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Reliable, easy-to-read patient information on common medical conditions — written in plain language, free of jargon, and grounded in current evidence. Browse the most frequent diagnoses, understand what they mean for everyday life, and learn which steps and questions help you have a focused conversation with your doctor.

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Colorectal cancer historical perspective

Introduction

Overview

Overview

The earliest confirmed case of colorectal cancer (CRC) was identified in an ancient Egyptian mummy. Aldred Warthin began studying a cancer-prone kindred (“Family G”) in 1895 and first described it in 1913; this is now recognized as the first Lynch syndrome family.[1] The term “Lynch syndrome” was proposed in 1984 and has replaced “hereditary nonpolyposis colorectal cancer” (HNPCC).[2][3] In 1993–1994, microsatellite instability was discovered and the first mismatch repair (MMR) genes were identified. Fearon and Vogelstein’s 1990 adenoma–carcinoma model established CRC as the paradigm of stepwise genetic carcinogenesis.[4] Organized screening began with the American Cancer Society’s 1980 guideline. In 2018 (ACS) and 2021 (USPSTF), the average-risk screening start age was lowered from 50 to 45 years.[5][6]

Historical Perspective

Historical Perspective

Ancient and Paleopathologic Evidence

  • The earliest confirmed diagnosis of colorectal cancer was made by Michael Zimmerman in an ancient Egyptian mummy from the Dakhleh Oasis, dated to approximately 200–400 CE. This shows that colorectal malignancy is not a purely modern disease.

Hereditary Colorectal Cancer and Lynch Syndrome

  • 1895–1913: Aldred Warthin, a pathologist at the University of Michigan, began studying “Family G” in 1895. His seamstress had predicted that she would die of cancer, as many of her relatives had. Warthin published the kindred in 1913, documenting hereditary clustering of colon, gastric, and endometrial cancers. This was the first documented hereditary cancer predisposition family.[1][2]
  • 1960s–1971: Henry Lynch described additional kindreds and introduced the term “cancer family syndrome.” With Anne Krush, he published an update of Family G in 1971.[2][7]
  • 1984: C. Richard Boland proposed replacing “cancer family syndrome” with the eponym Lynch syndrome (initially Lynch syndrome I and II). The I/II distinction is no longer used.[2][3]
  • “Hereditary nonpolyposis colorectal cancer” (HNPCC) was coined to distinguish the disorder from familial adenomatous polyposis. It is now considered a misnomer, because affected individuals develop a broad spectrum of extracolonic cancers and may have multiple adenomas.[3]
Key milestones in the recognition of Lynch syndrome
Year Milestone
1989 Formation of the International Collaborative Group on HNPCC (ICG-HNPCC), led by Hans Vasen, Jukka-Pekka Mecklin, Meera Khan, and Henry Lynch, to coordinate international family registries and research[1][3]
1990 Amsterdam Criteria I:
• ≥3 relatives with histologically confirmed CRC, one a first-degree relative of the other two
• ≥2 successive generations affected
• ≥1 CRC diagnosed before age 50
• Familial adenomatous polyposis excluded[1][3]
1993–1994 Discovery of microsatellite instability and identification of the first germline MMR genes (MSH2, MLH1), beginning the molecular era of Lynch syndrome. PMS2 and MSH6 were subsequently implicated.[1][8][7]
1998–1999 Amsterdam Criteria II broadened qualifying cancers to include endometrial, small bowel, ureteral, and renal pelvis tumors, to improve sensitivity[3]
Early 2000s ICG-HNPCC merged with the Leeds Castle Polyposis Group to form the International Society for Gastrointestinal Hereditary Tumours (InSiGHT)[3]
2015 onward Mismatch repair deficiency (dMMR)/MSI-high status recognized as a tumor-agnostic predictor of response to immune checkpoint inhibitors, the first histology-independent cancer treatment paradigm[3]
  • Lynch syndrome is now defined molecularly by a pathogenic germline MMR (or EPCAM) variant, rather than by family-history criteria.[8][3]
  • Universal tumor MMR/MSI testing of newly diagnosed CRC, regardless of family history, has replaced reliance on Amsterdam/Bethesda criteria alone for case-finding.[9]

Molecular Pathogenesis of Sporadic Colorectal Cancer

  • 1990: Fearon and Vogelstein published the genetic model of colorectal tumorigenesis (the adenoma–carcinoma sequence). It established CRC as the paradigm for stepwise, multigene solid-tumor carcinogenesis.[4]
    • In this model, normal epithelium progresses to adenoma and then to invasive carcinoma over roughly 10–15 years, through sequential APC inactivation, KRAS activation, and TP53 loss. This is the chromosomal instability (CIN) pathway, which accounts for 70–90% of CRCs.[10][11][12]
  • A distinct serrated neoplasia pathway was recognized later and accounts for 10–20% of CRCs.[10][11][12]
    • It is characterized by BRAF mutation, CpG island methylator phenotype (CIMP), and MLH1 promoter hypermethylation causing sporadic microsatellite instability.
    • These tumors typically arise in the proximal colon of older patients, with female predominance.
    • Recognition of this pathway refined the understanding of proximal versus distal tumor biology.

Evolution of Colorectal Cancer Screening

Milestones in U.S. colorectal cancer screening policy
Year Milestone
1980 First formal American Cancer Society CRC screening guideline[5]
1995 USPSTF endorsement of fecal occult blood testing and flexible sigmoidoscopy[13]
2001 Medicare coverage of screening colonoscopy[13]
Mid-2010s Multitarget stool DNA testing incorporated into screening options[13]
2018 American Cancer Society lowered the average-risk screening start age from 50 to 45 years, citing rising early-onset CRC incidence[5][6]
2021 USPSTF lowered the average-risk screening start age from 50 to 45 years[6][14]
  • Early post-implementation data show increased uptake among adults aged 45–49 years, with persistent gaps in provider recommendation rates.[14]
References

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP (2015). “Milestones of Lynch syndrome: 1895-2015”. Nat Rev Cancer. 15 (3): 181–94. doi:10.1038/nrc3878. PMID 25673086.
  2. ↑ 2.0 2.1 2.2 2.3 Boland CR, Lynch HT (2013). “The history of Lynch syndrome”. Fam Cancer. PMC 3720817. PMID 23546821.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Johannet P, Rousseau B, Aghajanian C, Foote MB, Diaz LA Jr (2025). “Therapeutic targeting of mismatch repair-deficient cancers”. Nat Rev Clin Oncol. 22 (10): 734–59. doi:10.1038/s41571-025-01054-6. PMID 40640471 Check |pmid= value (help).
  4. ↑ 4.0 4.1 Fearon ER, Vogelstein B (1990). “A genetic model for colorectal tumorigenesis”. Cell. 61 (5): 759–67.
  5. ↑ 5.0 5.1 5.2 Wender RC, Brawley OW, Fedewa SA, Gansler T, Smith RA (2019). “A blueprint for cancer screening and early detection: advancing screening’s contribution to cancer control”. CA Cancer J Clin. 69 (1): 50–79. doi:10.3322/caac.21550. PMID 30452086.
  6. ↑ 6.0 6.1 6.2 Sinicrope FA (2022). “Increasing incidence of early-onset colorectal cancer”. N Engl J Med. 386 (16): 1547–58. doi:10.1056/NEJMra2200869.
  7. ↑ 7.0 7.1 Stoffel EM, Boland CR (2015). “Genetics and genetic testing in hereditary colorectal cancer”. Gastroenterology. 149 (5): 1191–1203.e2. doi:10.1053/j.gastro.2015.07.021.
  8. ↑ 8.0 8.1 Peltomäki P, Nyström M, Mecklin JP, Seppälä TT (2023). “Lynch syndrome genetics and clinical implications”. Gastroenterology. 164 (5): 783–99. doi:10.1053/j.gastro.2022.08.058. PMID 36706841 Check |pmid= value (help).
  9. ↑ Monahan K, Hampel H, Stoffel E, Kupfer SS (2025). “In our scope of practice: genetic risk assessment and testing for gastrointestinal cancers and polyposis in gastroenterology”. Gastroenterology. 169 (6): 1147–65. doi:10.1053/j.gastro.2025.06.001. PMID 40484140 Check |pmid= value (help).
  10. ↑ 10.0 10.1 Nguyen LH, Goel A, Chung DC (2020). “Pathways of colorectal carcinogenesis”. Gastroenterology. 158 (2): 291–302. doi:10.1053/j.gastro.2019.08.059. PMID 31622622.
  11. ↑ 11.0 11.1 Brenner H, Kloor M, Pox CP (2014). “Colorectal cancer”. Lancet. 383 (9927): 1490–502. doi:10.1016/S0140-6736(13)61649-9. PMID 24225001.
  12. ↑ 12.0 12.1 Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB (2019). “Colorectal cancer”. Lancet. 394 (10207): 1467–80. doi:10.1016/S0140-6736(19)32319-0.
  13. ↑ 13.0 13.1 13.2 Lieberman D, Ladabaum U, Cruz-Correa M; et al. (2016). “Screening for colorectal cancer and evolving issues for physicians and patients: a review”. JAMA. 316 (20): 2135–45. doi:10.1001/jama.2016.17418.
  14. ↑ 14.0 14.1 Hong YR, Liu-Galvin R, Xie Z (2025). “Association of US Preventive Services Task Force guideline expansion with colorectal cancer screening uptake and recommendations among adults aged 45–49 years”. Gastroenterology. 169 (5): 1036–1038.e2. doi:10.1053/j.gastro.2025.06.004.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Saarah T. Alkhairy, M.D.