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Perspectives PERSPECTIVES The origins of LS TIMELINE The history of LS begins in 1895 with Warthin, a world-renowned pathologist at Milestones of Lynch syndrome: the University of Michigan, USA. Warthin became greatly moved by the story of his 1895–2015 seamstress, who attributed her depression to the many deaths throughout her family due to cancer, particularly of the colorec- Henry T. Lynch, Carrie L. Snyder, Trudy G. Shaw, Christopher D. Heinen and tum, stomach and uterus. Warthin began Megan P. Hitchins documenting her medical and cancer family history, as well as the pathology findings Abstract | Lynch syndrome, which is now recognized as the most common of cancer in the family. He assembled her hereditary colorectal cancer condition, is characterized by the predisposition to a pedigree, which he called Family G, along spectrum of cancers, primarily colorectal cancer and endometrial cancer. with two other cancer-prone pedigrees from We chronicle over a century of discoveries that revolutionized the diagnosis and records at the University of Michigan School clinical management of Lynch syndrome, beginning in 1895 with Warthin’s of Medicine and, in 1913, published his find- ings1. He also noted that transmission of observations of familial cancer clusters, through the clinical era led by Lynch and the cancer phenotype within these families the genetic era heralded by the discovery of causative mutations in mismatch was consistent with Mendel’s proposal of repair (MMR) genes, to ongoing challenges. autosomal dominant inheritance2. He con- tinued to follow Family G, and an update More than 100 hereditary cancer-prone syn- homologue 1 (MLH1), mutS homologue 2 was published in the mid‑1930s by Warthin’s dromes have been discovered, and many of (MSH2), MSH6 or postmeiotic segrega- colleagues Hauser and Weller3. The reports these harbour well-defined cancer-causing tion increased 2 (PMS2) — which result in on Family G were one of the first compre- germline mutations. Observational stud- loss of function of the encoded protein. In hensive recorded observations of the familial ies in cancer-prone families have enabled LS‑associated cancers, which arise following clustering of cancer, which laid the founda- clinicians, molecular geneticists and genetic the somatic loss of function of the remaining tion for the discovery of an inherited genetic counsellors to identify individuals who are wild-type allele of the affected MMR gene, basis to cancer and the disease now referred at enormous lifetime risk of developing can- downstream genetic mutations accumulate. to as LS. cer and to offer cancer prevention surveil- These cancers typically manifest micro­ In 1962, during his internal medicine res- lance, whereas family members without the satellite instability (MSI) — alterations in the idency, Henry Lynch encountered a patient causative mutation have general population length of tandem repeats within microsatel- from Nebraska with a family history similar risk for the syndrome-associated cancers. lite repeat regions — a molecular phenotype to that of Warthin’s seamstress. The proband, The knowledge accrued from studying that is a direct consequence of impaired while recovering from delirium tremens, told affected families has laid the foundation for MMR activity. Our current understanding of Lynch that he drank because he was con- population-based screening to identify those this cancer-prone condition has culminated vinced that he would die of colorectal cancer at the highest risk of cancer. Genetic coun- from more than a century of multidiscipli- (CRC), as “everybody” in the family died selling will be key to the clinical translation nary discoveries from observational studies of this disease. Lynch completed a detailed of the research. in affected families; pathology and molecu- family history, which showed excessive One of the first of these hereditary lar studies of their cancers; basic biology cases of CRC transmitted through multiple cancer-prone syndromes to be recognized, studies of the MMR system; and molecular generations. Lynch’s immediate thoughts Lynch syndrome (LS), is also one of the most genetic and epigenetic studies. Our objective focused on familial adenomatous polypo- prevalent. LS is now firmly established as an in this Timeline article is to describe the sis (FAP), as heretofore this was the most inherited condition of defective DNA mis- history of LS and chart the major contribu- favoured diagnosis of CRC-prone families. match repair (MMR) — the post-replicative tions that have collectively transformed the However, an intensive review of medical and proofreading and editing system that ensures clinical management of affected families, pathology records of family members failed genome integrity. LS is defined as the predis- from Aldred Warthin’s original discoveries to show evidence of multiple colonic adeno- position to a spectrum of cancers, primarily that particular cancers cluster in the family mas, a hallmark of FAP. Therefore, Lynch of the colorectum and endometrium, which of his seamstress in 1895 to the present day questioned whether this could be an unde- exhibit impaired MMR activity. This can- (FIG. 1). Looking ahead, we present some scribed syndrome with a segregating pattern cer predisposition is caused by autosomal of the challenges faced by the community of of CRC predisposition that is consistent with dominant heterozygous germline mutations LS patients, clinical management teams and an autosomal dominant mode of genetic in one of the four key MMR genes — mutL researchers, which warrant further research. transmission but without the presence of the NATURE REVIEWS | CANCER VOLUME 15 | MARCH 2015 | 181 © 2015 Macmillan Publishers Limited. All rights reserved PERSPECTIVES • MSI described in LS tumours34 and • Accelerated carcinogenesis • Advantage of subtotal colectomy shown to be due to MMR deficiency37 described38 Survival advantage of • Evidence for over segmental resection shown in • MSH2 identified as first LS locus45–48 • AFAP described185 LS-associated CRC compared prophylactic • Call for universal LS: reduction of synchronous and 179 • Human MSH2–MSH6 with sporadic CRC41 • Listing of LS gynaecological testing of CRC metachronous CRC heterodimer shown to bind to mutations surgery174 for LS; 1 in 35 of • MSH2 and MLH1 shown to have Prevalence of Muir–Torre Increased instability at DNA mismatches195,196 published198 • Heritability of CRCs are LS133 synthetically lethal interactions with Warthin Lynch publishes proximal colonic syndrome microsatellite repeats • Increased instability observed in Amsterdam II First case of MLH1 • Bethesda MSH2 • Recommendation BER DNA polymerases167 begins study pedigrees of tumours in LS identified as a observed in MMR-mutant simple repeat sequences within Criteria epimutation Guidelines epimutation for urological of Family G Families N and M4 described13 variant of CFS18 bacterial strains31 TGFBR2 in MSI+ tumours103 published24 identified74 revised27 shown80 screening in LS17 Excess polyps shown in LS10 1895 1913 1966 1971 1977 1978 1981 1984 1987 1991 1993 1994 1995 1997 1998 1999 2000 2002 2003 2004 2005 2006 2007 2008 2009 2010 2013 2014 Warthin CSF terminology Recommendation HNPCC9 and • Early description of extracolonic • MSH6 identified as • Conversion of diploidy Status risk • FCC-X described186,188 • Heritability of MLH1 EPCAM deletion • Standardized 5-tiered publishes study coined7 of prophylactic Lynch tumour spectrum in LS194 LS locus53 to haploidy identifies change due • Reconstitution of epimutation shown199 identified as an system for classification on Family G1 gynaecological syndrome8 • Amsterdam I Criteria published23 • Bethesda Guidelines the causative to genetic human MMR • X-ray crystal structure underlying cause of pathogenicity of surgery173 terminologies published26 mutation in Family G63 testing197 reaction82,83 of MSH2–MSH6 of MSH2 MMR variants145 coined • MLH1 and PMS2 identified as LS loci49–51 • Silencing of MLH1 • First extended study • MMR-deficient human complex bound to epimutation81 • Technology use in • Pathology of LS-associated CRC by promoter shows efficacy of cells shown to have DNA mismatch genetic counselling described40 hypermethylation colonoscopy in LS172 increased resistance solved146 summarized193 • Full colonoscopy to cecum reported in sporadic to 5-FU159 recommended14 MSI+ cancers137 Figure 1 | Historical timeline of LS. 5‑FU, 5‑fluorouracil; AFAP, attenuated familial adenomatous polyposis; BER, base excision repair; CFS, cancer family syndrome; CRC, colorectal cancer; EPCAM, epithelial cell adhesion molecule; FCC‑X, familial colorectal cancer type X; HNPCC, hereditary non-polyposis colorectal cancer; LS, Lynch syndrome; MLH1, mutL homologue 1; MMR, mismatch repair; MSH, mutS homologue; MSI, microsatellite instability; PMS2, postmeiotic segregation increased 2; TGFBR2, transforming growth factor‑β type II receptor. Nature Reviews | Cancer multiple colonic adenomas found in FAP. The term CFS was coined in 1971 to incidence of adenomas in patients with LS. Soon after, other cancers, particularly of the describe this familial clustering of can- By consensus, this cancer predisposition endometrium, were recognized as syndro- cers7. However, despite these and numer- syndrome is now referred to as LS11,12. mal throughout this family, which Lynch ous subsequent reports of comparable labelled Family N (for Nebraska). cancer-prone families, which consistently Clinicopathological features of LS Marjorie Shaw of the University of showed an autosomal
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