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Milestones of Lynch syndrome: 1895–2015

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.

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Figure 1: Historical timeline of LS.
Figure 2: Molecular mechanism of MSI.
Figure 3: CRC development in individuals with LS.
Figure 4: Pedigree of an LS family.

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Acknowledgements

This work was supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. H.T.L.'s work is partially funded through the Charles F. and Mary C. Heider Chair in Cancer Research, which he holds at Creighton University. The Creighton work also receives funding from “Kicks for a Cure”. The authors appreciate the intense and constant help provided by LS patients and their families. This clearly has made their research possible.

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PowerPoint slides

Glossary

Consanguineous

Related by blood, such as in a marriage between cousins.

Constitutional epimutation

An epigenetic aberration within normal somatic cells that predisposes to disease but neither precludes nor dictates that its origin is in the germ line or that it is distributed evenly throughout somatic tissues.

Delirium tremens

A condition in which an individual with chronic alcoholic history exhibits neurodegenerative features, which include occasional hallucination, fever and other neuroderangement.

Founder mutations

Mutations that are common to multiple families within a given population, with one or more ancestors carrying the mutation.

Muir–Torre syndrome

A variant of Lynch syndrome characterized by cutaneous signs (sebaceous adenomas and carcinomas, as well as multiple keratoacanthomas).

Mutator phenotype

A cancer with a high burden of somatic mutations across the genome (>12 mutations per 106 bases).

Neurofibromatosis

An autosomal dominant inherited syndrome with neurofibromin 1 (NF1) mutation and the presence of neuropathological findings of gliomas, neuroblastomas, 'café au lait' spots and multiple neurofibromas.

Proband

The key family member who is cooperative with respect to his or her diagnosis and who is a signature member of the cancer-prone family.

Signet cell features

Features of signet ring cells, which have intracytoplasmic mucin-filled vacuoles that cause lateral displacement of the nuclei.

Reflex testing

As performed in the context of colorectal cancer (CRC), the automatic testing of all incidence of CRC for microsatellite instability and/or immunohistochemical loss of mismatch repair activity in order to identify cases that warrant mutation testing for Lynch syndrome.

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Lynch, H., Snyder, C., Shaw, T. et al. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer 15, 181–194 (2015). https://doi.org/10.1038/nrc3878

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