Old paradigms die hard

A statement in a recent Nature editorial [ vol. 554 pp. 308 – 309 ’18 ] had me thinking that a real paradigm shift in our understanding of cancer was under way, but in fact it was an out of date paradigm that tripped up the editorialist.  Since breast cancer is likely to affect us individually or someone we know, it’s worth looking at this paper.

Ductal Carcinoma In Situ (DCIS) of the breast, is breast cancer confined to one of the ducts in the breast bringing milk to the nipple.  If it stayed there forever it would be harmless, like a benign mole on the skin. Unfortunately ‘up to’ 40% of DCIS invades the lining of the duct and the soft tissue of the breast becoming Invasive Ductal Carcinoma (IDC) where it is not harmless at all.  There is currently no way to tell which DCIS will stay quiet so everyone gets treated.

A heroic paper in cell (vol. 172 pp, 205 – 217 ’18 ) used the highest of high technology to study the question.  First they used Laser Capture Microdissection to separate a selected cell from its neighbors by tracing a laser beam around the cell.  Then they used laser catapulting in which energy from an ultraviolet laser propels the microdissected cell into a collection tube.  Then they performed exon sequencing on the collected cells (e.g. they sequenced the parts of the gene coding for protein), comparing cells which were DCIS from IDCs.  Some 1,293 cells from 10 patients were studied.

There was an average of 23 mutations/patient.  “The transition from DCIS to IDC was not associated with a notable increase in the number of mutations.”  “The authors’ main finding is the remarkable genetic similarity of a patient’s tumor cells in these two distinct states”

Hello.

I thought mutations caused cancer and that the more you had the worse the cancer.  Not so in this paper. A paradigm shift indeed.

What’s wrong with this thinking?  Think a bit before reading further.

If you are old enough, you may remember statements that we were 98% chimps based on our genome (or at least what was known of it at the time).  This is because the sequence of the amino acids in our 20,000 or so proteins varies only by 2% from that of the chimp.

That proves it.  Except that it doesn’t.  Amazingly enough, the amount of all 3,200,000,000 positions of our genome coding for protein is under 2%.  So 98% of or genome does NOT code for protein.  It contains the code to determine when, for how long, and where each gene is made into messenger RNA which is then made into protein.

An analogy may help.

This is like saying Monticello and Independence Hall are just the same because they’re both made out of bricks. One could chemically identify Monticello bricks as coming from the Virginia piedmont, and Independence Hall bricks coming from the red clay of New Jersey, but the real difference between the buildings is the plan.

It’s not the proteins, but where and when and how much of them are made. The control for this (plan if you will) lies outside the genes for the proteins themselves, in the rest of the genome (remember only 2% of the genome codes for the amino acids making up our 20,000 or so protein genes). The control elements have as much right to be called genes, as the parts of the genome coding for amino acids. Granted, it’s easier to study genes coding for proteins, because we’ve identified them and know so much about them. It’s like the drunk looking for his keys under the lamppost because that’s where the light is.

On this point it would be very worthwhile to look beyond the genes mutated in both sets of tumors, sequencing their promotors and enhancers.  I think it would likely show profound differences.

No further posts for a while.  We’re going to visit a new grandson, 3 days old, whose parents apparently lack the creativity to name him.

 

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