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The Molecular Basis of Lynch-like Syndrome

  • Gardenia Vargas-Parra
  • Matilde Navarro
  • Marta Pineda
  • Gabriel Capellá
Chapter

Abstract

Lynch-like syndrome (LLS) refers to individuals with MMR-deficient Lynch syndrome (LS) spectrum tumors (in the absence of MLH1 methylation), in which no pathogenic germline mutation has been identified. Patients and their first-degree relatives are considered to have an intermediate risk of developing cancer between LS and the general population.

In this chapter, we aimed to review the most promising work in the area. Double somatic variants in MMR genes have been frequently reported (27–82% of LLS cases), while somatic promoter hypermethylation does not play a role. Carriers of germline MMR variants of unknown significance and missed mutations are part of LLS. Germline mutations in POLE and biallelic MUTYH mutations have been reported rarely. With the advent of NGS technologies, other genes like FAN1, BUB1, MCM9, and SETD2 are emerging as candidate responsible genes for LLS.

Keywords

Lynch syndrome Lynch-like Next-generation sequencing Mismatch repair-deficiency Methylation Variant of unknown significance Double somatic hit 

Abbreviations

ASE

Allele-specific expression

CRC

Colorectal cancer

FFPE

Formalin-fixed paraffin embedded

IHC

Immunohistochemistry

LLS

Lynch-like syndrome

LOH

Loss of heterozygosity

LS

Lynch syndrome

MMR

Mismatch repair

MSI

Microsatellite instability

MS-MCA

Methylation-specific melting curve analysis

NGS

Next-generation sequencing

PBL

Peripheral blood leukocytes

VUS

Variant of unknown significance

Notes

Grant Support

This work was funded by the Spanish Ministry of Economy and Competitiveness (grant SAF2015–68016-R) and co-funded by FEDER (A Way to Build Europe) funds, the Spanish Association Against Cancer, the government of Catalonia (grant 2014SGR338), Fundación Mutua Madrileña (grant AP114252013), and RTICC MINECO Network RD12/0036/0031. This work is also supported by the Mexican National Council for Science and Technology (CONACyT) fellowship grant awarded to GV.

Disclosures

The authors declare no conflict of interest.

References

  1. 1.
    Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851–60.CrossRefGoogle Scholar
  2. 2.
    Moreira L, Balaguer F, Lindor N, de la Chapelle A, Hampel H, Aaltonen LA, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 2012;308:1555–65.  https://doi.org/10.1001/jama.2012.13088.CrossRefPubMedGoogle Scholar
  3. 3.
    Hampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2006;66:7810–7.CrossRefGoogle Scholar
  4. 4.
    Overbeek LIH, Kets CM, Hebeda KM, Bodmer D, van der Looij E, Willems R, et al. Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer. Br J Cancer. 2007;96:1605–12.  https://doi.org/10.1038/sj.bjc.6603754.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rodriguez-Soler M, Perez-Carbonell L, Guarinos C, Zapater P, Castillejo A, Barbera VM, et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology. 2013;144:924–6.  https://doi.org/10.1053/j.gastro.2013.01.044.CrossRefGoogle Scholar
  6. 6.
    Win AK, Buchanan DD, Rosty C, MacInnis RJ, Dowty JG, Dite GS, et al. Role of tumour molecular and pathology features to estimate colorectal cancer risk for first-degree relatives. Gut. 2015;64(1):101–10.  https://doi.org/10.1136/gutjnl-2013-306567.CrossRefPubMedGoogle Scholar
  7. 7.
    Vargas-Parra GM, Gonzalez-Acosta M, Thompson BA, Gomez C, Fernandez A, Damaso E, et al. Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis. Int J Cancer. 2017.  https://doi.org/10.1002/ijc.30820.
  8. 8.
    Kang SY, Park CK, Chang DK, Kim JW, Son HJ, Cho YB, et al. Lynch-like syndrome : characterization and comparison with EPCAM deletion carriers. Int J Cancer. 2015;136:1568–78.  https://doi.org/10.1002/ijc.29133.CrossRefPubMedGoogle Scholar
  9. 9.
    Chika N, Eguchi H, Kumamoto K, Suzuki O, Ishibashi K, Tachikawa T, et al. Prevalence of Lynch syndrome and lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population. Jpn J Clin Oncol. 2017;47(2):108–17.  https://doi.org/10.1093/jjco/hyw178.CrossRefPubMedGoogle Scholar
  10. 10.
    Mas-Moya J, Dudley B, Brand RE, Thull D, Bahary N, Nikiforova MN, et al. Clinicopathological comparison of colorectal and endometrial carcinomas in patients with lynch-like syndrome versus patients with Lynch syndrome. Hum Pathol. 2015;46(11):1616–25.  https://doi.org/10.1016/j.humpath.2015.06.022.CrossRefPubMedGoogle Scholar
  11. 11.
    O'Kane GM, Ryan E, McVeigh TP, Creavin B, Hyland JM, O'Donoghue DP, et al. Screening for mismatch repair deficiency in colorectal cancer: data from three academic medical centers. Cancer Med. 2017;6(6):1465–72.  https://doi.org/10.1002/cam4.1025.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Buchanan DD, Rosty C, Clendenning M, Win AK. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome). Appl Clin Genet. 2014;7:183–93.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Geurts-Giele WR, Leenen CH, Dubbink HJ, Meijssen IC, Post E, Sleddens HF, et al. Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers. J Pathol. 2014;234:548–59.  https://doi.org/10.1002/path.4419.CrossRefPubMedGoogle Scholar
  14. 14.
    Thompson BA, Spurdle AB, Plazzer J-P, Greenblatt MS, Akagi K, Al-Mulla F, et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet. 2014;46:107–15.  https://doi.org/10.1038/ng.2854.CrossRefPubMedGoogle Scholar
  15. 15.
    Chubb D, Broderick P, Frampton M, Kinnersley B, Sherborne A, Penegar S, et al. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(5):426–32.  https://doi.org/10.1200/JCO.2014.56.5689.CrossRefGoogle Scholar
  16. 16.
    Cragun D, Radford C, Dolinsky JS, Caldwell M, Chao E, Pal T. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet. 2014;86(6):510–20.  https://doi.org/10.1111/cge.12359.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Hermel DJ, McKinnon WC, Wood ME, Greenblatt MS. Multi-gene panel testing for hereditary cancer susceptibility in a rural Familial Cancer Program. Familial Cancer. 2017;16(1):159–66.  https://doi.org/10.1007/s10689-016-9913-5.CrossRefPubMedGoogle Scholar
  18. 18.
    Howarth DR, Lum SS, Esquivel P, Garberoglio CA, Senthil M, Solomon NL. Initial results of multigene panel testing for hereditary breast and ovarian cancer and Lynch syndrome. Am Surg. 2015;81(10):941–4.PubMedGoogle Scholar
  19. 19.
    Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, et al. Prevalence and Spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 2017;3(4):464–71.  https://doi.org/10.1001/jamaoncol.2016.5194.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ricker C, Culver JO, Lowstuter K, Sturgeon D, Sturgeon JD, Chanock CR, et al. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Genet. 2016;209(4):130–7.  https://doi.org/10.1016/j.cancergen.2015.12.013.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Rohlin A, Rambech E, Kvist A, Torngren T, Eiengard F, Lundstam U, et al. Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing. Familial Cancer. 2017;16(2):195–203.  https://doi.org/10.1007/s10689-016-9934-0.CrossRefPubMedGoogle Scholar
  22. 22.
    Slavin TP, Neuhausen SL, Nehoray B, Niell-Swiller M, Solomon I, Rybak C, et al. The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes. Familial Cancer. 2017.  https://doi.org/10.1007/s10689-017-0019-5.
  23. 23.
    Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology. 2015;149(3):604–13 e20.  https://doi.org/10.1053/j.gastro.2015.05.006.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(10):1086–95.  https://doi.org/10.1200/JCO.2016.71.0012.CrossRefGoogle Scholar
  25. 25.
    LaDuca H, Stuenkel AJ, Dolinsky JS, Keiles S, Tandy S, Pesaran T, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med Off J Am Coll Med Genet. 2014;16(11):830–7.  https://doi.org/10.1038/gim.2014.40.CrossRefGoogle Scholar
  26. 26.
    Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med Off J Am Coll Med Genet. 2016;18(8):823–32.  https://doi.org/10.1038/gim.2015.166.CrossRefGoogle Scholar
  27. 27.
    Clendenning M, Buchanan DD, Walsh MD, Nagler B, Rosty C, Thompson B, et al. Mutation deep within an intron of MSH2 causes Lynch syndrome. Familial Cancer. 2011;10:297–301.  https://doi.org/10.1007/s10689-011-9427-0.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, 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;41:112–7.  https://doi.org/10.1038/ng.283.CrossRefPubMedGoogle Scholar
  29. 29.
    Morak M, Koehler U, Schackert HK, Steinke V, Royer-Pokora B, Schulmann K, et al. Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome. J Med Genet. 2011;48:513–9.  https://doi.org/10.1136/jmedgenet-2011-100050.CrossRefPubMedGoogle Scholar
  30. 30.
    Wagner A, van der Klift H, Franken P, Wijnen J, Breukel C, Bezrookove V, et al. A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. Genes Chromosomes Cancer. 2002;35(1):49–57.  https://doi.org/10.1002/gcc.10094.CrossRefPubMedGoogle Scholar
  31. 31.
    Mork ME, Rodriguez A, Taggart MW, Rodriguez-Bigas MA, Lynch PM, Bannon SA, et al. Identification of MSH2 inversion of exons 1-7 in clinical evaluation of families with suspected Lynch syndrome. Familial Cancer. 2016.  https://doi.org/10.1007/s10689-016-9960-y.
  32. 32.
    Rhees J, Arnold M, Boland CR. Inversion of exons 1-7 of the MSH2 gene is a frequent cause of unexplained Lynch syndrome in one local population. Familial Cancer. 2014;13:219–25.  https://doi.org/10.1007/s10689-013-9688-x.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Liu Q, Hesson LB, Nunez AC, Packham D, Williams R, Ward RL, et al. A cryptic paracentric inversion of MSH2 exons 2-6 causes Lynch syndrome. Carcinogenesis. 2016;37(1):10–7.  https://doi.org/10.1093/carcin/bgv154.CrossRefPubMedGoogle Scholar
  34. 34.
    Liu Q, Thompson BA, Ward RL, Hesson LB, Sloane MA. Understanding the pathogenicity of noncoding mismatch repair gene promoter variants in Lynch syndrome. Hum Mutat. 2016;37(5):417–26.  https://doi.org/10.1002/humu.22971.CrossRefPubMedGoogle Scholar
  35. 35.
    Wilding JL, McGowan S, Liu Y, Bodmer WF. Replication error deficient and proficient colorectal cancer gene expression differences caused by 3'UTR polyT sequence deletions. Proc Natl Acad Sci U S A. 2010;107(49):21058–63.  https://doi.org/10.1073/pnas.1015604107.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Valeri N, Gasparini P, Braconi C, Paone A, Lovat F, Fabbri M, et al. MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci. 2010;107:21098–103.  https://doi.org/10.1073/pnas.1015541107.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sourrouille I, Coulet F, Lefevre JH, Colas C, Eyries M, Svrcek M, et al. Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Familial Cancer. 2013;12:27–33.CrossRefGoogle Scholar
  38. 38.
    Pastrello C, Fornasarig M, Pin E, Berto E, Pivetta B, Viel A. Somatic mosaicism in a patient with Lynch syndrome. Am J Med Genet A. 2009;149:212–5.  https://doi.org/10.1002/ajmg.a.32620.CrossRefGoogle Scholar
  39. 39.
    Haraldsdottir S, Hampel H, Tomsic J, Frankel WL, Pearlman R, de la Chapelle A, et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology. 2014;147:1308–16.e1.  https://doi.org/10.1053/j.gastro.2014.08.041.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Mensenkamp AR, Vogelaar IP, van Zelst–Stams WAG, Goossens M, Ouchene H, Hendriks–Cornelissen SJB, et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology. 2014;146:643–6.e8.  https://doi.org/10.1053/j.gastro.2013.12.002.CrossRefPubMedGoogle Scholar
  41. 41.
    Jansen AM, Geilenkirchen MA, van Wezel T, Jagmohan-Changur SC, Ruano D, van der Klift HM, et al. Whole gene capture analysis of 15 CRC susceptibility genes in suspected Lynch syndrome patients. PLoS One. 2016;11(6):e0157381.  https://doi.org/10.1371/journal.pone.0157381.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. 1998;95(12):6870–5.CrossRefGoogle Scholar
  43. 43.
    Yamamoto H, Imai K. Microsatellite instability: an update. Arch Toxicol. 2015;89:899–921.  https://doi.org/10.1007/s00204-015-1474-0.CrossRefPubMedGoogle Scholar
  44. 44.
    Nagasaka T, Rhees J, Kloor M, Gebert J, Naomoto Y, Boland CR, et al. Somatic hypermethylation of MSH2 is a frequent event in Lynch syndrome colorectal cancers. Cancer Res. 2010;70:3098–108.  https://doi.org/10.1158/0008-5472.CAN-09-3290.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Rumilla K, Schowalter KV, Lindor NM, Thomas BC, Mensink KA, Gallinger S, et al. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn. 2011;13:93–9.CrossRefGoogle Scholar
  46. 46.
    Lima EM. DNA mismatch repair gene methylation in gastric cancer in individuals from northern Brazil. Biocell. 2008;32:237–43.Google Scholar
  47. 47.
    Vymetalkova VP, Slyskova J, Korenkova V, Bielik L, Langerova L, Prochazka P, et al. Molecular characteristics of mismatch repair genes in sporadic colorectal tumors in Czech patients. BMC Med Genet. 2014;15:17.  https://doi.org/10.1186/1471-2350-15-17.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers J-O, et al. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology. 2005;128:1160–71.  https://doi.org/10.1053/j.gastro.2005.01.056.CrossRefPubMedGoogle Scholar
  49. 49.
    Morak M, Heidenreich B, Keller G, Hampel H, Laner A, de la Chapelle A, et al. Biallelic MUTYH mutations can mimic Lynch syndrome. Eur J Hum Genet. 2014;22:1334–7.  https://doi.org/10.1038/ejhg.2014.15.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Castillejo A, Vargas G, Castillejo I, Navarro M, Barbera VM, Gonzalez S, et al. Prevalence of germline MUTYH mutations among lynch-like syndrome patients. European. J Cancer. 2014;50:2241–50.  https://doi.org/10.1016/j.ejca.2014.05.022.CrossRefGoogle Scholar
  51. 51.
    Gomez-Fernandez N, Castellvi-Bel S, Fernandez-Rozadilla C, Balaguer F, Munoz J, Madrigal I, et al. Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations? BMC Med Genet. 2009;10:57.CrossRefGoogle Scholar
  52. 52.
    Guarinos C, Juárez M, Egoavil C, Rodríguez-Soler M, Pérez-Carbonell L, Salas R, et al. Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20:1158–68.  https://doi.org/10.1158/1078-0432.CCR-13-1490.CrossRefGoogle Scholar
  53. 53.
    Nielsen M, Morreau H, Vasen HF, Hes FJ. MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol. 2011;79:1–16.  https://doi.org/10.1016/j.critrevonc.2010.05.011.CrossRefPubMedGoogle Scholar
  54. 54.
    Balaguer F, Castellvi-Bel S, Castells A, Andreu M, Munoz J, Gisbert JP, et al. Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2007;5:379–87.  https://doi.org/10.1016/j.cgh.2006.12.025.CrossRefGoogle Scholar
  55. 55.
    Cleary SP, Cotterchio M, Jenkins MA, Kim H, Bristow R, Green R, et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology. 2009;136(4):1251–60.CrossRefGoogle Scholar
  56. 56.
    Colebatch A, Hitchins M, Williams R, Meagher a, Hawkins NJ, Ward RL. The role of MYH and microsatellite instability in the development of sporadic colorectal cancer. Br J Cancer. 2006;95:1239–43.  https://doi.org/10.1038/sj.bjc.6603421.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Lefevre JH, Colas C, Coulet F, Bonilla C, Mourra N, Flejou JF, et al. MYH biallelic mutation can inactivate the two genetic pathways of colorectal cancer by APC or MLH1 transversions. Familial Cancer. 2010;9(4):589–94.CrossRefGoogle Scholar
  58. 58.
    Seguí N, Navarro M, Pineda M, Köger N, Bellido F, González S, et al. Exome sequencing identifies MUTYH mutations in a family with colorectal cancer and an atypical phenotype. Gut. 2015;64:355–6.  https://doi.org/10.1136/gutjnl-2014-307084.CrossRefPubMedGoogle Scholar
  59. 59.
    Giráldez MD, Balaguer F, Bujanda L, Cuatrecasas M, Muñoz J, Alonso-Espinaco V, et al. MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2010;16:5402–13.  https://doi.org/10.1158/1078-0432.CCR-10-1491.CrossRefGoogle Scholar
  60. 60.
    Knopperts AP, Nielsen M, Niessen RC, Tops CMJ, Jorritsma B, Varkevisser J, et al. Contribution of bi-allelic germline MUTYH mutations to early-onset and familial colorectal cancer and to low number of adenomatous polyps: case-series and literature review. Familial Cancer. 2013;12:43–50.  https://doi.org/10.1007/s10689-012-9570-2.CrossRefPubMedGoogle Scholar
  61. 61.
    Wang L, Baudhuin LM, Boardman LA, Steenblock KJ, Petersen GM, Halling KC, et al. MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology. 2004;127:9–16.CrossRefGoogle Scholar
  62. 62.
    Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110:223–62.CrossRefGoogle Scholar
  63. 63.
    Croitoru ME, Cleary SP, Berk T, Nicola NDI, Kopolovic I, Bapat B, et al. Germline MYH mutations in a clinic-based series of Canadian multiple colorectal adenoma patients. J Surg Oncol. 2007:499–506.  https://doi.org/10.1002/jso.CrossRefGoogle Scholar
  64. 64.
    Jones N, Vogt S, Nielsen M, Christian D, Wark PA, Eccles D, et al. Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology. 2009;137:489–94., 94.e1; quiz 725–6.  https://doi.org/10.1053/j.gastro.2009.04.047.CrossRefPubMedGoogle Scholar
  65. 65.
    Khalaf R, Jones C, Strutt W, Williamson P. Colorectal cancer in a monoallelic MYH mutation carrier. J Gastrointest Surg Off J Soc Surg Aliment Tract. 2013;17:1500–2.  https://doi.org/10.1007/s11605-013-2206-5.CrossRefGoogle Scholar
  66. 66.
    Win AK, Dowty JG, Cleary SP, Kim H, Buchanan DD, Young JP, et al. Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology. 2014;146(5):1208–11 e1–5.  https://doi.org/10.1053/j.gastro.2014.01.022.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27:3975–80.  https://doi.org/10.1200/JCO.2008.21.6853.CrossRefGoogle Scholar
  68. 68.
    Ma X, Zhang B, Zheng W. Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Gut. 2014;63:326–36.  https://doi.org/10.1136/gutjnl-2012-304121.CrossRefPubMedGoogle Scholar
  69. 69.
    Theodoratou E, Campbell H, Tenesa A, Houlston R, Webb E, Lubbe S, et al. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer. 2010;103:1875–84.  https://doi.org/10.1038/sj.bjc.6605966.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Palles C, Cazier J-B, Howarth KM, Domingo E, Jones AM, Broderick P, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2012;45:136–44.  https://doi.org/10.1038/ng.2503.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Valle L, Hernandez-Illan E, Bellido F, Aiza G, Castillejo A, Castillejo M-I, et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet. 2014;23:3506–12.  https://doi.org/10.1093/hmg/ddu058.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Elsayed FA, Kets CM, Ruano D, van den Akker B, Mensenkamp AR, Schrumpf M, et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur J Hum Genet EJHG. 2014:1–5.  https://doi.org/10.1038/ejhg.2014.242.
  73. 73.
    Jansen AM, van Wezel T, van den Akker BE, Ventayol Garcia M, Ruano D, Tops CM, et al. Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers. Eur J Hum Genet. 2016;24(7):1089–92.  https://doi.org/10.1038/ejhg.2015.252.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Yoshida R, Miyashita K, Inoue M, Shimamoto A, Yan Z, Egashira A, et al. Concurrent genetic alterations in DNA polymerase proofreading and mismatch repair in human colorectal cancer. Eur J Hum Genet. 2011;19(3):320–5.  https://doi.org/10.1038/ejhg.2010.216.CrossRefPubMedGoogle Scholar
  75. 75.
    Seguí N, Mina LB, Lázaro C, Sanz-Pamplona R, Pons T, Navarro M, et al. Germline mutations in FAN1 cause hereditary colorectal cancer by impairing DNA repair. Gastroenterology. 2015:1–4.  https://doi.org/10.1053/j.gastro.2015.05.056.
  76. 76.
    Smith AL, Alirezaie N, Connor A, Chan-Seng-Yue M, Grant R, Selander I, et al. Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer. Cancer Lett. 2016;370(2):302–12.  https://doi.org/10.1016/j.canlet.2015.10.030.CrossRefPubMedGoogle Scholar
  77. 77.
    Broderick P, Dobbins SE, Chubb D, Kinnersley B, Dunlop MG, Tomlinson I, et al. Validation of recently proposed colorectal cancer susceptibility gene variants in an analysis of families and patients-a systematic review. Gastroenterology. 2017;152(1):75–7 e4.  https://doi.org/10.1053/j.gastro.2016.09.041.CrossRefPubMedGoogle Scholar
  78. 78.
    Cannavo E, Gerrits B, Marra G, Schlapbach R, Jiricny J. Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS2. J Biol Chem. 2007;282:2976–86.  https://doi.org/10.1074/jbc.M609989200.CrossRefPubMedGoogle Scholar
  79. 79.
    Kinch LN, Ginalski K, Rychlewski L, Grishin NV. Identification of novel restriction endonuclease-like fold families among hypothetical proteins. Nucleic Acids Res. 2005;33:3598–605.  https://doi.org/10.1093/nar/gki676.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    MacKay C, Déclais A-C, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, et al. Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell. 2010;142:65–76.  https://doi.org/10.1016/j.cell.2010.06.021.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    O'Donnell L, Durocher D. DNA repair has a new FAN1 club. Mol Cell. 2010;39:167–9.  https://doi.org/10.1016/j.molcel.2010.07.010.CrossRefPubMedGoogle Scholar
  82. 82.
    Traver S, Coulombe P, Peiffer I, Hutchins JR, Kitzmann M, Latreille D, et al. MCM9 is required for mammalian DNA mismatch repair. Mol Cell. 2015;59(5):831–9.  https://doi.org/10.1016/j.molcel.2015.07.010.CrossRefPubMedGoogle Scholar
  83. 83.
    Nishimura K, Ishiai M, Horikawa K, Fukagawa T, Takata M, Takisawa H, et al. Mcm8 and Mcm9 form a complex that functions in homologous recombination repair induced by DNA interstrand crosslinks. Mol Cell. 2012;47(4):511–22.  https://doi.org/10.1016/j.molcel.2012.05.047.CrossRefPubMedGoogle Scholar
  84. 84.
    Goldberg Y, Halpern N, Hubert A, Adler SN, Cohen S, Plesser-Duvdevani M, et al. Mutated MCM9 is associated with predisposition to hereditary mixed polyposis and colorectal cancer in addition to primary ovarian failure. Cancer Genet. 2015;208(12):621–4.  https://doi.org/10.1016/j.cancergen.2015.10.001.CrossRefPubMedGoogle Scholar
  85. 85.
    Liu Q, Hesson LB, Nunez AC, Packham D, Hawkins NJ, Ward RL, et al. Pathogenic germline MCM9 variants are rare in Australian lynch-like syndrome patients. Cancer Genet. 2016;209(11):497–500.  https://doi.org/10.1016/j.cancergen.2016.10.001.CrossRefPubMedGoogle Scholar
  86. 86.
    Phelan CM, Iqbal J, Lynch HT, Lubinski J, Gronwald J, Moller P, et al. Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study. Br J Cancer. 2014;110(2):530–4.  https://doi.org/10.1038/bjc.2013.741.CrossRefPubMedGoogle Scholar
  87. 87.
    Leland S, Nagarajan P, Polyzos A, Thomas S, Samaan G, Donnell R, et al. Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice. Proc Natl Acad Sci U S A. 2009;106:12776–81.  https://doi.org/10.1073/pnas.0903075106.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    de Voer RM, Geurts van Kessel A, Weren RD, Ligtenberg MJL, Smeets D, Fu L, et al. Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. Gastroenterology. 2013;145:544–7.  https://doi.org/10.1053/j.gastro.2013.06.001.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Hanks S, Coleman K, Reid S, Plaja A, Firth H, FitzPatrick D, et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet. 2004;36:1159–61.  https://doi.org/10.1038/ng1449.CrossRefPubMedGoogle Scholar
  90. 90.
    Li F, Mao G, Tong D, Huang J, Gu L, Yang W, et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell. 2013;153:590–600.  https://doi.org/10.1016/j.cell.2013.03.025.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Choi YJ, Oh HR, Choi MR, Gwak M, An CH, Chung YJ, et al. Frameshift mutation of a histone methylation-related gene SETD1B and its regional heterogeneity in gastric and colorectal cancers with high microsatellite instability. Hum Pathol. 2014;45:1674–81.  https://doi.org/10.1016/j.humpath.2014.04.013.CrossRefPubMedGoogle Scholar
  92. 92.
    Billingsley CC, Cohn DE, Mutch DG, Stephens JA, Suarez AA, Goodfellow PJ. Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing. Cancer. 2015;121:386–94.  https://doi.org/10.1002/cncr.29046.CrossRefPubMedGoogle Scholar
  93. 93.
    Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet. 2015;47:257–62.  https://doi.org/10.1038/ng.3202.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Gardenia Vargas-Parra
    • 1
  • Matilde Navarro
    • 1
  • Marta Pineda
    • 1
  • Gabriel Capellá
    • 1
  1. 1.Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL and CIBERONC, Hospitalet de LlobregatBarcelonaSpain

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