Our concept of cancer latency, the interval from when a cancer starts until it is diagnosed, has changed dramatically. A prior widely-used definition was the interval between an exposure to a cancer-causing substance and cancer diagnosis. However, this definition does not accurately reflect current knowledge of how most cancers develop assuming, mostly incorrectly, one exposure is the sole cause of a cancer, ignoring the possibility the cancer being considered would have developed anyway but that the exposure accelerated cancer development and eliding the randomness in when a cancer is diagnosed. We show, using chronic myeloid leukaemia as a model, that defining cancer latency is not as simple as it once seemed. It is difficult or impossible to know at which event or mutation to start to clock to measure cancer latency. It is equally difficult to know when to stop the clock given the stochastic nature of when cancers are diagnosed. Importantly, even in genetically-identical twins with the same driver mutation intervals to develop cancer vary substantially. And we discuss other confonders. Clearly we need a new definition of cancer latency or we need to abandon the concept of cancer latency in the modern era of cancer biology.
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Nadler DL, Zurbenko IG. Developing a Weibull Model extension to estimate cancer latency. Int Sch Res Notices. 2013:Article ID: 750857. https://doi.org/10.5402/2013/750857.
Bejar R. CHIP, ICUS, CCUS and other four-letter words. Leukemia. 2017;31:1869–71.
Ezoe S. Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor. Int J Environ Res Public Health. 2012;9:2444–53.
Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016;538:378–82.
Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993;4:138–41.
The Cancer Genome Atlas Research Network. Genomic epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.
The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519–25.
The Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. 2015. https://doi.org/10.1016/j.Cell.2015.10.025.
The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.
Goldman JM, Melo JV. Chonic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451–64.
Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824–30.
Dreazon O, Canaani E, Gale RP. Molecular biology of chronic myelogenous leukemia. Semin Hematol. 1988;1:35–48.
Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315:550–4.
Apperley JF. Chronic myeloid leukaemia. Lancet. 2015;385:1447–59.
Deininger MW, Goldman JM, Melo V. The molecular biology of chronic myeloid leukemia. Blood. 2000;96:3343–56.
Bose S, Deininger M, Gora-Tybor J, Goldman JM, Melo JV. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood. 1998;92:3362–7.
Biernaux C, Loos M, Sels A, Hues G, Stryckmans P. Detection of major Bcr-Abl gene expression at a very love lewel in blood cells of some healthy individuals. Blood. 1995;86:3118–22.
Kuan JW, Su AT, Leong CF, Osato M, Sahida G. Systematic reciew of normal subjects harboring BCR-ABL1 fusion gene. Acta Haematol. 2020;143:96–111.
Fialkow PJ, Martin PJ, Najfeld V. Evidence of a multi-step pathogenesis of chronic myelogenous leukemia. Blood. 1982;58:158–63.
Schmidt M, Rinke J, Schäfer V, Schnittger S, Kohlman A, Obstfelder E. et al. Molecular-definded clonal evolution in patients with chronic myeloid leukemia independent of teh BCR-ABL status. Leukemia. 2014;28:2292–9.
Hsu WL, Preston DL, Soda M, Sugiyama H, Funamoto S, Kodoma K, et al. The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950–2001. Radiat Res. 2013;179:361–82.
Corso A, Lazzarino M, Morra E, Merante S, Astori C, Berensconi P, et al. Chronic myelogenous leukemia and exposure to ionizing radiation—a retrospective study of 443 patients. Ann Hematol. 1995;70:79–82.
Smith PG, Doll R. Mortality among patients with ankylosing spondylitis after a single treatrment course with x rays. Br Med J (Clinc Res Ed). 1982;28:449–60.
Rinke ET, Hagen J, Dmytrenko I, Hochhaus A, Dyagli I. Molecular-defined clonal evolution in patients with chronic myeloid leukemia who were exposed to ionizing radiation following the Chernobyl nuclear disaster. Leukemia. 2020;34:645–50.
Gunes AM, Millot F, Kalwak K, Lausen B, Sedlacek P, Verslujis B, et al. Features and outcome of chronic myeloid leukemia (CML) at very young age: data from the International Pediatric CML Registry (I-CML-Ped Study). Blood. 2018;132(Suppl 1):1748.
Score J, Calasanz MJ, Ottman O, Pane F, Yeh RF, Sobrinho-Simões MA, et al. Analysis of genomic breakpoints in p190 and p210 BCR-ABL indicate distinct mechanisms of formation. Leukemia. 2010;24:1742–50.
Biondi A, Gandemer V, De Lorenzo P. Imatinib treatment of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (EsPhALL2010): a prospective, intergroup, open-label, single-arm clinical trial. The Lancet Hematol. 2018;5:e641–52.
Hijiya N, Schultz KR, Metzler M, Millot F, Suttorp M. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach. Blood. 2016;127:392–9.
Tasian SK, Lohl ML, Hunger SP. Philadelphia chromosome-like acute lymphoblastic leukemia. Blood. 2017;130:2064–72.
Aye L, Loghavi S, Yound KH, Siddiq I, Yin CC, Routhort MJ, et al. Preleukemic phase of chronic myelogenous leukemia: morphilogic and immunohistochemical characterization of 7 cases. Ann Diagn Pathol. 2016;21:53–8.
Hudnall SD, Northup J, Panova N, Suleman K, Velagaleti G. Prolonged preleukemic phase of chronic myelogenous leukemia. Exp Mol Pathol. 2007;83:484–9.
Bennett JM, Dsouza KG, Patel M, O’Dwyer K. “Preleukemic or smoldering” chronic myelogenous leukemia (CML): BCR-ABL1 positive: a brief case resport. Leuk Res Rep. 2014;4:12–4.
Clarkson B, Strife A, Wisniewski D, Lambek CL, Liu C. Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies. Leukemia. 2003;17:1211–62.
Gale RP, Apperley J. What does chronic myeloid leukaemia tell us about other leukaemias? Curr Hematol Malig Rep. 2019;14:477–9.
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzer KW. Cancer genome landscapes. Science. 2013;339:1546–58.
Ortman CA, Kent DG, Nagalia J, Silber Y, Wedge DC, Grinfield J, et al. Effect of mutation order on myeloproliferative neoplasms. N Engl J Med. 2015;372:601–12.
Kent DG, Green AR. Order matters: the order of somatic mutations infucences cancer evolution. Cold Spring Harbor Perspect Med. 2017;7:a027060.
Grasveld JL, Vana DW, Rscoruia FJ, McGuire W, West KW. Pancreatic tumors in children: analysis of 13 cases. J Pediatr Surg. 1990;25:1057–62.
Yu DC, Grabowski MJ, Kozakewich HP, Perez-Atayde AR, Voss SD, Shamberger RC, et al. Primary lung tumors in children and adolescents: a 90-year experience. Pediatr Surg. 2010;45:1090–5.
Kazakov VS, Demidchik EP, Astakhova LN. Thyroid cancer after Chernobyl. Nature. 1992;359:21.
Baverstock K, Egloff B, Pinchera A, Ruchti C, Williams D. Thyroid cancer after Chernobyl. Nature. 1992;359:21–2.
Greaves MF, Maia AT, Wiemels JL, Ford AM. Leukemia in twins: lessons in natural history. Blood. 2003;102:2321–33.
Greaves M. A causal mechanism for childhood acute lymphoblastic leukaemia. Nat Rev Cancer. 2018;18:471–84.
Gale KB, Ford AM, Repp R, Borkhardt A, Keller C, Eden OB, et al. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc Natl Acad Sci USA. 1997;94:13950–4.
Cazzaniga G, van Delft FW, Nigro LL, Ford AM, Score J, Iacobucci I, et al. Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia. Blood. 2011;118:5559–65.
Alpar D, Wren D, Ermini L, Mansur MB, van Delft FW, Bateman CM, et al. Clonal origins of ETV6-RUNX1+ acute lymphoblastic leukemia: studies in monozygotic twins. Leukemia. 2015;29:839–46.
KMS is funded by the Leukemia & Lymphoma Society Translational Research Program (6587-20), Cure Childhood Cancer, Hyundai Hope on Wheels, Pediatric Cancer Research Foundation, Stanford SPARK program, and Stanford Maternal Child Health Research Institute. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.
Conflict of interest
NH and NCPC are consultants for Novartis and Incyte.
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Abecasis, M., Cross, N.C.P., Brito, M. et al. Is cancer latency an outdated concept? Lessons from chronic myeloid leukemia. Leukemia 34, 2279–2284 (2020). https://doi.org/10.1038/s41375-020-0957-z