{
  "cutoff": "2026-10-13",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "22056504",
      "year": "2011",
      "title": "Measured body mass index in adolescence and the incidence of colorectal cancer in a cohort of 1.1 million males.",
      "doi": "10.1158/1055-9965.EPI-11-0531",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22056504/",
      "interpretation": "Measured adolescent BMI linked prospectively to later colon risk; exposure age and diagnosis age remain distinct."
    },
    {
      "pmid": "21559014",
      "year": "2011",
      "title": "Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes.",
      "doi": "10.1038/bjc.2011.172",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21559014/",
      "interpretation": "Early-adult BMI associations occur in mismatch-repair carriers and noncarriers; hereditary ascertainment remains separate."
    },
    {
      "pmid": "25777804",
      "year": "2015",
      "title": "Early life body fatness and risk of colorectal cancer in u.s. Women and men-results from two large cohort studies.",
      "doi": "10.1158/1055-9965.EPI-14-0909-T",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25777804/",
      "interpretation": "Early-life fatness associations differ by sex in two cohorts and mainly later-life outcomes."
    },
    {
      "pmid": "25986947",
      "year": "2016",
      "title": "Adolescent body mass index and erythrocyte sedimentation rate in relation to colorectal cancer risk.",
      "doi": "10.1136/gutjnl-2014-309007",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25986947/",
      "interpretation": "Measured adolescent BMI and inflammatory ESR predict later CRC in Swedish men."
    },
    {
      "pmid": "27427428",
      "year": "2016",
      "title": "Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer.",
      "doi": "10.1093/ije/dyw129",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27427428/",
      "interpretation": "Adult-adiposity MR supports a broader CRC causal link rather than an age-specific intervention effect."
    },
    {
      "pmid": "27978560",
      "year": "2017",
      "title": "Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.",
      "doi": "10.1001/jamaoncol.2016.5194",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27978560/",
      "interpretation": "Unselected EOCRC germline testing finds a real susceptibility subgroup without explaining a secular trend."
    },
    {
      "pmid": "28803329",
      "year": "2017",
      "title": "Childhood body mass index and height in relation to site-specific risks of colorectal cancers in adult life.",
      "doi": "10.1007/s10654-017-0289-0",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28803329/",
      "interpretation": "Measured childhood BMI is associated with adult colon, but not rectal, cancer."
    },
    {
      "pmid": "30326010",
      "year": "2019",
      "title": "Association of Obesity With Risk of Early-Onset Colorectal Cancer Among Women.",
      "doi": "10.1001/jamaoncol.2018.4280",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30326010/",
      "interpretation": "NHSII directly observes a prospective adiposity gradient for CRC before50 in women."
    },
    {
      "pmid": "32106218",
      "year": "2020",
      "title": "Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli.",
      "doi": "10.1038/s41586-020-2080-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32106218/",
      "interpretation": "Isogenic-control human organoid exposure identifies a colibactin mutation signature matching human tumors."
    },
    {
      "pmid": "33327948",
      "year": "2020",
      "title": "Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.",
      "doi": "10.1186/s12916-020-01855-9",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33327948/",
      "interpretation": "Sex/site-specific adult-adiposity MR supports overall CRC causality under instrument assumptions."
    },
    {
      "pmid": "33037055",
      "year": "2021",
      "title": "Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer.",
      "doi": "10.1136/gutjnl-2020-321661",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33037055/",
      "interpretation": "Claims-based metabolic syndrome associates with EOCRC but does not isolate adiposity."
    },
    {
      "pmid": "34273347",
      "year": "2021",
      "title": "The Sulfur Microbial Diet Is Associated With Increased Risk of Early-Onset Colorectal Cancer Precursors.",
      "doi": "10.1053/j.gastro.2021.07.008",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34273347/",
      "interpretation": "A sulfur-microbial dietary score associates with early adenomas, not a direct clinical cancer outcome."
    },
    {
      "pmid": "35029165",
      "year": "2022",
      "title": "Antibiotic Therapy and Risk of Early-Onset Colorectal Cancer: A National Case-Control Study.",
      "doi": "10.14309/ctg.0000000000000437",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35029165/",
      "interpretation": "Large Swedish antibiotic analysis finds no conclusive overall EOCRC association."
    },
    {
      "pmid": "34914944",
      "year": "2022",
      "title": "Associations of Body Mass Index at Different Ages With Early-Onset Colorectal Cancer.",
      "doi": "10.1053/j.gastro.2021.12.239",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34914944/",
      "interpretation": "German early-adult obesity associations use a<55 outcome threshold."
    },
    {
      "pmid": "36869385",
      "year": "2023",
      "title": "Identification of specific susceptibility loci for the early-onset colorectal cancer.",
      "doi": "10.1186/s13073-023-01163-w",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36869385/",
      "interpretation": "Age-specific susceptibility GWAS does not constitute MR of adiposity."
    },
    {
      "pmid": "38552658",
      "year": "2024",
      "title": "Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.",
      "doi": "10.1016/S1470-2045(24)00026-3",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38552658/",
      "interpretation": "Inherited repair deficiency establishes a distinct high-risk early-cancer context."
    },
    {
      "pmid": "39506107",
      "year": "2024",
      "title": "Colibactin-driven colon cancer requires adhesin-mediated epithelial binding.",
      "doi": "10.1038/s41586-024-08135-z",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39506107/",
      "interpretation": "Adhesin perturbation narrows a colibactin carcinogenic mechanism in a predisposed mouse model."
    },
    {
      "pmid": "40267983",
      "year": "2025",
      "title": "Geographic and age variations in mutational processes in colorectal cancer.",
      "doi": "10.1038/s41586-025-09025-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40267983/",
      "interpretation": "Human genomic signatures link historical colibactin mutagenesis with younger tumors, distinct from current bacteria."
    },
    {
      "pmid": "41191353",
      "year": "2025",
      "title": "Epidemiological Classification Changes and Incidence of Early-Onset Colorectal Cancer.",
      "doi": "10.1001/jamanetworkopen.2025.41732",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41191353/",
      "interpretation": "Histological reclassification contributes materially to some local young-age incidence trends."
    },
    {
      "pmid": "39587448",
      "year": "2025",
      "title": "Body mass index at birth and early life and colorectal cancer: A two-sample Mendelian randomization analysis in European and East Asian genetic similarity populations.",
      "doi": "10.1111/ijpo.13186",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39587448/",
      "interpretation": "Early-childhood BMI MR is near-null for all-age CRC, distinguishing timing from adult adiposity."
    },
    {
      "pmid": "41422343",
      "year": "2026",
      "title": "A prospective investigation of early-onset colorectal cancer risk factors-pooled analysis of three large-scale European cohorts.",
      "doi": "10.1038/s41416-025-03303-y",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41422343/",
      "interpretation": "Pooled European cohort establishes sex/site heterogeneity but defines early onset as<55."
    },
    {
      "pmid": "42610385",
      "year": "2026",
      "title": "Traditional Risk Factors Are Not Associated with the Rise of Early-Onset Colorectal Cancer: An All of Us Study.",
      "doi": "10.1097/DCR.0000000000004351",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42610385/",
      "interpretation": "AllofUs shows no age-specific BMI interaction; this is not proof of a zero overall effect."
    },
    {
      "pmid": "41231486",
      "year": "2026",
      "title": "Ultraprocessed Food Consumption and Risk of Early-Onset Colorectal Cancer Precursors Among Women.",
      "doi": "10.1001/jamaoncol.2025.4777",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41231486/",
      "interpretation": "UPF association concerns early conventional adenomas and not serrated lesions."
    }
  ],
  "gaps": [
    "A causal-instrument estimate matching strictly under50 CRC and timed prediagnostic adiposity.",
    "Absolute risk and effect heterogeneity by sex, site, ancestry and inherited background without outcome-defined scopes.",
    "Distinguishing childhood adiposity effects from persistent adult exposure and correlated diet/activity.",
    "A valid population decomposition of how much adiposity contributes to secular incidence, separating detection and histological classification.",
    "Independent diet, antibiotic-class/timing and specific microbial exposure causal tests; precursor outcomes and diagnostic signatures remain separate.",
    "Mechanism-specific prevention consequences in humans, without transferring susceptible-mouse or transplanted progression results to spontaneous young-age initiation."
  ],
  "decisive_experiment": "A preregistered consortium analysis combining measured repeated adiposity before diagnosis with an age-stratified valid genetic/natural-experiment design, explicitly reporting colorectal cancer diagnosed before50 and separating adult from childhood exposure, sex, colon/rectum, ancestry, hereditary syndromes and screening/diagnostic contact."
}