我们演化出抑制癌症系统的环境，与当今社会截然不同。在那个世界里面，没有自动售货机，没有自动扶梯，没有轮班工作，没有香烟。我们演化出癌症抑制系统时所处的世界是我们从事狩猎采集的祖先的世界。在日常生活当中，狩猎采集者每天要步行许多公里来收集水果和浆果或猎杀动物，攀爬悬崖和树木来寻找蜂巢、采集蜂蜜，还要经常费力地挖掘植物的块茎。狩猎采集者吃进去的每卡路里的热量都来之不易，这与现代生活相去甚远。在现代生活中，我们所摄入的热量很容易就会超过我们身体所需要的数量，而且步行的距离要远小于狩猎采集者，即便我们的可穿戴设备所记录下的步数看起来已经不少了。
现代化的便利使得我们摄入更多热量，更容易久坐不动，增加了疾病风险。[55]除此之外，我们的生活还与其他因素相关联，比如化学致癌物[56]（其中最重要的是在香烟中发现的致癌物），更高水平的生殖激素（因为营养更好[57]，且女性的排卵频率更高[58]），以及更多对睡眠的干扰[59]（人工照明、轮班工作和深夜使用有屏幕的电子设备）。在一生之中，我们接触了许多我们的狩猎采集者祖先所从未接触过的物质和事件，而且这些变化发生得太快了，我们人类尚未来得及演化出更好的癌症抑制机制。
癌症本身是一种古老的疾病，但现代的生活方式让我们暴露在更多致癌物质之下，或使体内的微妙平衡从细胞管控向细胞自由倾斜，从而增加了基因突变率。例如，更高水平的生殖激素可使人体细胞增殖更快，从而有可能牺牲DNA修复或体细胞维护过程中的其他可能有助于预防癌症的方面。得益于更好的营养和更好的医疗服务，我们的寿命也比我们的祖先更长，而这意味着在我们生命的尽头的更多年月里，癌症会随时出现。
我们对癌症的易感性始于我们最初受孕之时，但是造成这种易感性的许多因素，在我们的父母相遇之前，在现代人类在演化中出现之前，甚至在胎盘生殖出现之前很久，就已经确立了。我们对癌症的易感性源于我们演化长河里遥远的过去，但它也涉及我们一生之中在我们内部细胞之间所发生的演化争斗。作为多细胞生物，为了发挥正常功能，我们的细胞要能够增殖、迁移，并利用它们周遭的资源。但是细胞的这些能力也导致了我们容易患上癌症。放弃癌症抑制可以带来演化上的巨大优势，例如体型更大、生育能力更强。这就得出一个与我们的直觉相反的结论，即对于某个生物来讲，其最佳的癌症风险水平并不是零。如果我们想要完全抑制癌症，那么我们所要付出的演化代价可能会很高，高到不可能出现的地步。
[1] still hotbeds for cancer mutations and precancerous growths M. Greaves, “Does Everyone Develop Covert Cancer?,” Nature Reviews Cancer 14, no..4 (2014): 209–10.
[2] seemingly healthy cells had two to six mutations per million bases, similar to the mutational load found in many cancers Inigo Martincorena et.al., “Tumor Evolution: High Burden and Pervasive Positive Selection of Somatic Mutations in Normal Human Skin,” Science 348, no..6237 (May.2015): 880–86.
[3] approximately 0.24.percent of sun-exposed cells were acquiring TP53 mutations each year Patrik.L. St.hl et.al., “Sun-Induced Nonsynonymous p53 Mutations Are Extensively Accumulated and Tolerated in Normal Appearing Human Skin,” Journal of Investigative Dermatology 131, no..2 (February.2011): 504–8.
[4] Almost half of conceptions are estimated to fail, 80.percent of which fail before a pregnancy is detectable by standard clinical measures Kathy Hardy and Philip John Hardy, “1st.Trimester Miscarriage: Four Decades of Study,” Translational Pediatrics 4, no..2 (April.2015): 189–200.
[5] Humans have diverse mating and marriage patterns, including simultaneously having multiple mates (in the cases of polygyny and polyandry), serially having multiple mates (including serial monogamy, a common pattern for modern Western humans), and sometimes lifelong monogamy as well Melvin Ember, Carol.R. Ember, and Bobbi.S. Low, “Comparing Explanations of Polygyny,” Cross-Cultural Research 41, no..4 (November.2007): 428–40; Frank.W. Marlowe, “The Mating System of Foragers in the Standard Cross-Cultural Sample,” Cross-Cultural Research 37, no..3 (August.2003): 282–306; Robert J. Quinlan and Marsha.B. Quinlan, “Evolutionary Ecology of Human Pair-Bonds: Cross-Cultural Tests of Alternative Hypotheses,” Cross-Cultural Research 41, no..2 (May.2007): 149–69.
[6] David Haig proposed what has come to be known as the “milkshake model,” which asks us to imagine a mother who has bought a milkshake for her children to share David Haig, “Genomic Imprinting and the Theory of Parent-Offspring Conflict,” Seminars in Developmental Biology 3 (1992): 153–60.
[7] placentas of later-borns tend to be bigger than the placentas of earlier-borns Thomas McKeown and R..G. Record, “The Influence of Placental Size on Foetal Growth according to Sex and Order of Birth,” Journal of Endocrinology 10, no..1 (November.1953): 73–81.
[8] on the other hand, both copies expressing “paternal” growth-promoting gene products leads to a huge placenta Wolf Reik et.al., “Regulation of Supply and Demand for Maternal Nutrients in Mammals by Imprinted Genes,” Journal of Physiology 547, pt. 1 (February.2003): 35–44.
[9] Researchers have found that paternally expressed genes contribute to the production of more growth factors and greater placental invasiveness, whereas maternally expressed genes do the opposite P..M. Coan, G..J. Burton, and A..C. Ferguson-Smith, “Imprinted Genes in the Placenta — A Review,” Placenta 26, suppl. A (2005): S10–S20.
[10] gene expression in the placenta (but not the fetus) was dominated by paternally expressed genes Xu Wang et.al., “Paternally Expressed Genes Predominate in the Placenta,” Proceedings of the National Academy of Sciences of the United States of America 110, no..26 (June.2013): 10705–10.
[11] but also for susceptibility to cancer later in life David Haig, “Maternal-Fetal Conflict, Genomic Imprinting and Mammalian Vulnerabilities to Cancer,” Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences 370, no..1673 (July.2015), https://doi.org/10.1098/rstb.2014.0178.
[12] placental genes driving growth and invasion that should be silent later in life are re-expressed in cancer M. Monk and C. Holding, “Human Embryonic Genes Re-Expressed in Cancer Cells,” Oncogene 20, no..56 (December.2001): 8085–91.
[13] paternal evolutionary interests can favor cellular phenotypes that are more cancer-like: more proliferative, more invasive, and better able to extract resources from the host K. Summers, J. da Silva, and M..A. Farwell, “Intragenomic Conflict and Cancer,” Medical Hypotheses 59, no..2 (August.2002): 170–79.
[14] maternally expressed genes produce antibodies that can bind to and inactivate growth factors that are produced by paternally expressed genes Haig, “Maternal-Fetal Conflict,” 370.
[15] Beckwith-Wiedemann, which is associated with rapid growth in the womb, large size as a child, and an increased risk of cancer Haig, “Maternal-Fetal Conflict,” 370.
[16] It can take decades for cells with cancerous mutations to proliferate and grow into cancers Georg.E. Luebeck et.al., “Implications of Epigenetic Drift in Colorectal Neoplasia,” Cancer Research 79, no..3 (February.2019): 495–504.
[17] mutations that occur early in development can have reverberating effects over the remaining lifespan R. Meza, E..G. Luebeck, and S..H. Moolgavkar, “Gestational Mutations and Carcinogenesis,” Mathematical Biosciences 197, no..2 (2005): 188–210; S..A. Frank and M..A. Nowak, “Cell Biology: Developmental Predisposition to Cancer,” Nature 422, no..6931 (2003): 494.
[18] Women who have their first pregnancy earlier in life are likely to spend less time with undifferentiated stem cells in their breasts Benjamin Tiede and Yibin Kang, “From Milk to Malignancy: The Role of Mammary Stem Cells in Development, Pregnancy and Breast Cancer,” Cell Research 21, no..2 (February.2011): 245–57.
[19] women who get pregnant earlier in life have a substantially lower risk of hormone-positive breast cancer C. Athena Aktipis et.al., “Modern Reproductive Patterns Associated with Estrogen Receptor Positive but Not Negative Breast Cancer Susceptibility,” Evolution, Medicine, and Public Health 2015, no..1 (2015): 52–74, https://dx.doi.org/10.1093/emph/eou028; Fabienne Meier-Abt, Mohamed Bentires-Alj, and Christoph Rochlitz, “Breast Cancer Prevention: Lessons to Be Learned from Mechanisms of Early Pregnancy-Mediated Breast Cancer Protection,” Cancer Research 75, no..5 (March.2015): 803–7.
[20] cancer cells can evolve to get around this restriction, extending their replicative lives beyond what is optimal for the body Manuel Collado, Maria.A. Blasco, and Manuel Serrano, “Cellular Senescence in Cancer and Aging,” Cell 130, no..2 (July.2007): 223–33.
[21] they are also key players in the connections between aging and cancer Judith Campisi, “Cancer and Ageing: Rival Demons?,” Nature Reviews Cancer 3, no..5 (May.2003): 339–49.
[22] the mice that overproduce telomerase exhibit a higher risk for cancer, but if they don’t die from cancer, they live longer Collado, Blasco, and Serrano, “Cellular Senescence in Cancer and Aging,” 223–33.
[23] Mice that are deficient in producing telomerase or otherwise have shortened telomeres age more quickly, but also have a lower risk of developing cancer Collado, Blasco, and Serrano, “Cellular Senescence in Cancer and Aging,” 223–33.
[24] when the telomeres of cancer-prone mice are shortened, the risk of cancer goes down Collado, Blasco, and Serrano, “Cellular Senescence in Cancer and Aging,” 223–33.
[25] Killing healthy cells takes those cells out of the population and eventually depletes the renewal capacity of tissues Campisi, “Cancer and Ageing,” 2–13.
[26] mice had lower cancer rates yet did not age more quickly Campisi, “Cancer and Ageing,” 2–13.
[27] cancer is sometimes referred to as “the wound that does not heal” Harold.F. Dvorak, “Tumors: Wounds That Do Not Heal,” New England Journal of Medicine 315, no..26 (December.1986): 1650–59.
[28] Leukemias affect a surprisingly large proportion of children before the age of 15 Mel Greaves, “A Causal Mechanism for Childhood Acute Lymphoblastic Leukaemia,” Nature Reviews Cancer 18, no..8 (August.2018): 471–84.
[29] the majority of cases of leukemia are diagnosed in adults over the age of 65 “Leukemia—Cancer Stat Facts,” Surveillance, Epidemiology, and End Results Program, National Cancer Institute, accessed June.20, 2019, https://seer.cancer.gov/statfacts/html/leuks.html.
[30] The abnormal translocations were already present in the blood of the newborns later diagnosed with leukemia K..B. Gale et.al., “Backtracking Leukemia to Birth: Identification of Clonotypic Gene Fusion Sequences in Neonatal Blood Spots,” Proceedings of the National Academy of Sciences of the United States of America 94, no..25 (December.1997): 13950–54.
[31] Approximately 1.percent of newborns have preleukemic clones with these translocations, but only a tiny fraction of them go on to develop clinical ALL Greaves, “A Causal Mechanism for Childhood Acute Lymphoblastic Leukaemia.”
[32] they had fewer exposures to infections in general during early development (compared to those children who were exposed to other children from an early age) Greaves, “A Causal Mechanism for Childhood Acute Lymphoblastic Leukaemia.”
[33] both produce proteins that are responsible for DNA repair, and also play a role in the formation of oocytes (cells in the ovary) and embryonic development Tuya Pal et.al., “Fertility in Women with BRCA Mutations: A Case-Control Study,” Fertility and Sterility 93, no..6 (April.2010): 1805–8.
[34] BRCA mutations are associated with many other cancers as well “BRCA Mutations: Cancer Risk and Genetic Testing,” National Cancer Institute, February.5, 2018, https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet.
[35] some BRCA mutations are not associated with elevated risk of cancer Melissa.S. Cline et.al., “BRCA Challenge: BRCA Exchange as a Global Resource for Variants in BRCA1 and BRCA2,” PLoS Genetics 14, no..12 (December.2018):e1007752.
[36] many of these women never receive genetic counseling that might help them interpret their results and better understand their risk Allison.W. Kurian et.al., “Gaps in Incorporating Germline Genetic Testing into Treatment Decision-Making for Early-Stage Breast Cancer,” Journal of Clinical Oncology 35, no..20 (July.2017): 2232–39.
[37] there are many possible mutations in the BRCA1 and BRCA2 genes, and some of these mutations contribute to our risk of cancer Cline et.al., “BRCA Challenge.”
[38] BRCA mutations confer a 65–80 percent risk of breast cancer in women who harbor these mutations, compared to a 12–13 percent risk in the general female population Hagit Daum, Tamar Peretz, and Neri Laufer, “BRCA Mutations and Reproduction,” Fertility and Sterility 109, no..1 (January.2018): 33–38.
[39] About 25 percent of BRCA1 mutation carriers are diagnosed with breast cancer before the age of forty, and 72 percent are diagnosed by the age of eighty Karoline.B. Kuchenbaecker et.al., “Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers,” Journal of the American Medical Association 317, no. 23 (June 2017): 2402–16.
[40] BRCA mutations are not limited to women; men with BRCA mutations have increased risk of breast and prostate cancer Daum, Peretz, and Laufer, “BRCA Mutations and Reproduction,” 33–38.
[41] They found that women with BRCA mutations had female ancestors that had more off spring — with an average of 1.9 more offspring compared to the ancestors of women without these BRCA mutations (for women born before 1930 the controls had on average 4.19 offspring, whereas carriers had an average of 6.22 offspring) K..R. Smith et.al., “Effects of BRCA1 and BRCA2 Mutations on Female Fertility,” Proceedings of the Royal Society of London, Series B 279, no..1732 (2011): 1389–95, https://doi.org/10.1098/rspb.2011.1697.
[42] Women with BRCA mutations in this sample had more children (1.8 more on average compared to controls), were less likely to have no children, and had lower rates of miscarriage Fabrice Kwiatkowski et.al., “BRCA Mutations Increase Fertility in Families at Hereditary Breast/Ovarian Cancer Risk,” PloS One 10, no..6 (June.2015): e0127363.
[43] a study of women from the United States and Canada did not find a significant relationship between fertility and BRCA mutations Pal et.al., “Fertility in Women with BRCA Mutations.”
[44] found no evidence of increased fertility in women with BRCA mutations, though the researchers did find that women with BRCA mutations had more female offspring (almost 60 percent females) than women without these mutations (who had just over 50.percent female offspring) Roxana Moslehi et.al., “Impact of BRCA Mutations on Female Fertility and Offspring Sex Ratio,” American Journal of Human Biology 22, no..2 (March.2010): 201–5.
[45] Many of these mutations are associated with increased risk of breast and ovarian cancer — though the risk of cancer varies for the particular mutation and for the particular population Brad Keoun, “Ashkenazim Not Alone: Other Ethnic Groups Have Breast Cancer Gene Mutations, Too,” Journal of the National Cancer Institute 89, no..1 (January.1997): 8–9.
[46] it helps suppress metastasis in breast cancer and melanoma Aktipis et.al., “Modern Reproductive Patterns Associated with Estrogen Receptor Positive but Not Negative Breast Cancer Susceptibility.”
[47] high levels of testosterone are also correlated with higher risk of prostate cancer in the long term L..C. Alvarado, “Do Evolutionary Life-History Trade-Offs Influence Prostate Cancer Risk? A Review of Population Variation in Testosterone Levels and Prostate Cancer Disparities,” Evolutionary Applications 6, no..1 (2013): 117–33.
[48] Cancer defense only paid off when extrinsic mortality (the likelihood of dying from random causes) was low and competitiveness made little difference to reproductive success (when it was not a “winner-take-all” mating system) A..M. Boddy et.al., “Cancer Susceptibility and Reproductive Trade-Offs: A Model of the Evolution of Cancer Defences,” Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences 370, no..1673 (2015), https://doi.org/10.1098/rstb.2014.0220.
[49] Traits like faster cell proliferation, sloppier DNA repair, and more permissive conditions for conception and/or implantation of an embryo can provide an organism-level advantage in terms of reproductive competitiveness, but may come at a cost in terms of cancer susceptibility Boddy et.al., “Cancer Susceptibility and Reproductive Trade-Offs,” 370.
[50] We live with precancerous growth for decades, usually without any prob-lems Greaves, “Does Everyone Develop Covert Cancer?”
[51] our hunter-gatherer ancestors likely invested in their offspring and even grand-offspring for decades after birth K. Hawkes et.al., “Grandmothering, Menopause, and the Evolution of Human Life Histories,” Proceedings of the National Academy of Sciences of the United States of America 95, no..3 (February.1998): 1336–39.
[52] selection for cancer suppression can remain high enough after reproduction to favor cancer suppression mechanisms in old age J..S. Brown and C..A. Aktipis, “Inclusive Fitness Effects Can Select for Cancer Suppression into Old Age,” Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences 370, no..1673 (2015), https://doi.org/10.1098/rstb.2015.0160.
[53] Data from modern hunter-gatherers show that humans in conditions similar to those of our ancestors often live past seventy years old M. Gurven and H. Kaplan, “Longevity among Hunter-Gatherers: A Cross-Cultural Examination,” Population and Development Review 33, no..2 (2007): 321–65, https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1728-4457.2007.00171.x.
[54] we are less likely to die of other causes early in life — like accidents and infections Office for National Statistics, “Causes of Death over 100.Years,” September.18, 2017, https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeath sandmarriages/deaths/articles/causesofdeathover100years/2017-09-18.
[55] In addition to increased risk from more calories and more sedentary behav-ior Véronique Bouvard et al., “Carcinogenicity of Consumption of Red and Processed Meat,” Lancet Oncology 16, no..16 (December.2015): 1599–1600.
[56] thanks to modern conveniences, our life is associated with other exposures like chemical carcinogens “Carcinogens Listed in the Eleventh Report,” in The Report on Carcinogens, 11th.ed. (Durham, NC: National Toxicology Program, U.S. Department of Health and Human Services, 2011), https://web.archive .org/web/20090507123840if_/http://ntp.niehs.nih.gov/ntp/roc/eleventh /known.pdf.
[57] higher levels of reproductive hormones (because of better nutrition Alvarado, “DoEvolutionary Life-History Trade-Offs InfluenceProstateCancer Risk?”
[58] and, for women, more frequent ovulation F. Clavel-Chapelon and E3N Group, “Cumulative Number of Menstrual Cycles and Breast Cancer Risk: Results from the E3N Cohort Study of French Women,” Cancer Causes and Control 13, no..9 (November.2002): 831–38.
[59] and greater disruption to our sleep S. Davis, D..K. Mirick, and R..G. Stevens, “Night Shift Work, Light at Night, and Risk of Breast Cancer,” Journal of the National Cancer Institute 93, no..20 (October.2001): 1557–62.