Update on Lynch syndrome genomics

Päivi Peltomäki, Päivi Peltomäki

Abstract

Four main DNA mismatch repair (MMR) genes have been identified, MLH1, MSH2, MSH6, and PMS2, which when mutated cause susceptibility to Lynch syndrome (LS). LS is one of the most prevalent hereditary cancer syndromes in man and accounts for 1-3 % of unselected colorectal carcinomas and some 15 % of those with microsatellite instability and/or absent MMR protein. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) maintains a database for LS-associated mutations since 1996. The database was recently reorganized to efficiently gather published and unpublished data and to classify the variants according to a five-tiered scheme linked to clinical recommendations. This review provides an update of germline mutations causing susceptibility to LS based on information available in the InSiGHT database and the latest literature. MMR gene mutation profiles, correlations between genotype and phenotype, and possible mechanisms leading to the characteristic spectrum of tumors in LS are discussed in light of the different functions of MMR proteins, many of which directly serve cancer avoidance.

Keywords: DNA mismatch repair; Epimutation; Lynch syndrome; Mutation; Tumor spectrum.

Figures

Fig. 1
Fig. 1
The different hMutS and hMutL complexes in human MMR. In addition to MMR proteins, the repair process requires a number of other proteins, such as proliferating cell nuclear antigen (PCNA), replication factor C (RFC), EXO1 (a 5′–3′ exonuclease), DNA helicases, RPA (replication protein A, a single-stranded DNA binding protein), DNA polymerases, and DNA ligase
Fig. 2
Fig. 2
Distributions of the types of germline variants across each MMR gene. The analysis is based on data deposited in the InSiGHT database [17] and is restricted to variants with coding changes. The total numbers of variants per gene included in the analysis are 1104 for MLH1, 883 for MSH2, 414 for MSH6, and 197 for PMS2
Fig. 3
Fig. 3
Distributions of the different pathogenicity classes within the LS-associated MMR genes. The relative shares of normal variants (pathogenicity classes 1 and 2), VUSes (class 3), and pathogenic mutations (classes 4 and 5) reported for each MMR gene in the InSiGHT database [16] are depicted. The analysis includes 932 sequence variants for MLH1, 842 for MSH2, 449 for MSH6, and 137 for PMS2
Fig. 4
Fig. 4
Tumor-specific patterns of MMR defects. Percentages of tumors with MSI-high and MMR protein inactivation among cancers arising in different organs in germline carriers of MMR gene mutations from a nation-wide registry [57, 61, 62] are shown

References

    1. Modrich P. Mechanisms in eukaryotic mismatch repair. J Biol Chem. 2006;281:30305–30309. doi: 10.1074/jbc.R600022200.
    1. Peltomäki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21:1174–1179. doi: 10.1200/JCO.2003.04.060.
    1. Bridge G, Rashid S, Martin SA. DNA mismatch repair and oxidative DNA damage: implications for cancer biology and treatment. Cancers. 2014;6:1597–1614. doi: 10.3390/cancers6031597.
    1. Stojic L, Brun R, Jiricny J. Mismatch repair and DNA damage signalling. DNA Repair. 2004;3:1091–1101. doi: 10.1016/j.dnarep.2004.06.006.
    1. Surtees JA, Argueso JL, Alani E. Mismatch repair proteins: key regulators of genetic recombination. Cytogenet Genome Res. 2004;107:146–159. doi: 10.1159/000080593.
    1. Clark N, Wu X, Her C. MutS Homologues hMSH4 and hMSH5: genetic variations, functions, and implications in human diseases. Curr Genomics. 2013;14:81–90. doi: 10.2174/1389202911314020002.
    1. Bak ST, Sakellariou D, Pena-Diaz J. The dual nature of mismatch repair as antitumor and mutator: for better or for worse. Front Genet. 2014;5:287. doi: 10.3389/fgene.2014.00287.
    1. Peltomäki P. Lynch syndrome genes. Fam Cancer. 2005;4:227–232. doi: 10.1007/s10689-004-7993-0.
    1. Li G-M. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008;18:85–98. doi: 10.1038/cr.2007.115.
    1. Jiricny J. Postreplicative mismatch repair. Cold Spring Harb Perspect Biol. 2013;5:a012633. doi: 10.1101/cshperspect.a012633.
    1. Sanchez de Abajo A, de la Hoya M, van Puijenbroek M, et al. Dual role of LOH at MMR loci in hereditary non-polyposis colorectal cancer? Oncogene. 2006;25:2124–2130. doi: 10.1038/sj.onc.1209233.
    1. Hendriks YMC, Jagmohan-Changur S, van der Klift HM, et al. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma. Gastroenterology. 2006;130:312–322. doi: 10.1053/j.gastro.2005.10.052.
    1. WuY Berends MJW, Mensink RGJ, et al. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. 1999;65:1291–1298. doi: 10.1086/302612.
    1. Wu Y, Berends MJW, Sijmons RH, et al. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nat Genet. 2001;29:137–138. doi: 10.1038/ng1001-137.
    1. Liu H-X, Zhou X-L, Liu T, et al. The role of hMLH3 in familial colorectal cancer. Cancer Res. 2003;63:1894–1899.
    1. Thompson BA, Spurdle AB, Plazzer J-P, et al. Application of a five-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants lodged on the InSiGHT locus-specific database. Nat Genet. 2014;46:107–115. doi: 10.1038/ng.2854.
    1. Plazzer JP, Sijmons RH, Woods MO, et al. The InSiGHT database: utilizing 100 years of insights into Lynch syndrome. Fam Cancer. 2013;12:175–180. doi: 10.1007/s10689-013-9616-0.
    1. Win AK, Jenkins MA, Buchanan DD, et al. Determining the frequency of de novo germline mutations in DNA mismatch repair genes. J Med Genet. 2011;48:530–534. doi: 10.1136/jmedgenet-2011-100082.
    1. Ponti G, Castellsague E, Ruini C, et al. Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clin Genet. 2015;87:507–516. doi: 10.1111/cge.12529.
    1. Desai DC, Lockman JC, Chadwick RB, et al. Recurrent germline mutation in MSH2 arises frequently de novo. J Med Genet. 2000;37:646–652. doi: 10.1136/jmg.37.9.646.
    1. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary non-polyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261–268. doi: 10.1093/jnci/djh034.
    1. Froggatt NJ, Green J, Brassett C, et al. A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. J Med Genet. 1999;36:97–102.
    1. Moisio A-L, Sistonen P, Weissenbach J, et al. Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer. Am J Hum Genet. 1996;59:1243–1251.
    1. Vasen HF, Mecklin JP, Khan PM, Lynch HT. 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 HF, Watson P, Mecklin JP, Lynch HT. 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. Mangold E, Pagenstecher C, Friedl W, et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005;116:692–702. doi: 10.1002/ijc.20863.
    1. Lagerstedt Robinson K, Liu T, et al. Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics in 2006. J Natl Cancer Inst. 2007;99:291–299. doi: 10.1093/jnci/djk051.
    1. Nyström-Lahti M, Wu Y, Moisio A-L, et al. DNA mismatch repair gene mutations in 55 verified or putative kindreds with hereditary non-polyposis colorectal cancer. Hum Mol Genet. 1996;5:763–769. doi: 10.1093/hmg/5.6.763.
    1. Wijnen J, Khan PM, Vasen H, et al. Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch repair gene mutations. Am J Hum Genet. 1997;61:329–335. doi: 10.1086/514847.
    1. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer) N Engl J Med. 2005;352:1851–1859. doi: 10.1056/NEJMoa043146.
    1. Van der Klift H, Wijnen J, Wagner A, et al. Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC) Genes Chromosomes Cancer. 2005;44:123–138. doi: 10.1002/gcc.20219.
    1. Haraldsdottir S, Hampel H, Tomsic J, et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology. 2014;147:1308–1316. doi: 10.1053/j.gastro.2014.08.041.
    1. Mensenkamp AR, Vogelaar IP, van Zelst-Stams WAG, et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch repair deficiency in Lynch syndrome-like tumors. Gastroenterology. 2014;146:643–646. doi: 10.1053/j.gastro.2013.12.002.
    1. Geurts-Giele WRR, Leenen CHM, Dubbink HJ, et al. Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers. J Pathol. 2014;234:548–559. doi: 10.1002/path.4419.
    1. Jansen AML, van Wezel T, van den Akker BEWM et al (2015) Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers. Eur J Hum Genet (in press)
    1. Lindor NM, Rabe K, Petersen GM, 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. Nieminen TT, Abdel-Rahman WM, Ristimäki A, et al. BMPR1A mutations in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency. Gastroenterology. 2011;141:e23–e26. doi: 10.1053/j.gastro.2011.03.063.
    1. Nieminen TT, O’Donohue M-F, Wu Y. Germline mutation of RPS20, encoding a ribosomal protein, predisposes to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency. Gastroenterology. 2014;147:595–598. doi: 10.1053/j.gastro.2014.06.009.
    1. Dominguez-Valentin M, Therkildsen C, Da Silva S, Nilbert M. Familial colorectal cancer type X: genetic profiles and phenotypic features. Mod Pathol. 2015;28:30–36. doi: 10.1038/modpathol.2014.49.
    1. Gylling A, Ridanpää M, Vierimaa O, et al. Large genomic rearrangements and germline epimutations in Lynch syndrome. Int J Cancer. 2009;124:2333–2340. doi: 10.1002/ijc.24230.
    1. Ward RL, Dobbins T, Lindor NM, et al. Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry. Genet Med. 2013;15:25–35. doi: 10.1038/gim.2012.91.
    1. Niessen RC, Hofstra RMW, Westers H, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer. 2009;48:737–744. doi: 10.1002/gcc.20678.
    1. Hitchins MP, Wong JJ, Suthers G, et al. Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med. 2007;356:697–705. doi: 10.1056/NEJMoa064522.
    1. Kwok CT, Vogelaar IP, van Zelst-Stams WA, et al. The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype. Eur J Hum Genet. 2014;22:617–624. doi: 10.1038/ejhg.2013.200.
    1. Castillejo A, Hernandez-Illan E, Rodriguez-Soler M, et al. Prevalence of constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer. J Med Genet. 2015;52:498–502. doi: 10.1136/jmedgenet-2015-103076.
    1. Ligtenberg MJ, Kuiper RP, Chan TL, 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. Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304–2310. doi: 10.1001/jama.2011.743.
    1. Vasen HFA, Stormorken A, Menko FH, et al. 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. Baglietto L, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102:193–201. doi: 10.1093/jnci/djp473.
    1. Senter L, Clendenning M, Sotamaa K, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135:419–428. doi: 10.1053/j.gastro.2008.04.026.
    1. Bandipalliam B, Garber J, Syngal S, Kolodner RD. Clinical presentation correlates with the type of mismatch repair gene involved in hereditary nonpolyposis colon cancer. Gastroenterology. 2004;126:936–937. doi: 10.1053/j.gastro.2004.01.038.
    1. Hendriks YMC, Wagner A, Morreau H, et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counselling and surveillance. Gastroenterology. 2004;127:17–25. doi: 10.1053/j.gastro.2004.03.068.
    1. Ten Broeke SW, Brohet RM, Tops CM, et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol. 2014;33:319–325. doi: 10.1200/JCO.2014.57.8088.
    1. Engel C, Loeffler M, Steinke V, et al. Risks of less common cancers in proven mutation carriers with Lynch syndrome. J Clin Oncol. 2012;30:4409–4415. doi: 10.1200/JCO.2012.43.2278.
    1. Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30:958–964. doi: 10.1200/JCO.2011.39.5590.
    1. Gylling A, Abdel-Rahman WM, Juhola M, et al. Is gastric cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer? A molecular genetic study. Gut. 2007;56:926–933. doi: 10.1136/gut.2006.114876.
    1. Niskakoski A, Kaur S, Renkonen-Sinisalo L, et al. Distinct molecular profiles in Lynch syndrome-associated and sporadic ovarian carcinomas. Int J Cancer. 2013;133:2596–2608.
    1. Karamurzin Y, Zeng Z, Stadler ZK, et al. Unusual DNA mismatch repair-deficient tumors in Lynch syndrome: a report of new cases and review of the literature. Hum Pathol. 2012;43:1677–1687. doi: 10.1016/j.humpath.2011.12.012.
    1. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA mismatch repair genes. Int J Cancer. 1999;81:214–218. doi: 10.1002/(SICI)1097-0215(19990412)81:2<214::AID-IJC8>;2-L.
    1. Watson P, Vasen HF, Mecklin J-P, et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 2008;123:444–449. doi: 10.1002/ijc.23508.
    1. Lotsari JE, Gylling A, Abdel-Rahman WM, et al. Breast carcinoma and Lynch syndrome—molecular analysis of tumors arising in mutation carriers, non-carriers, and sporadic cases. Breast Cancer Res. 2012;14:R90. doi: 10.1186/bcr3205.
    1. Gylling A, Nieminen TT, Abdel-Rahman WM. Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis. 2008;29:1351–1359. doi: 10.1093/carcin/bgn133.
    1. Giuffre G, Müller A, Brodegger T, et al. Microsatellite analysis of hereditary nonpolyposis colorectal cancer-associated colorectal adenomas by laser-assisted microdissection: correlation with mismatch repair protein expression provides new insights in early steps of tumorigenesis. J Mol Diagn. 2005;7:160–170. doi: 10.1016/S1525-1578(10)60542-9.
    1. Beggs AD, Domingo E, Abulafi M. A study of genomic instability in early preneoplastic colonic lesions. Oncogene. 2013;32:5333–5337. doi: 10.1038/onc.2012.584.
    1. Kuismanen SA, Moisio A-L, Schweizer P. Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability. Am J Pathol. 2002;160:1953–1958. doi: 10.1016/S0002-9440(10)61144-3.
    1. Woerner SM, Benner A, Sutter C, et al. Pathogenesis of DNA repair-deficient cancers: a statistical meta-analysis of putative Real Common Target genes. Oncogene. 2003;22:2226–2235. doi: 10.1038/sj.onc.1206421.
    1. Bodo S, Colas C, Buhard O, et al. Diagnosis of constitutional mismatch repair-deficiency syndrome based on microsatellite instability and lymphocyte tolerance to methylating agents. Gastroenterology. 2015;149:1017–1029. doi: 10.1053/j.gastro.2015.06.013.
    1. Wang Q, Montmain G, Ruano E, et al. Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. Hum Genet. 2003;112:117–123.
    1. Knudson AG., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68:820–823. doi: 10.1073/pnas.68.4.820.
    1. Yurgelun MB, Goel A, Homick JL, et al. Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res. 2012;5:574–582. doi: 10.1158/1940-6207.CAPR-11-0519.
    1. Valo S, Kaur S, Ristimäki A, et al. DNA hypermethylation appears early and shows increased frequency with dysplasia in Lynch syndrome-associated colorectal adenomas and carcinomas. Clin Epigenetics. 2015;7:71. doi: 10.1186/s13148-015-0102-4.
    1. Cejka P, Stojic L, Mojas N, et al. Methylation-induced G(2)/M arrest requires a full complement of the mismatch repair protein hMLH1. EMBO J. 2003;22:2245–2254. doi: 10.1093/emboj/cdg216.
    1. Kawate H, Itoh R, Sakumi K, et al. A defect in a single allele of the Mlh1 gene causes dissociation of the killing and tumorigenic actions of an alkylating carcinogen in methyltransferase-deficient mice. Carcinogenesis. 2000;21:301–305. doi: 10.1093/carcin/21.2.301.
    1. Ollikainen M, Hannelius U, Lindgren CM. Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach. Oncogene. 2007;26:4541–4549. doi: 10.1038/sj.onc.1210236.
    1. Smith-Roe SL, Löhr CV, Bildfell RJ, et al. Induction of aberrant crypt foci in DNA mismatch repair-deficient mice by the food-borne carcinogen 2-amino-1-methyl-6-phenyl-imidazo [4,5-b] pyridine (PhIP) Cancer Lett. 2006;244:79–85. doi: 10.1016/j.canlet.2005.12.002.
    1. Derry MM, Raina K, Agarwal C, et al. Identifying molecular targets of lifestyle modifications in colon cancer prevention. Front Oncol. 2013;3:119. doi: 10.3389/fonc.2013.00119.
    1. Botma A, Vasen HFA, van Duijnhoven FJB, et al. Dietary patterns and colorectal adenomas in Lynch syndrome. Cancer. 2013;119:512–521. doi: 10.1002/cncr.27726.
    1. Winkels RM, Botma A, van Duijnhoven FJB, et al. Smoking increases the risk of colorectal adenomas in patients with Lynch syndrome. Gastroenterology. 2012;142:241–247. doi: 10.1053/j.gastro.2011.10.033.
    1. Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science. 2015;347:78–81. doi: 10.1126/science.1260825.
    1. Albanes D, Winick M. Are cell number and cell proliferation risk factors for cancer? J Natl Cancer Inst. 1988;80:772–775. doi: 10.1093/jnci/80.10.772.
    1. Drescher KM, Sharma P, Lynch HT. Current hypotheses on how microsatellite instability leads to enhanced survival of Lynch syndrome patients. Clin Dev Immunol. 2010;2010:170432. doi: 10.1155/2010/170432.
    1. Shia J, Black D, Hummer AJ, et al. Routinely assessed morphological features correlate with microsatellite instability status in endometrial cancer. Hum Pathol. 2008;39:116–125. doi: 10.1016/j.humpath.2007.05.022.
    1. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumors: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306. doi: 10.1038/nrc3245.
    1. Kloor M, von Knebel Doeberitz M. Immune evasion of microsatellite unstable colorectal cancers. Int J Cancer. 2010;127:1001–1010. doi: 10.1002/ijc.25283.
    1. Pritchard CC, Smith C, Salipante SJ, et al. ColoSeq provides comprehensive Lynch and polyposis syndrome mutational analysis using massively parallel sequencing. J Mol Diagn. 2012;14:357–366. doi: 10.1016/j.jmoldx.2012.03.002.
    1. Yurgelun MB, Allen B, Kaldate RR, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology. 2015;149:604–613. doi: 10.1053/j.gastro.2015.05.006.
    1. Schulz E, Klampfl P, Holzapfel S, et al. Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X. Nat Commun. 2014;5:5191. doi: 10.1038/ncomms6191.
    1. Segui N, Mina LB, Lazaro C, et al. Germline mutations in FAN1 cause hereditary colorectal cancer by impairing DNA repair. Gastroenterology. 2015;149:563–566. doi: 10.1053/j.gastro.2015.05.056.
    1. The Cancer Genome Atlas Network Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. doi: 10.1038/nature11252.
    1. The Cancer Genome Atlas Network Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73. doi: 10.1038/nature12113.
    1. Kloth M, Ruesseler V, Engel C et al (2015) Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer. Gut (in press)

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