Milestones of Lynch Syndrome: 1895-2015

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2015 Feb 13

PMID 25673086

Citations 363

Authors

Henry T Lynch

Carrie L Snyder

Trudy G Shaw

Christopher D Heinen

Megan P Hitchins

Affiliations

Soon will be listed here.

Abstract

Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.

Citing Articles

The impact of integrated genomic analysis on molecular classifications and prognostic risk stratification in endometrial cancer: a Chinese experience.

Zheng Q, Shao D, Shu J, Zhang Q, Huang M, Wang D Front Oncol. 2025; 15:1541562.

PMID: 39980551 PMC: 11839450. DOI: 10.3389/fonc.2025.1541562.

DMMR status and synchronous lesions predicts metachronous lesions after curative resection for rectal cancer.

Chen X, Chen J, Xu L, Lin D, Hong X, Peng J Front Surg. 2025; 12:1510400.

PMID: 39906700 PMC: 11790672. DOI: 10.3389/fsurg.2025.1510400.

Frequency and Molecular Characteristics of Mismatch Repair-deficient Status among Multiple Synchronous Colorectal Cancers.

Chikatani K, Chika N, Tanabe N, Mori Y, Suzuki O, Matsuyama T J Anus Rectum Colon. 2025; 9(1):145-155.

PMID: 39882230 PMC: 11772799. DOI: 10.23922/jarc.2024-092.

The mismatch repair factor Mlh1-Pms1 uses ATP to compact and remodel DNA.

Collingwood B, Bhalkar A, Manhart C bioRxiv. 2025; .

PMID: 39868200 PMC: 11760735. DOI: 10.1101/2025.01.16.633381.

Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences.

Moller P, Ahadova A, Kloor M, Seppala T, Burn J, Haupt S Hered Cancer Clin Pract. 2025; 23(1):3.

PMID: 39849512 PMC: 11755794. DOI: 10.1186/s13053-025-00305-y.

References

Douglas J, Gruber S, Meister K, Bonner J, Watson P, Krush A . History and molecular genetics of Lynch syndrome in family G: a century later. JAMA. 2005; 294(17):2195-202. DOI: 10.1001/jama.294.17.2195. View

Charbonnier F, Olschwang S, Wang Q, Boisson C, Martin C, Buisine M . MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res. 2002; 62(3):848-53. View

Church J . Prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer. Ann Med. 1996; 28(6):479-82. DOI: 10.3109/07853899608999111. View

Scaife C, Rodriguez-Bigas M . Lynch syndrome: implications for the surgeon. Clin Colorectal Cancer. 2003; 3(2):92-8. DOI: 10.3816/CCC.2003.n.015. View

Bartley A, Parikh N, Hsu C, Roe D, Buckmeier J, Corley L . Colorectal adenoma stem-like cell populations: associations with adenoma characteristics and metachronous colorectal neoplasia. Cancer Prev Res (Phila). 2013; 6(11):1162-70. PMC: 4079278. DOI: 10.1158/1940-6207.CAPR-13-0113. View

Jones N, Vogt S, Nielsen M, Christian D, Wark P, Eccles D . Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology. 2009; 137(2):489-94, 494.e1. DOI: 10.1053/j.gastro.2009.04.047. View

Braun M, Richman S, Quirke P, Daly C, Adlard J, Elliott F . Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol. 2008; 26(16):2690-8. DOI: 10.1200/JCO.2007.15.5580. View

Wijnen J, van der Klift H, Vasen H, Khan P, Menko F, Tops C . MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet. 1998; 20(4):326-8. DOI: 10.1038/3795. View

Wimmer K, Etzler J . Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?. Hum Genet. 2008; 124(2):105-22. DOI: 10.1007/s00439-008-0542-4. View

10.

Lynch H, Riegert-Johnson D, Snyder C, Lynch J, Hagenkord J, Boland C . Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. Am J Gastroenterol. 2011; 106(10):1829-36. PMC: 3805505. DOI: 10.1038/ajg.2011.203. View

11.

Vaughn C, Baker C, Samowitz W, Swensen J . The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene. Genes Chromosomes Cancer. 2012; 52(1):107-12. DOI: 10.1002/gcc.22011. View

12.

Al-Tassan N, Chmiel N, Maynard J, Fleming N, Livingston A, Williams G . Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet. 2002; 30(2):227-32. DOI: 10.1038/ng828. View

13.

Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed J . Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997; 275(5302):967-9. DOI: 10.1126/science.275.5302.967. View

14.

Hemminki A, Peltomaki P, Mecklin J, Jarvinen H, Salovaara R, Nystrom-Lahti M . Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet. 1994; 8(4):405-10. DOI: 10.1038/ng1294-405. View

15.

Vasen H, Wijnen J, Menko F, Kleibeuker J, Taal B, Griffioen G . Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996; 110(4):1020-7. DOI: 10.1053/gast.1996.v110.pm8612988. View

16.

Farabaugh P, Schmeissner U, Hofer M, Miller J . Genetic studies of the lac repressor. VII. On the molecular nature of spontaneous hotspots in the lacI gene of Escherichia coli. J Mol Biol. 1978; 126(4):847-57. DOI: 10.1016/0022-2836(78)90023-2. View

17.

Kastrinos F, Mukherjee B, Tayob N, Wang F, Sparr J, Raymond V . Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009; 302(16):1790-5. PMC: 4091624. DOI: 10.1001/jama.2009.1529. View

18.

Jass J . Hereditary Non-Polyposis Colorectal Cancer: the rise and fall of a confusing term. World J Gastroenterol. 2006; 12(31):4943-50. PMC: 4087395. DOI: 10.3748/wjg.v12.i31.4943. View

19.

Heinen C, Rasmussen L . Determining the functional significance of mismatch repair gene missense variants using biochemical and cellular assays. Hered Cancer Clin Pract. 2012; 10(1):9. PMC: 3434035. DOI: 10.1186/1897-4287-10-9. View

20.

Fishel R, Kolodner R . Identification of mismatch repair genes and their role in the development of cancer. Curr Opin Genet Dev. 1995; 5(3):382-95. DOI: 10.1016/0959-437x(95)80055-7. View