- Email: [email protected]
Beyond bad luck: induced mutations and hallmarks of cancer
Comment
In March, 2017, the American Association for the Advancement of Science (AAAS) published a headline stating “Random errors in DNA replication play a major role in cancer”, referring to a new paper by Tomasetti and colleagues,1 a follow-up to their first paper in 2015. Headlines subsequently appeared on many news and social media outlets reading “Most cancer cases arise from ‘bad luck’” (Scientific American) or “‘Bad luck’ mutations increase cancer risk more than behavior, study says” (CNN). Such a message, suggesting that cancers are largely due to bad luck, is an incorrect interpretation of the authors’ results, and is ultimately misleading. We are concerned about the adverse effect this message might have on public health policies to prevent cancers. Here, we emphasise that mutations are a necessary but insufficient cause of cancer, and additional mechanisms (the hallmarks of cancer) are at work, including altered immune function. Both papers by Tomasetti and colleagues, published in Science, use mathematical modelling to analyse the probability of developing cancer based on the rate of stem-cell divisions occurring in different organs. The authors’ analysis stops at the molecular level, and therefore so should all ensuing conclusions. Random occurrences of mutations do not equate to random occurrence of cancers. This difference is partly because a whole other aspect of the carcinogenic process is missing, which has been described as the hallmarks of cancer: for example, non-genotoxic alterations at the cellular level.2 Key among such alterations is immune function. A mutation at the cellular level must be followed by other non-genotoxic events, such as immune surveillance failure, for a cancer to develop. Tomasetti and colleagues highlight that cell replication is a major factor determining the appearance of tumour cells. However, mutation is a necessary— but not sufficient—condition for development of a cancer. Cancers occur when several biological systems become dysfunctional, in particular the immune system. Immune surveillance must fail to identify and destroy a mutated cell, allowing it to replicate3,4 and eventually form a tumour. However, the behaviour of the immune system has not been shown to be random. Indeed, immune system functioning and the failure of immune surveillance might be vulnerable to many exogenous www.thelancet.com/oncology Vol 18 August 2017
factors such as infections or health behaviours.5 Even when stem-cell mutations occur at random, the initiation and development of a cancer cannot be viewed as a random process. On a global scale, the most commonly occurring cancers in women include breast, cervical, liver, and lung cancers, and those in men include colorectal, oesophageal, lung, and prostate cancers.6 In some high-income countries, the incidence of cancers remains high but has stabilised or started to decrease in the past decade, with more evident decreases in mortality.6 These changes are occurring because of prevention policies, early detection, and improved treatment. Huge spatial and temporal changes in cancer incidence are not compatible with the theory of stem-cell replication rates; if stochastic processes were responsible for cancer incidence through stem-cell replication rates, we would not observe these contextual changes. The incidence of liver cancer in men (the number of newly diagnosed cancer cases per 100 000 men per year) ranges from two in 100 000 in Iceland to almost 100 in 100 000 in Mongolia, with even larger variation if incidence in high-risk versus low-risk subgroups of populations is considered. Acquired mutations, such as those related to tobacco, are more strongly correlated with the incidence of cancers than with the rate of stem-cell divisions. Moreover, a meta-analysis has outlined the significant contribution of obesity to the incidence of 11 cancers.7 For example, the increase in the risk of developing cancer for every 5 kg/m2 increase in body-mass index was 9% for rectal cancer among men, and 11% for postmenopausal breast cancer among women who had never used hormone replacement therapy.7 Since tobacco use and obesity are partly linked to social determinants, the probability of some acquired mutations is thus socially distributed, and the same is true for the risk of cancer.8 Evidence also exists across national contexts to suggest that many of the most commonly occurring cancers are socially patterned.9,10 If random mutations explain a different baseline risk of cancer at the organ level, they cannot explain social trends unless we assume that a different rate of stemcell division occurs within different social groups—an idea that is unsupported by evidence. In fact, such trends indicate that the most prevalent cancers are
Paul Wootton/Science Photo Library
Beyond bad luck: induced mutations and hallmarks of cancer
For the AAAS article see https:// www.aaas.org/news/randomerrors-dna-replication-playmajor-role-cancer For the Scientific American article see https://www. scientificamerican.com/article/ most-cancer-cases-arise-frombad-luck/ For the CNN article see http:// edition.cnn.com/2017/03/23/ health/cancer-mutations-badluck-study/index.html
999
Comment
not occurring at random at the population level. Risk calculated at the tissue or organ level should not lead to population-level assumptions. In conclusion, the idea that cancers are caused by bad luck is misleading and dangerous if it leads to policy makers and the public thinking that there is nothing to be done to prevent cancers. Although tumour-cell production might have an inherent stochastic nature, this is just one component of an interaction between complex systems at the individual and population level, which are eminently not random. Medicine and public health need to persist in finding areas of cancer prevention moving above and beyond classic risk factors, taking whole systems—both social and biological—into account. *Michelle Kelly-Irving, Cyrille Delpierre, Paolo Vineis INSERM, and Université Toulouse III Paul-Sabatier, UMR1027, F-31000 Toulouse, France (MK-I, CD); and Faculty of Medicine, School of Public Health, Imperial College London, London, UK (PV) [email protected]
We declare no competing interests. All authors participate in the Lifepath project, funded by the European Commission (Horizon 2020 grant no 633666). 1
Tomasetti C, Li L, Vogelstein B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 2017; 355: 1330–34. 2 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70. 3 Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology 2007; 121: 1–14. 4 Stewart TJ, Abrams SI. How tumours escape mass destruction. Oncogene 2008; 27: 5894–903. 5 Cramer DW, Finn OJ. Epidemiologic perspective on immune-surveillance in cancer. Curr Opin Immunol 2011; 23: 265–71. 6 Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol Biomarkers Prev 2016; 25: 16–27. 7 Kyrgiou M, Kalliala I, Markozannes G, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ 2017; 356: j477. 8 Alexandrov LB, Ju YS, Haase K, et al. Mutational signatures associated with tobacco smoking in human cancer. Science 2016; 354: 618–622. 9 Boscoe, FP, Johnson CJ, Sherman RL, Stinchcomb DG, Lin G, Henry KA. The relationship between area poverty rate and site-specific cancer incidence in the United States. Cancer 2014; 120: 2191–98. 10 Mallath MK, Taylor DG, Badwe RA, et al. The growing burden of cancer in India: epidemiology and social context. Lancet Oncol 2014; 15: e205–12.
Increasing global access to cancer care: models of care with non-oncologists as primary providers Lawrence N Shulman
The rapidly increasing incidence of cancer in low-income and middle-income countries is compounded by a profound shortage of both oncologists and facilities with the capacity for cancer care in these settings.1,2 In a model where only oncologists treat cancer, patients—many with curable diseases—will die waiting for oncologists to be trained. Thus, it is imperative to develop innovative models of care that address the immediate needs of patients with cancer. One possibility is task-shifting, whereby general medical practitioners can be trained to deliver safe and effective oncology services. Task shifting was essential in facilitating the scaling up of successful HIV care in the 2000s, and so this success could be replicated today with oncology provision.3 Rwanda is no exception to the cancer care challenges faced by low-income and middle-income countries. In 2012, with one haematologist and no oncologists serving 12 million people, the Ministry of Health, in partnership with Partners In Health, the Dana-Farber Cancer Institute/Brigham and Women’s Cancer Center 1000
(DFCI/BWH; Boston, MA, USA), established the Butaro Cancer Center of Excellence (BCCOE). This rural cancer centre is focused on task shifting to generalists as a means to provide safe, effective, and quality oncology services, based on a structured programme with measured outcomes. In a task-shifting model, disease-based diagnostic and treatment protocols that are contextually appropriate serve as the foundation of clinical practice. Detailed treatment pathways, adapted for the local context, from sources such as the National Comprehensive Cancer Network (NCCN) clinical practice guidelines provide support for non-oncology providers—physicians and nurses. Agreed upon treatment pathways also allow for better predictive models for cancer drug needs, and uniformity of treatment makes assessment of patient outcomes more useful. Readily accessible to all clinical staff, protocols can be used in the care of all patients and include important guidance on diagnosis, evaluation, treatment, and follow-up of patients. In BCCOE, the scope of oncology practice is defined through www.thelancet.com/oncology Vol 18 August 2017
In March, 2017, the American Association for the Advancement of Science (AAAS) published a headline stating “Random errors in DNA replication play a major role in cancer”, referring to a new paper by Tomasetti and colleagues,1 a follow-up to their first paper in 2015. Headlines subsequently appeared on many news and social media outlets reading “Most cancer cases arise from ‘bad luck’” (Scientific American) or “‘Bad luck’ mutations increase cancer risk more than behavior, study says” (CNN). Such a message, suggesting that cancers are largely due to bad luck, is an incorrect interpretation of the authors’ results, and is ultimately misleading. We are concerned about the adverse effect this message might have on public health policies to prevent cancers. Here, we emphasise that mutations are a necessary but insufficient cause of cancer, and additional mechanisms (the hallmarks of cancer) are at work, including altered immune function. Both papers by Tomasetti and colleagues, published in Science, use mathematical modelling to analyse the probability of developing cancer based on the rate of stem-cell divisions occurring in different organs. The authors’ analysis stops at the molecular level, and therefore so should all ensuing conclusions. Random occurrences of mutations do not equate to random occurrence of cancers. This difference is partly because a whole other aspect of the carcinogenic process is missing, which has been described as the hallmarks of cancer: for example, non-genotoxic alterations at the cellular level.2 Key among such alterations is immune function. A mutation at the cellular level must be followed by other non-genotoxic events, such as immune surveillance failure, for a cancer to develop. Tomasetti and colleagues highlight that cell replication is a major factor determining the appearance of tumour cells. However, mutation is a necessary— but not sufficient—condition for development of a cancer. Cancers occur when several biological systems become dysfunctional, in particular the immune system. Immune surveillance must fail to identify and destroy a mutated cell, allowing it to replicate3,4 and eventually form a tumour. However, the behaviour of the immune system has not been shown to be random. Indeed, immune system functioning and the failure of immune surveillance might be vulnerable to many exogenous www.thelancet.com/oncology Vol 18 August 2017
factors such as infections or health behaviours.5 Even when stem-cell mutations occur at random, the initiation and development of a cancer cannot be viewed as a random process. On a global scale, the most commonly occurring cancers in women include breast, cervical, liver, and lung cancers, and those in men include colorectal, oesophageal, lung, and prostate cancers.6 In some high-income countries, the incidence of cancers remains high but has stabilised or started to decrease in the past decade, with more evident decreases in mortality.6 These changes are occurring because of prevention policies, early detection, and improved treatment. Huge spatial and temporal changes in cancer incidence are not compatible with the theory of stem-cell replication rates; if stochastic processes were responsible for cancer incidence through stem-cell replication rates, we would not observe these contextual changes. The incidence of liver cancer in men (the number of newly diagnosed cancer cases per 100 000 men per year) ranges from two in 100 000 in Iceland to almost 100 in 100 000 in Mongolia, with even larger variation if incidence in high-risk versus low-risk subgroups of populations is considered. Acquired mutations, such as those related to tobacco, are more strongly correlated with the incidence of cancers than with the rate of stem-cell divisions. Moreover, a meta-analysis has outlined the significant contribution of obesity to the incidence of 11 cancers.7 For example, the increase in the risk of developing cancer for every 5 kg/m2 increase in body-mass index was 9% for rectal cancer among men, and 11% for postmenopausal breast cancer among women who had never used hormone replacement therapy.7 Since tobacco use and obesity are partly linked to social determinants, the probability of some acquired mutations is thus socially distributed, and the same is true for the risk of cancer.8 Evidence also exists across national contexts to suggest that many of the most commonly occurring cancers are socially patterned.9,10 If random mutations explain a different baseline risk of cancer at the organ level, they cannot explain social trends unless we assume that a different rate of stemcell division occurs within different social groups—an idea that is unsupported by evidence. In fact, such trends indicate that the most prevalent cancers are
Paul Wootton/Science Photo Library
Beyond bad luck: induced mutations and hallmarks of cancer
For the AAAS article see https:// www.aaas.org/news/randomerrors-dna-replication-playmajor-role-cancer For the Scientific American article see https://www. scientificamerican.com/article/ most-cancer-cases-arise-frombad-luck/ For the CNN article see http:// edition.cnn.com/2017/03/23/ health/cancer-mutations-badluck-study/index.html
999
Comment
not occurring at random at the population level. Risk calculated at the tissue or organ level should not lead to population-level assumptions. In conclusion, the idea that cancers are caused by bad luck is misleading and dangerous if it leads to policy makers and the public thinking that there is nothing to be done to prevent cancers. Although tumour-cell production might have an inherent stochastic nature, this is just one component of an interaction between complex systems at the individual and population level, which are eminently not random. Medicine and public health need to persist in finding areas of cancer prevention moving above and beyond classic risk factors, taking whole systems—both social and biological—into account. *Michelle Kelly-Irving, Cyrille Delpierre, Paolo Vineis INSERM, and Université Toulouse III Paul-Sabatier, UMR1027, F-31000 Toulouse, France (MK-I, CD); and Faculty of Medicine, School of Public Health, Imperial College London, London, UK (PV) [email protected]
We declare no competing interests. All authors participate in the Lifepath project, funded by the European Commission (Horizon 2020 grant no 633666). 1
Tomasetti C, Li L, Vogelstein B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 2017; 355: 1330–34. 2 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70. 3 Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology 2007; 121: 1–14. 4 Stewart TJ, Abrams SI. How tumours escape mass destruction. Oncogene 2008; 27: 5894–903. 5 Cramer DW, Finn OJ. Epidemiologic perspective on immune-surveillance in cancer. Curr Opin Immunol 2011; 23: 265–71. 6 Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol Biomarkers Prev 2016; 25: 16–27. 7 Kyrgiou M, Kalliala I, Markozannes G, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ 2017; 356: j477. 8 Alexandrov LB, Ju YS, Haase K, et al. Mutational signatures associated with tobacco smoking in human cancer. Science 2016; 354: 618–622. 9 Boscoe, FP, Johnson CJ, Sherman RL, Stinchcomb DG, Lin G, Henry KA. The relationship between area poverty rate and site-specific cancer incidence in the United States. Cancer 2014; 120: 2191–98. 10 Mallath MK, Taylor DG, Badwe RA, et al. The growing burden of cancer in India: epidemiology and social context. Lancet Oncol 2014; 15: e205–12.
Increasing global access to cancer care: models of care with non-oncologists as primary providers Lawrence N Shulman
The rapidly increasing incidence of cancer in low-income and middle-income countries is compounded by a profound shortage of both oncologists and facilities with the capacity for cancer care in these settings.1,2 In a model where only oncologists treat cancer, patients—many with curable diseases—will die waiting for oncologists to be trained. Thus, it is imperative to develop innovative models of care that address the immediate needs of patients with cancer. One possibility is task-shifting, whereby general medical practitioners can be trained to deliver safe and effective oncology services. Task shifting was essential in facilitating the scaling up of successful HIV care in the 2000s, and so this success could be replicated today with oncology provision.3 Rwanda is no exception to the cancer care challenges faced by low-income and middle-income countries. In 2012, with one haematologist and no oncologists serving 12 million people, the Ministry of Health, in partnership with Partners In Health, the Dana-Farber Cancer Institute/Brigham and Women’s Cancer Center 1000
(DFCI/BWH; Boston, MA, USA), established the Butaro Cancer Center of Excellence (BCCOE). This rural cancer centre is focused on task shifting to generalists as a means to provide safe, effective, and quality oncology services, based on a structured programme with measured outcomes. In a task-shifting model, disease-based diagnostic and treatment protocols that are contextually appropriate serve as the foundation of clinical practice. Detailed treatment pathways, adapted for the local context, from sources such as the National Comprehensive Cancer Network (NCCN) clinical practice guidelines provide support for non-oncology providers—physicians and nurses. Agreed upon treatment pathways also allow for better predictive models for cancer drug needs, and uniformity of treatment makes assessment of patient outcomes more useful. Readily accessible to all clinical staff, protocols can be used in the care of all patients and include important guidance on diagnosis, evaluation, treatment, and follow-up of patients. In BCCOE, the scope of oncology practice is defined through www.thelancet.com/oncology Vol 18 August 2017