On cancer genetics

What 'causes' cancer?  This was a very mysterious disease for a long time, and there were many theories about it.  Prominently, in the 1970s or so, a major idea was proposed by Nobel laureate Macfarlane Burnet, an eminent Australian immunologist.  The idea was known as the 'forbidden clone' theory and was about autoimmune disease but, more generally, about somatic mutation.  The idea of cancer as a somatic mutational disease made sense if cancer arose from single founder cells, as accumulating evidence suggested, and yet was generally not inherited.  If it is 'genetic' in its etiological mechanism, what else could it be?  Viral causes were found, though I cannot recall when, relative to the rest of this history.

The idea of a mix of inherited and somatic mutations had appeal in the sense that if you inherited part of a mutational pathway to cancer, but not all of it, your parents would be unaffected but you would only have to 'await' complementary somatic mutation in order for some cell to be transformed to a cancer state.  This thinking led Al Knudsen in the early 70s to propose such a mechanism for the pediatric eye cancer retinoblastoma--a marvelous insight for which a Nobel prize would not have been inappropriate.  There, it has turned out that the major event is a second, somatic, mutational 'hit' in the RB gene itself, and the tumors occur so early in life that perhaps few other somatic events are needed to transform a retinoblast.  Also, retinoblasts may not divide much if at all after development, so if you escape the second event while the retina is developing, then you're safe.

The idea of cancer as a somatic mutational disease is widely acknowledged, though most of the ink is spilled lauding discoveries of inherited tumor variants, of which the best-known are variants in the BRCA1 and 2 genes (but there are others).  Virally induced cancers seem to be due to viruses incorporating into inappropriate locations in the genome, so while they are externally 'inherited', the cell-specific mechanism is consistent with other ideas.

It is still correct that, with a few exceptions like retinoblastoma, even those who inherit a high-risk variant such as in the BRCA genes typically do not get their cancer till much later in life.  And it is also true that inherited variants seem to need many subsequent complimentary mutations for a cell to be transformed.  Thus, even BRCA mutations are in themselves not a cause of cancer.  Indeed, if the story is correctly being understood, the BRCA genes are involved in mutation detection and repair, so that the associated breast and ovarian (and perhaps a few other) cancers are really due, at the cellular level, to other mutational changes that directly affect the cell's behavior.

Somatic mutations are generally hard to study, but even in cancer, a concentrated source of cells with such mutations, this is a challenge because a tumor grows rapidly and spreads, so even if all tumor cells are somatic descendants of the original transformed cell, these cells continue to acquire further mutations.  This accounts, in part at least, for the spread (metastasis) and evolution of drug resistance of tumors.

Most attention has been on protein causing changes--exome mutations--in the search for cancer-related  mutations.  But if cancer is a lineage of cells that do not constrain their processes or rate of cell division, then one might suspect that regulatory variation would be comparably or even more important than protein structure itself; that is, normal proteins related to cell behavior may cause problems if there are too many or too few of them in a cell under various conditions.  This has led to expanded, though more difficult, searches of DNA sequence in tumors.

Regulatory somatic mutations in cancer
A paper in the November 2014 issue of Nature Genetics, by Weihnold et al., reports on regulatory mutations found in cancer cells.  The authors used some existing cancer genome data bases that compared cancerous tissue to normal ('matched normal') control samples.  The samples were small and had other various limitations as the authors note, but the point is that in screening whole genome sequence they found a number of gene-regulating areas that had multiple mutations in the data and thus seemed to indicate regulatory somatic mutations.

This is interesting beyond even the tentative nature of the paper itself.  One might speculate that even when protein variation is responsible for the cell's initial transformation to found a tumor, the subsequent aspects of growth, metastasis, drug resistance and so on may well be due to changes in the regulatory behavior of the cells descendant from the original tumor.

It is theoretically obvious and well-documented specifically, that different parts of tumors contain different somatic-origin mutations.  This paper suggests that classical genes are not the only place to look for such variation.  Searching the 'noncoding' parts of the genome, which is the vast majority and is still largely not understood, will be daunting.  How complex, unique to individuals and tractable this approach will turn out to be is hard to predict.  But as we've noted recently here on MT, the evolution of cells within a given individual's lifetime is comparably (or more) complex than the evolution of individuals in a species,  Documenting this variation in adequate detail may require very different sorts of methods, but the story is surely going to be interesting.  How well it aids therapy is another story entirely.