Familial Cancer

, Volume 15, Issue 3, pp 395–403 | Cite as

Recent discoveries in the molecular genetics of Lynch syndrome

Original Article
First Online:

Abstract

Lynch syndrome is the inherited predisposition to cancer caused by a germline mutation in a DNA mismatch repair gene. The consequent tumors have a characteristic microsatellite instability (MSI) phenotype. Genomic sequencing of Lynch syndrome-associated colorectal cancers (CRCs) has demonstrated that these tumors have a substantially greater number of mutations than non-MSI CRCs, and that the target mutations driving tumor behavior are also different from what occurs in sporadic tumors. There are multiple non-Lynch syndrome entities that can create clinical confusion with that disease, including the acquired methylation of MLH1, Lynch-like syndrome, and Familial CRC-Type X. Patients with Lynch syndrome-associated CRCs have a substantially better prognosis, and there is growing evidence that this is due to the generation of immunogenic frameshift peptides as a consequence of defective DNA mismatch repair, and an effective immune response to the tumor.

Keywords

Lynch syndrome Colorectal cancer Microsatellite instability Genomic sequencing Lynch-like syndrome Hypermutated Germline mutation Somatic mutation MSH2 MLH1 
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References

  1. 1.
    Boland CR, Lynch HT (2013) The history of Lynch syndrome. Fam Cancer 12(2):145–157CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348(10):919–932CrossRefPubMedGoogle Scholar
  3. 3.
    Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW et al (1998) 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 58(22):5248–5257PubMedGoogle Scholar
  4. 4.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767CrossRefPubMedGoogle Scholar
  5. 5.
    Cancer Genome Atlas Network (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337CrossRefGoogle Scholar
  6. 6.
    Tomasetti C, Vogelstein B (2015) Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347(6217):78–81CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96(15):8681–8686CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95(12):6870–6875CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M et al (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 41(1):112–117CrossRefPubMedGoogle Scholar
  10. 10.
    Rhees J, Arnold M, Boland CR (2014) Inversion of exons 1–7 of the MSH2 gene is a frequent cause of unexplained Lynch syndrome in one local population. Fam Cancer 13(2):219–225CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Rodriguez-Soler M, Perez-Carbonell L, Guarinos C, Zapater P, Castillejo A, Barbera VM et al (2013) Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology 144(5):926.e1–932.e1 (quiz e13-4) CrossRefGoogle Scholar
  12. 12.
    Sourrouille I, Coulet F, Lefevre JH, Colas C, Eyries M, Svrcek M et al (2013) Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Fam Cancer 12(1):27–33CrossRefPubMedGoogle Scholar
  13. 13.
    Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA, Goossens M, Ouchene H, Hendriks-Cornelissen SJ et al (2014) Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146(3):643.e8–646.e8CrossRefGoogle Scholar
  14. 14.
    Haraldsdottir S, Hampel H, Tomsic J, Frankel WL, Pearlman R, de la Chapelle A et al (2014) Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology 147(6):1308.e1–1316.e1CrossRefGoogle Scholar
  15. 15.
    Moreira L, Munoz J, Cuatrecasas M, Quintanilla I, Leoz ML, Carballal S et al (2015) Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer. Cancer 121(9):1395–1404CrossRefPubMedGoogle Scholar
  16. 16.
    Goel A, Nguyen TP, Leung HC, Nagasaka T, Rhees J, Hotchkiss E et al (2011) De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. Int J Cancer 128(4):869–878CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Suter CM, Martin DI, Ward RL (2004) Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 36(5):497–501CrossRefPubMedGoogle Scholar
  18. 18.
    Hitchins MP, Wong JJ, Suthers G, Suter CM, Martin DI, Hawkins NJ et al (2007) Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 356(7):697–705CrossRefPubMedGoogle Scholar
  19. 19.
    Hitchins MP, Rapkins RW, Kwok CT, Srivastava S, Wong JJ, Khachigian LM et al (2011) Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5′UTR. Cancer Cell 20(2):200–213CrossRefPubMedGoogle Scholar
  20. 20.
    Boland CR (2005) Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer 4(3):211–218CrossRefPubMedGoogle Scholar
  21. 21.
    Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J et al (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293(16):1979–1985CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Goel A, Xicola RM, Nguyen TP, Doyle BJ, Sohn VR, Bandipalliam P et al (2010) Aberrant DNA methylation in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency. Gastroenterology 138(5):1854–1862CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301(5895):89–92CrossRefPubMedGoogle Scholar
  24. 24.
    Goel A, Nagasaka T, Spiegel J, Meyer R, Lichliter WE, Boland CR (2010) Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer. Clin Gastroenterol Hepatol 8(11):966–971CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Giraldez MD, Balaguer F, Bujanda L, Cuatrecasas M, Munoz J, Alonso-Espinaco V et al (2010) MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer. Clin Cancer Res 16(22):5402–5413CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Antelo M, Balaguer F, Shia J, Shen Y, Hur K, Moreira L et al (2012) A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer. PLoS One 7(9):e45357CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Nieminen TT, Abdel-Rahman WM, Ristimaki A, Lappalainen M, Lahermo P, Mecklin JP et al (2011) BMPR1A mutations in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency. Gastroenterology 141(1):e23–e26CrossRefPubMedGoogle Scholar
  28. 28.
    Nieminen TT, O’Donohue MF, Wu Y, Lohi H, Scherer SW, Paterson AD et al (2014) Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency. Gastroenterology 147(3):595.e5–598.e5CrossRefGoogle Scholar
  29. 29.
    Schulz E, Klampfl P, Holzapfel S, Janecke AR, Ulz P, Renner W et al (2014) Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X. Nat Commun 5:5191CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wei C, Peng B, Han Y, Chen WV, Rother J, Tomlinson GE et al (2015) Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers. Fam Cancer 14(2):297–306CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Balaguer F, Moreira L, Lozano JJ, Link A, Ramirez G, Shen Y et al (2011) Colorectal cancers with microsatellite instability display unique miRNA profiles. Clin Cancer Res 17(19):6239–6249CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260(5109):816–819CrossRefPubMedGoogle Scholar
  33. 33.
    Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB et al (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342(2):69–77CrossRefPubMedGoogle Scholar
  34. 34.
    Phipps AI, Limburg PJ, Baron JA, Burnett-Hartman AN, Weisenberger DJ, Laird PW et al (2015) Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology 148(1):77.e2–87.e2CrossRefGoogle Scholar
  35. 35.
    Sinicrope FA, Shi Q, Smyrk TC, Thibodeau SN, Dienstmann R, Guinney J et al (2015) Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology 148(1):88–99CrossRefPubMedGoogle Scholar
  36. 36.
    Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363(6429):558–561CrossRefPubMedGoogle Scholar
  37. 37.
    Kloor M, Von Knebel Doeberitz M (2016) The immune biology of microsatellite-unstable cancer. Trends Cancer (in press) Google Scholar
  38. 38.
    Kloor M, Huth C, Voigt AY, Benner A, Schirmacher P, von Knebel Doeberitz M et al (2012) Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncol 13(6):598–606CrossRefPubMedGoogle Scholar
  39. 39.
    Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP et al (2008) Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 134(4):988–997CrossRefPubMedGoogle Scholar
  40. 40.
    Reuschenbach M, Kloor M, Morak M, Wentzensen N, Germann A, Garbe Y et al (2010) Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome. Fam Cancer 9(2):173–179CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Bauer K, Michel S, Reuschenbach M, Nelius N, von Knebel Doeberitz M, Kloor M (2011) Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer. Fam Cancer 10(3):557–565CrossRefPubMedGoogle Scholar
  42. 42.
    de Miranda NF, Goudkade D, Jordanova ES, Tops CM, Hes FJ, Vasen HF et al (2012) Infiltration of Lynch colorectal cancers by activated immune cells associates with early staging of the primary tumor and absence of lymph node metastases. Clin Cancer Res 18(5):1237–1245CrossRefPubMedGoogle Scholar
  43. 43.
    von Knebel Doeberitz M, Kloor M (2013) Towards a vaccine to prevent cancer in Lynch syndrome patients. Fam Cancer 12(2):307–312CrossRefGoogle Scholar
  44. 44.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520CrossRefPubMedGoogle Scholar
  45. 45.
    Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349(3):247–257CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht (outside the USA) 2016

Authors and Affiliations

  1. 1.GI Cancer Research LaboratoryBaylor University Medical CenterDallasUSA
  2. 2.GI Cancer Research LaboratoryBaylor Scott & White Research InstituteDallasUSA

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