Does Somatic Variation Affect Early Cancer Detection With Circulating DNA?

David J. Kerr, CBE, MD, DSc


March 15, 2023

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine at University of Oxford. I'd like to turn your attention to a fantastic review article that I enjoyed reading recently in Annals of Oncology. The title is "Somatic Variations in Normal Tissues: Friend or Foe of Cancer Early Detection?" and it's from an excellent group from the Francis Crick Institute in London. This is a really thoughtful, interesting article.

With the advent of much more sophisticated, sensitive DNA sequencing, analytical, and bioinformatic techniques, it has become apparent that in normal tissues, we can find somatic mutations in many of the so-called driver genes, which are involved in the process of carcinogenesis.

As we get older, we accumulate more of these mutations in normal tissue, so we find a patchwork quilt. It depends on the geography of the tissue, the type of tissue, how old we are, and so on.

We assume, don't we, that normal tissue is normal genetically and phenotypically, and cancer is a collection of mutations, where eventually there's a tipping of balance in which a cell that has accumulated the most driver mutations is the one that outgrows and behaves like a cancer cell —hyperproliferative, invasive, with metastatic potential.

What they've shown and what we've learned with these new DNA sequencing techniques is that normal tissues can harbor quite a patchwork of these somatic mutations. There's some work in lung cancer demonstrating that 49% of patients with lung cancer have mutations in P53, but so do 11% of normal healthy controls.

For those who are interested in the biological evolution of tumors, the biology tells us about the fitness of some tumor cells to succeed and why they are different from others. We know that, in terms of somatic mutation or variation in normal tissues, some of these mutated clones can come and go. They can disappear. They can be outcompeted. There's something fascinating about the ability of some driver mutations to outcompete others. Again, this is tissue-specific in terms of the meta-analysis.

Think about these new tests that are coming along, like GRAIL, in which we're being persuaded that in normal individuals with low-circulating, low-copy-number DNA, if we can detect mutations in TP53, RAS, RAF, or whatever we think the important drivers might be, that these might be reflecting, especially in older people, nonmalignant changes in normal tissue.

The possibility of false-positives is a very significant reality and something that will be tested in some of the enormous prospective studies that are going on. This is a challenging piece of biology, and in some ways it's not surprising, of course, that only now we're able to detect these, given the depth of DNA sequencing that we can now undertake.

Of course, there will be a field change in colonic tissues based on exposure to the various dietary carcinogens and the various insults of normal life that we go through. This complicates how we aim to look for early detection of cancer using genomic tests.

I accept that rather than just looking for circulating fragments of DNA, you may look for patterns of methylation and so on; this might help to distinguish genuinely precancerous tissue from just quasi-passenger somatic mutations in normal tissue in healthy people.

It's going to be a challenge for those who believe that we can use circulating DNA as a holy grail or the answer to us being able to detect tumor at an incredibly early stage.

Have a look at the article — it's beautifully written. It's a thoughtful piece about the biological evolution of cancer and fitness to proceed, but also with a potentially clinical element to it, as to what this might mean for large-scale genetic testing as a means of detecting cancer at an earlier stage, which is terribly, terribly important.

I'd be very interested in what your thoughts are, so please post them.

For the time being, Medscapers, ahoy. Thank you.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

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