Lynch syndrome: an updated review

Rishabh Sehgal, Kieran Sheahan, Patrick R O'Connell, Ann M Hanly, Sean T Martin, Desmond C Winter, Rishabh Sehgal, Kieran Sheahan, Patrick R O'Connell, Ann M Hanly, Sean T Martin, Desmond C Winter

Abstract

Lynch syndrome is one of the most common cancer susceptibility syndromes. Individuals with Lynch syndrome have a 50%-70% lifetime risk of colorectal cancer, 40%-60% risk of endometrial cancer, and increased risks of several other malignancies. It is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. In a subset of patients, Lynch syndrome is caused by 3' end deletions of the EPCAM gene, which can lead to epigenetic silencing of the closely linked MSH2. Relying solely on age and family history based criteria inaccurately identifies eligibility for Lynch syndrome screening or testing in 25%-70% of cases. There has been a steady increase in Lynch syndrome tumor screening programs since 2000 and institutions are rapidly adopting a universal screening approach to identify the patients that would benefit from genetic counseling and germline testing. These include microsatellite instability testing and/or immunohistochemical testing to identify tumor mismatch repair deficiencies. However, universal screening is not standard across institutions. Furthermore, variation exists regarding the optimum method for tracking and disclosing results. In this review, we summarize traditional screening criteria for Lynch syndrome, and discuss universal screening methods. International guidelines are necessary to standardize Lynch syndrome high-risk clinics.

References

    1. Hampel H., Frankel W.L., Martin E., Arnold M., Khanduja K., Kuebler P., Clendenning M., Sotamaa K., Prior T., Westman J.A., et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J. Clin. Oncol. 2008;26:5783–5788. doi: 10.1200/JCO.2008.17.5950.
    1. De Jong A.E., Morreau H., van Puijenbroek M., Eilers P.H., Wijnen J., Nagengast F.M., Griffioen G., Cats A., Menko F.H., Kleibeuker J.H. The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. Gastroenterology. 2004;126:42–48. doi: 10.1053/j.gastro.2003.10.043.
    1. Warthin A.S. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895–1913. Arch. Intern. Med. 1913;12:546–555. doi: 10.1001/archinte.1913.00070050063006.
    1. Thorson A.G., Knezetic J.A., Lynch H.T. A century of progress in hereditary nonpolyposis colorectal cancer (Lynch syndrome) Dis. Colon Rectum. 1999;42:1–9. doi: 10.1007/BF02235175.
    1. Boland C.R., Lynch H.T. The History of Lynch Syndrome. Fam. Cancer. 2013;12:145–157. doi: 10.1007/s10689-013-9637-8.
    1. Lynch H.T., Krush A.J. Cancer family “G” revisited: 1895–1970. Cancer. 1971;27:1505–1511. doi: 10.1002/1097-0142(197106)27:6<1505::AID-CNCR2820270635>;2-L.
    1. Douglas J.A., Gruber S.B., Meister K.A., Bonner J., Watson P., Krush A.J., Lynch H.T. History and molecular genetics of Lynch syndrome in family G: A century later. JAMA. 2005;294:2195–2202.
    1. Boland C.R., Troncale F.J. Familial colonic cancer without antecedent polyposis. Ann. Intern. Med. 1984;100:700–701. doi: 10.7326/0003-4819-100-5-700.
    1. Lynch H.T., Kimberling W., Albano W.A. Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). I. Clinical description of resource. Cancer. 1985;56:934–938. doi: 10.1002/1097-0142(19850815)56:4<934::AID-CNCR2820560439>;2-I.
    1. Lynch H.T., Schuelke G.S., Kimberling W.J. Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). II. Biomarker studies. Cancer. 1985;56:939–951. doi: 10.1002/1097-0142(19850815)56:4<939::AID-CNCR2820560440>;2-T.
    1. Vasen H.F., Mecklin J.P., Khan P.M., Lynch H.T. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) Dis. Colon Rectum. 1991;34:424–425. doi: 10.1007/BF02053699.
    1. Vasen H.F., Watson P., Mecklin J.P., Lynch H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999;116:1453–1456. doi: 10.1016/S0016-5085(99)70510-X.
    1. Rodriguez-Bigas M.A., Boland C.R., Hamilton S.R., Henson D.E., Jass J.R., Khan P.M., Lynch H., Perucho M., Smyrk T., Sobin L., et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: Meeting highlights and Bethesda guidelines. J. Natl. Cancer Inst. 1997;89:1758–1762. doi: 10.1093/jnci/89.23.1758.
    1. Boland C.R., Thibodeau S.N., Hamilton S.R., Sidransky D., Eshleman J.R., Burt R.W., Meltzer S.J., Rodriguez-Bigas M.A., Fodde R., Ranzani G.N., et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–5257.
    1. Umar A., Boland C.R., Terdiman J.P., Syngal S., de la Chapelle A., Rüschoff J., Fishel R., Lindor N.M., Burgart L.J., Hamelin R., et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 2004;96:261–268. doi: 10.1093/jnci/djh034.
    1. Boland C.R., Shike M. Report from the Jerusalem workshop on Lynch syndrome-hereditary nonpolyposis colorectal cancer. Gastroenterology. 2010;138:2197.e1–2197.e17.
    1. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group Recommendations from the EGAPP Working Group: Genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet. Med. 2009;11:35–41. doi: 10.1097/GIM.0b013e31818fa2ff.
    1. Aaltonen L.A., Peltomaki P., Leach F.S., Sistonen P., Pylkkänen L., Mecklin J.P., Järvinen H., Powell S.M., Jen J., Hamilton S.R., et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260:812–816.
    1. Thibodeau S.N., Bren G., Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–819.
    1. Ionov Y., Peinado M.A., Malkhosyan S., Shibata D., Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363:558–561. doi: 10.1038/363558a0.
    1. Fishel R., Kolodner R.D. Identification of mismatch repair genes and their role in the development of cancer. Curr. Opin. Genet. Dev. 1995;5:382–395. doi: 10.1016/0959-437X(95)80055-7.
    1. Lynch H.T., Boland C.R., Rodriguez-Bigas M.A., Amos C., Lynch J.F., Lynch P.M. Who should be sent for genetic testing in hereditary colorectal cancer syndromes? J. Clin. Oncol. 2007;25:3534–3542. doi: 10.1200/JCO.2006.10.3119.
    1. Jass J.R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50:113–130. doi: 10.1111/j.1365-2559.2006.02549.x.
    1. Laurent-Puig P., Cayre A., Manceau G., Buc E., Bachet J.B., Lecomte T., Rougier P., Lievre A., Landi B., Boige V. Analysis of PTEN, BRAF, and EGFRstatus in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J. Clin. Oncol. 2009;27:5924–5930. doi: 10.1200/JCO.2008.21.6796.
    1. Barnetson R.A., Tenesa A., Farrington S.M., Nicholl I.D., Cetnarskyj R., Porteous M.E., Campbell H., Dunlop M.G. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N. Engl. J. Med. 2006;354:2751–2763. doi: 10.1056/NEJMoa053493.
    1. Hampel H., Frankel W.L., Martin E., Arnold M., Khanduja K., Kuebler P., Nakagawa H., Sotamaa K., Prior T.W., Westman J., et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer) N. Engl. J. Med. 2005;352:1851–1860. doi: 10.1056/NEJMoa043146.
    1. Vasen H.F., Stormorken A., Menko F.H., Nagengast F.M., Kleibeuker J.H., Griffioen G., Taal B.G., Moller P., Wijnen J.T. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: A study of hereditary nonpolyposis colorectal cancer families. J. Clin. Oncol. 2001;19:4074–4080.
    1. Lin K.M., Shashidharan M., Ternent C.A., Thorson A.G., Blatchford G.J., Christensen M.A., Lanspa S.J., Lemon S.J., Watson P., Lynch H.T., et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis. Colon Rectum. 1998;41:428–433. doi: 10.1007/BF02235755.
    1. Hendriks Y.M., Wagner. A., Morreau. H., Menko F., Stormorken A., Quehenberger F., Sandkuijl L., Møller P., Genuardi M., van Houwelingen H. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: Impact on counseling and surveillance. Gastroenterology. 2004;127:17–25. doi: 10.1053/j.gastro.2004.03.068.
    1. Buchanan D.D., Tan Y.Y., Walsh M.D., Clendenning M., Metcalf A.M., Ferguson K., Arnold S.T., Thompson B.A., Lose F.A., Parsons M.T., et al. Tumor Mismatch Repair Immunohistochemistry and DNA MLH1 Methylation Testing of Patients With Endometrial Cancer Diagnosed at Age Younger Than 60 Years Optimizes Triage for Population-Level Germline Mismatch Repair Gene Mutation Testing. J. Clin. Oncol. 2014;32:90–100. doi: 10.1200/JCO.2013.51.2129.
    1. Senter L., Clendenning M., Sotamaa K., Hampel H., Green J., Potter J.D., Lindblom A., Lagerstedt K., Thibodeau S.N., Lindor N.M., et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135:419–428.
    1. Ligtenberg M.J., Kuiper R.P., Chan T.L., Goossens M., Hebeda K.M., Voorendt M., Lee T.Y., Bodmer D., Hoenselaar E., Hendriks-Cornelissen S.J., et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat. Genet. 2009;41:112–117. doi: 10.1038/ng.283.
    1. Kempers M.J., Kuiper R.P., Ockeloen C.W., Chappuis P.O., Hutter P., Rahner N., Schackert H.K., Steinke V., Holinski-Feder E., Morak M., et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: A cohort study. Lancet Oncol. 2011;12:49–55. doi: 10.1016/S1470-2045(10)70265-5.
    1. Vasen H.F., Blanco I., Aktan-Collan K., Gopie J.P., Alonso A., Aretz S., Bernstein I., Bertario L., Burn J., Capella G., et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): Recommendations by a group of European experts. Gut. 2013;62:812–823. doi: 10.1136/gutjnl-2012-304356.
    1. Wijnen J.T., Brohet R.M., van Eijk R., Jagmohan-Changur S., Middeldorp A., Tops C.M., van Puijenbroek M., Ausems M.G., Gómez García E., Hes F.J., et al. Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome. Gastroenterology. 2009;136:131–137. doi: 10.1053/j.gastro.2008.09.033.
    1. Lindor N.M., Rabe K., Petersen G.M., Haile R., Casey G., Baron J., Gallinger S., Bapat B., Aronson M., Hopper J., et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: Familial colorectal cancer type X. JAMA. 2005;293:1979–1985. doi: 10.1001/jama.293.16.1979.
    1. InSiGHT: Colon Cancer Gene Variant Databases. [(accessed on 5 February 2014)]. Available online:
    1. Kohonen-Corish M.R., Macrae F., Genuardi M., Aretz S., Bapat B., Bernstein I.T., Burn J., Cotton R.G., den Dunnen J.T., Frebourg T., et al. Deciphering the colon cancer genes—Report of the InSiGHT-Human Variome Project Workshop, UNESCO, Paris, 2010. Hum. Mutat. 2011;32:491–494. doi: 10.1002/humu.21450.
    1. Thompson B.A., Spurdle A.B., Plazzer J.P., Greenblatt M.S., Akagi K., Al-Mulla F., Bapat B., Bernstein I., Capellá G., den Dunnen J.T., et al. Application of a 5 tiered scheme for standardized classification of 2360 unique mismatch repair gene variants in the InSiGHT locus specific database. Nat. Genet. 2014;46:107–115.
    1. Smith R.A., von Eschenbach A.C., Wender R., Levin B., Byers T., Rothenberger D., Brooks D., Creasman W., Cohen C., Runowicz C., et al. American Cancer Society guidelines for the early detection of cancer: Update of early detection guidelines for prostate, colorectal, and endometrial cancers. CA Cancer J. Clin. 2001;51:38–75. doi: 10.3322/canjclin.51.1.38.
    1. Winawer S., Fletcher R., Rex D., Bond J., Burt R., Ferrucci J., Ganiats T., Levin T., Woolf S., Johnson D., et al. Colorectal cancer screening and surveillance: Clinical guidelines and rationale update based on new evidence. Gastroenterology. 2003;124:544–560. doi: 10.1053/gast.2003.50044.
    1. Church J., Simmang C., Standards Task Force. American Society of Colon and Rectal Surgeons. Collaborative Group of the Americas on Inherited Colorectal Cancer and the Standards Committee of The American Society of Colon and Rectal Surgeons Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer) Dis. ColonRectum. 2003;46:1001–1012.
    1. National Comprehensive Cancer Network: NCCN Practice Guidelines in Oncology. [(accessed on 26 January 2014)]. Available online:
    1. Cohen S.A. Current Lynch Syndrome Tumor Screening Practices: A Survey of Genetic Counselors. J. Genet. Couns. 2014;23:38–47. doi: 10.1007/s10897-013-9603-5.
    1. Patel S.G., Ahnen D.J. Familial colon cancer syndromes: An update of a rapidly evolving field. Curr. Gastroenterol. Rep. 2012;14:428–438. doi: 10.1007/s11894-012-0280-6.
    1. Polakis P. The many ways of Wnt in cancer. Curr. Opin. Genet. Dev. 2007;17:45–51. doi: 10.1016/j.gde.2006.12.007.
    1. De la Chapelle A., Palomaki G., Hampel H. Identifying Lynch syndrome. Int. J. Cancer. 2009;125:1492–1493. doi: 10.1002/ijc.24491.
    1. Kastrinos F., Balmaña J., Syngal S. Prediction models in Lynch syndrome. Fam. Cancer.20. 1312:217–228.
    1. Tranø G., Wasmuth H.H., Sjursen W., Hofsli E., Vatten L.J. Awareness of heredity in colorectal cancer patients is insufficient among clinicians: A Norwegian population-based study. Colorectal Dis. 2009;11:456–461. doi: 10.1111/j.1463-1318.2009.01830.x.
    1. Mvundura M., Grosse S.D., Hampel H., Palomaki G.E. The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer. Genet. Med. 2010;12:93–104.
    1. Aoki K., Taketo M.M. Adenomatous polyposis coli (APC): A multi-functional tumor suppressor gene. J. Cell. Sci. 2007;120:3327–3335. doi: 10.1242/jcs.03485.
    1. Hampel H. Point: Justification for Lynch syndrome screening among all patients with newly diagnosed colorectal cancer. J. Natl. Compr. Cancer Netw. 2010;8:597–601.
    1. Sanchez J.A., Vogel J.D., Kalady M.F., Bronner M.P., Skacel M., Church J.M. Identifying Lynch syndrome: We are all responsible. Dis. Colon Rectum. 2008;51:1750–1756. doi: 10.1007/s10350-008-9414-1.
    1. Moreira L., Balaguer F., Lindor N., de la Chapelle A., Hampel H., Aaltonen L.A., Hopper J.L., Le Marchand L., Gallinger S., Newcomb P.A., et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 2012;308:1555–1565. doi: 10.1001/jama.2012.13088.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅