Bad Luck Theory

Cristian Tomasetti & Bert Vogelstein explain the Bad Luck Theory

Two factors are widely recognized as causing cancer: environment (E) and heredity (H).

A paper published in Science in 2015 provided evidence for a third factor: the random mistakes made when normal stem cells divide. The results in this paper showed that there was a strong correlation between the lifetime number of normal stem cell divisions in an organ and its lifetime cancer incidence. This contributes to explain why certain cancer types have a much higher incidence than others.

The authors, mathematician Cristian Tomasetti and cancer geneticist Bert Vogelstein, interpreted this finding as a strong indication that random replicative errors – i.e. DNA mutations occurring during normal cell division – are a potent source of cancer driver gene mutations, and therefore of cancer. They called this third factor R and the “Bad Luck Theory” (also known as the TV Theory, as called by others, due to the initials of the authors’ last names) was born. This Bad Luck theory suggests that R mutations play a major role in cancer, but the correlation they found did not allow to measure how large that role is in any specific cancer type or in cancer overall.

However, the paper attracted a lot of attention, both by scientists and the public, and it was considered controversial. This was not surprising given the current paradigm for cancer etiology – that cancers are caused by environment and heredity. Many criticisms were raised. For example, breast and prostate cancers, two of the most common cancers, were not included in the 2015 study. And the 2015 analysis was based only on U.S. data. Given the large variation in environmental exposures, lifestyles, and cancer incidences across the world, would the correlation between stem cell divisions and cancer incidences in various organs be found in these other countries?

In 2017, the authors published another paper in Science (free reprint, and full text), where these two questions were addressed. The answer: the results were essentially identical when breast and prostate cancers were included, and strong correlations between number of stem cell divisions and cancer incidences were found in each of 69 countries examined. In the new paper, the authors also asked a different but related question: what is the proportion of mutations that can be attributed to each of the three factors: E, R, and H. Using evidence based only on epidemiological and cancer sequencing data, they estimated that 66% of the mutations found among all cancer types are due to R, 29% to E, and 5% to H. The proportions varied with cancer type. In prostate, brain, and bone cancers, for example, 95% of the mutations were attributed to R. In lung cancer, however, only 35% were attributed to R and the remaining 65% were due to E, primarily as a result of exposure to cigarette smoke. This was the first time that such proportions had been measured.

Etiology of driver gene mutations in women with cancer. For each of 18 representative cancer types, the schematic depicts the proportion of mutations that are inherited, due to environmental factors, or due to errors in DNA replication (i.e., not attributable to either heredity or environment).The sum of these three proportions is 100%. The color codes for hereditary, replicative, and environmental factors are identical and span white (0%) to brightest red (100%). The numerical values used to construct this figure, as well as the values for 14 other cancer types not shown in the figure, are provided in table S6 of the paper. B,brain; Bl, bladder; Br, breast; C, cervical; CR, colorectal; E, esophagus; HN, head and neck; K, kidney; Li, liver; Lk, leukemia; Lu, lung; M, melanoma; NHL, non-Hodgkin lymphoma; O, ovarian; P, pancreas; S, stomach; Th, thyroid; U, uterus. [Image: The Johns Hopkins University] From Tomasetti, Li, Vogelstein – Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 2017, 355(6331):1330-1334.

As with all  scientific research, it will take time to consolidate (or disprove) the Bad Luck theory. This website is meant to provide a description of the main findings supporting the Bad Luck theory, as well as its major criticisms, with comments from Tomasetti and Vogelstein when appropriate.

More Resources

Free access to Tomasetti, Lu, Vogelstein Science 2017 paper here: reprint and full text.

NIH Director’s Blog by Dr. Francis Collins.

Watch a Press Briefing held by the AAAS in Washington DC on 3/22/2017.

Listen to a Podcast by Elizabeth Tracey

Read the Johns Hopkins Medicine Media Press Release