Environment, heritability and random mutation during stem cell replication

It is “human” for us to search for explanations of catastrophic events and rule out mere “chance” or “bad luck.” When it comes to human cancer, the issue of “natural causes” vs “bad luck” was raised by Tomasetti and Vogelstein [Science 2o15]. That study was widely misinterpreted as saying that most cancers are due neither to genetic inheritance nor environmental factors –– but simply bad luck, and it sparked a lot of controversy. During the past 2 years, several hundred papers have been written in response, including some in agreement and others to opposite conclusions. The controversy raised was that Tomasetti and Vogelstein had concluded ~65% of the differences, in risk of certain cancers, is linked to stem cell divisions in the various cancerous tissues examined. In the attached article, Tomasetti et al. provide further evidence that this conclusion is not specific to the United States.

Cancers are caused by mutations that may be: inherited, i.e. due to heredity (H); induced by environmental factors (E); or result from DNA replication errors (R). Authors [attached article] studied the relationship between the number of normal stem-cell divisions and the risk of 17 cancer types in 69 countries throughout the world. The data showed a strong correlation (median = 0.80) between cancer incidence and normal stem-cell divisions in all countries, regardless of their environment

The major role of DNA-replication-error mutations in cancer etiology was supported by an independent approach –– based solely on cancer genome sequencing and epidemiological data, which suggested that DNA-replication-error mutations are responsible for two-thirds of mutations in human cancers. All these results are consistent with epidemiological estimates of the fraction of cancers that can be prevented by changes in the environment. Furthermore, the data underscore the importance of early detection and intervention to reduce deaths from the numerous cancers that arise from unavoidable DNA-replication-error mutations.

Science 24 Mar 2o17; 355, 13301334


Glad to see that Tomasetti and Vogelstein are back with this most logical and fundamentally sound hypothesis.  While I understand the (over)reaction to their first publication, I agree that many people over/mis-interpretted what they were saying.  Given the number of cells in the body, and the error rate, albeit remarkably low, in DNA replication, it only stands to reason that populations of cells (tissues) that have higher rates of stem cell-derived replication *might* have higher rates of incorrectly repaired mutations over time.

The one thing I find confusing is why small intestinal (not colon) cancer rates are remarkably low, when the small intestinal epithelium is known to have such a high turnover rate.  I’ve always attributed that to the short lifespan of the cells (and thus the necessarily high replication rate), but that is not really supported by the relatively high rate of basal cell carcinoma associated with dermal epithelial cells.

Hwever, perhaps the difference is that the latter (basal cell carcinoma) is subject to much higher environmental (sunlight) causes of mutations, relative to intestinal crypt stem cells.  Hmmm.Dave


Following on Dave’s comment below, one wonders if it is the turnover (short-life span) of small bowel cells that prevents small bowel cancer, why doesn’t the (comparably short) turnover of colon cells prevent the development of colon cancer?

Equally,  it is also quite odd that the hematopoietic stem cell, which is under continuous replicative pressure, and particularly whenever we expose patients to chemotherapy or radiotherapy or other stressors, is relatively under-represented in terms of tumors and particularly when compared with lung/colon/breast etc cancers.

The answer almost certainly lies in one of the fundamental problems/assumptions of the original 2015 paper, and that is still not addressed in the most recent paper.

We can assume that the data on the frequency of human cancers is probably correct.

Although there may be problems in details of classification, many countries have been collecting that data for many years: it is reasonable to assume it is reliable.

However the data that is suspect, is the number of stem cell divisions in a particular tissue.

The authors did nothing to validate that key data even though it is central to their conclusion.

The first section in the Supplementary material “justifies” the determination of number of stem cell divisions in the hematopoietic compartment.

This is the basis for estimates of human AML and CLL.

Tomasetti and Vogelstein state “hematopoietic stem cells have been estimated to divide every ~15, 17, 30, 57 days. Thus we assume they divide every 30 days”.

The authors cite 5 papers that form the basis of their estimate of 30 days.

However, they neglect to mention that the data are for MOUSE hematopoietic stem cells.

Quite an oversight…

What we really need to see then is the relative frequency of AML in mice, not humans.

Similarly Tomasetti and Vogelstein state “…as noted in the section on the small intestine, the duodenal stem cells divide ~1/3 as frequently as those of the colon”.

Two references are cited.

One examined 13 human small intestines using bisulphite sequencing to assess methylation patterns. Despite the claim by Tomasetti and Vogelstein, the authors themselves state in their Abstract “Human large and small intestine crypt niches appeared to have similar stem cell dynamics…”

The other paper cited directly measured stem cell kinetics in the small bowel….of transgenic MICE.

Again, Tomasetti and Vogelstein did not provide the data regarding the relative frequency of small bowel tumors in mice.

One wonders if/how these papers were reviewed?

This exchange about stem cells and the causes of cancer brings to mind a good example of “environment-induced” acute myelocytic leukemia (AML), i.e. treatment-related AML in adult and child cancer patients –– caused by etoposide and some other anti-cancer agents –– probably by the formation of double-strand DNA damage and formation of fusion genes such as MLL-rearrangements and some others.

In these cases, “environment” is practically or certainly known. However, the role of inherent, possibly hereditary factors –– is less well delineated.


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