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Adv."],"published-print":{"date-parts":[[2026,9,4]]},"abstract":"<jats:p>Understanding when key mutations occur in cancer is critical for prevention and detection, especially for early-onset cancers that have risen in recent years. Yet, intermediate mutational steps remain difficult to observe. Here, we extend a tumor kinetic model and combine it with long-term cancer registry data to estimate mutational timelines. Using differential equation systems to represent sequential carcinogenic stages and a convolution-based method, we derive and estimate the expected ages of mutational transitions for breast, colorectal, and thyroid cancers. Model results suggest early-life initiations across all cancers. Malignant transitions occur \u223c10 years earlier in early- vs late-onset breast and colorectal cancers (late 30s versus late 40s to 50s), while thyroid cancer shows similarly early transitions (late 20s) regardless of onset age. Across cohorts (1950\u20131954, 1965\u20131969, and 1980\u20131984), more recent cohorts show accelerated progression and earlier malignancy. These findings can inform early-onset cancer etiologic studies and intervention strategies.<\/jats:p>","DOI":"10.1126\/sciadv.aec2357","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:59:26Z","timestamp":1788371966000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Estimating the carcinogenesis timelines in early-onset versus late-onset cancers and changes across birth cohorts"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0971-0514","authenticated-orcid":true,"given":"Navid Mohammad","family":"Mirzaei","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7555-9728","authenticated-orcid":true,"given":"Wan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA."},{"name":"Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University Irving Medical Center, New York, NY, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00672-8"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602297"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1539-6924.1988.tb00502.x"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-25-0186"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2198"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1177\/0272989X11408730"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1177\/0272989X17741634"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1914589117"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1907-7"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1421839112"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.EJ17-0026"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2013.0367"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2019.07.006"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.4331\/wjbc.v14.i2.13"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-6684-z"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.36358"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00330-024-10740-5"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(20)30401-0"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canep.2021.102014"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.2719"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000148"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01233-9"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020107271"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1553"},{"key":"e_1_3_2_26_2","first-page":"1000165","article-title":"Genomic instability and cancer","volume":"5","author":"Yao Y.","year":"2014","unstructured":"Y. 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