9 ms·

As whole-exome sequencing has now dipped below $1,000 [1], this really should become a diagnostic assay of first resort. That said, further improvements are req

As whole-exome sequencing has now dipped below $1,000 [1], this really should become a diagnostic assay of first resort. That said, further improvements are required as it appears the majority of cancer causing sequence variants are found in non-coding regions of the genome [2], suggesting that greater sequencing coverage is tremendously valuable. [1] https://www.genome.gov/sequencingcosts/ https://www.genome.gov/sequencingcosts/ [2] http://www.nature.com/nrg/journal/v17/n2/abs/nrg.2015.17.html http://www.nature.com/nrg/journal/v17/n2/abs/nrg.2015.17.htm...

mbreese 10y ago
> the majority of cancer causing sequence variants are found in non-coding regions of the genome That's not entirely accurate. The majority of variants occurs in the non-coding genome, but that's also because the vast majority of the genome is non-coding. There certainly are non-coding variants that are oncogenic (e.g. hTERT promoter), but for the most part the functional significance of a given non-coding variant is unknown. I'm not suggesting greater sequencing isn't important, but there are a lot of considerations that goes into what part of a cancer genome get sequenced (WGS, exome, gene panels, specific variants). We simply don't know what a lot of the variants do, but for those that suggest a particular therapy (BRAF V600E), it can be quite effective.
chrisamiller 10y ago
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.

mbreese 10y ago

> the majority of cancer causing sequence variants are found in non-coding regions of the genome That's not entirely accurate. The majority of variants occurs in the non-coding genome, but that's also because the vast majority of the genome is non-coding. There certainly are non-coding variants that are oncogenic (e.g. hTERT promoter), but for the most part the functional significance of a given non-coding variant is unknown. I'm not suggesting greater sequencing isn't important, but there are a lot of considerations that goes into what part of a cancer genome get sequenced (WGS, exome, gene panels, specific variants). We simply don't know what a lot of the variants do, but for those that suggest a particular therapy (BRAF V600E), it can be quite effective.

chrisamiller 10y ago

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.