) Exome sequencing is below $1000, but analyzing that data adds a non-negligible cost. That is by and large the most significant factor that we've seen which slows adoption of more widespread whole-exome or whole-genome sequencing. It takes less than a day and costs less than $1000 to sequence your exome (and even your whole genome), but the backlog for analysis of the sequencing results in labs can be 9 months or more. There are patients that could be treated from the analysis of their genome that aren't even considered if their prognosis is shorter than the amount of time it will take to get clinically actionable results from the lab, which is the really sad part. This problem is actually what led us to create our company, Genomenon, to help make the analysis much faster and alleviate the bioinformatics bottleneck at the sequencing labs.

bozoUser 10y ago
> It takes less than a day and costs less than $1000 to sequence your exome (and even your whole genome), but the backlog for analysis of the sequencing results in labs can be 9 months or more. Layman qs. what is stopping the labs to quickly analyze the genome? Computational power or few labs doing this kind of work?
- jfarlow 10y ago
  In general it's a (computationally) hard problem to restitch a genome together. Even today, when you 'get your genome sequenced' you are not getting a full read-through of your entire genome's data. Imagine you want to reconstruct the data on two RAIDs that are mostly, but importantly not exactly, mirrors of each other. Each RAID has 23 drives. Each drive has ~1Gb or so of data. And much of the data is not only mirrored between the two RAIDs, but is also mirrored between the 23 drives - and many of that mirrored data is 'off by 1' in very important ways (both 'must', and 'must not' scenarios). Further some of the data contains very long sections of highly repetitive data. And some of the data is mechanically biased to be harder to read than others. You must now reconstruct those two RAIDs with single-bit accuracy - as a single bit-flip in certain sections determines whether or not you get cancer. The data you are given to do the reconstruction is a 200Gb single column CSV file with each row being 12 bytes of data. Go.

bradleyjg 10y ago

> The bottom line is, If you get cancer, fight like hell to get your tumor sequenced. Most insurers cover at least some kind of genomic test for cancer these days. Is this something that has to go through your oncologist or can you drive the process independently?