Genetic and Environmental Modifiers of Cancer Risk in Lynch Syndrome

Chapter

Abstract

Lynch syndrome, caused by pathogenic mutations in DNA mismatch repair genes, is associated with high risks of colorectal and endometrial cancer. Approximately 1 in 280 (0.35%) of the population are estimated to carry a pathogenic mutation in one of these genes. However, penetrance (age-specific cancer risk) estimates for mutation carriers have been found to vary substantially depending on person’s sex and which gene is mutated. Further, penetrance is also highly variable across carriers with mutations in the same gene. These observed differences in risk are consistent with that genetic and environmental factors are likely to modify cancer risks for people with Lynch syndrome. Identifying and characterising these risk-modifying factors are essential to enable targeted risk-based screening/treatment and risk-reduction strategies on the basis of ‘individual’ risk estimates rather than ‘average’ risk estimates. In this chapter, we review the latest evidence on genetic and environmental factors that have been investigated in association with cancer risk, primarily colorectal cancer, for people with Lynch syndrome.

Keywords

Lynch syndrome Colorectal cancer Endometrial cancer Modifiers Penetrance 

References

  1. 1.
    Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer. 2015;15(3):181–94. https://doi.org/10.1038/nrc3878.
  2. 2.
    Scott RJ, McPhillips M, Meldrum CJ, Fitzgerald PE, Adams K, Spigelman AD, et al. Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet. 2001;68(1):118–27. https://doi.org/10.1086/316942.Google Scholar
  3. 3.
    Dowty JG, Win AK, Buchanan DD, Lindor NM, Macrae FA, Clendenning M, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum Mutat. 2013;34(3):490–7.  https://doi.org/10.1002/humu.22262.CrossRefPubMedGoogle Scholar
  4. 4.
    Win AK, Jenkins MA, Dowty JG, Antoniou AC, Lee A, Giles GG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomark Prev. 2017;26(3):404–12.  https://doi.org/10.1158/1055-9965.epi-16-0693.CrossRefGoogle Scholar
  5. 5.
    Quehenberger F, Vasen HFA, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet. 2005;42(6):491–6.  https://doi.org/10.1136/jmg.2004.024299.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bonadona V, Bonaiti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305(22):2304–10. https://doi.org/10.1001/jama.2011.743.Google Scholar
  7. 7.
    Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135(2):419–28. https://doi.org/10.1053/j.gastro.2008.04.026.Google Scholar
  8. 8.
    Stoffel E, Mukherjee B, Raymond VM, Tayob N, Kastrinos F, Sparr J, et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009;137(5):1621–7.  https://doi.org/10.1053/j.gastro.2009.07.039.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Choi YH, Cotterchio M, McKeown-Eyssen G, Neerav M, Bapat B, Boyd K, et al. Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario. Hered Cancer Clin Pract. 2009;7(1):14. https://doi.org/10.1186/1897-4287-7-14.Google Scholar
  10. 10.
    Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet. 1997;6(1):105–10. https://doi.org/10.1093/hmg/6.1.105.Google Scholar
  11. 11.
    Hampel H, Stephens JA, Pukkala E, Sankila R, Aaltonen LA, Mecklin JP, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005;129(2):415–21. https://doi.org/10.1016/j.gastro.2005.05.011.Google Scholar
  12. 12.
    Win AK, Young JP, Lindor NM, Tucker KM, Ahnen DJ, Young GP, 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(9):958–64. https://doi.org/10.1200/JCO.2011.39.5590.Google Scholar
  13. 13.
    ten Broeke SW, Brohet RM, Tops CM, van der Klift HM, Velthuizen ME, Bernstein I, et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol. 2015;33(4):319–25.  https://doi.org/10.1200/jco.2014.57.8088.CrossRefPubMedGoogle Scholar
  14. 14.
    Moller P, Seppala T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017;66(3):464–72.  https://doi.org/10.1136/gutjnl-2015-309675.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Moller P, Seppala T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, et al. Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut. 2017;66(9):1657–64. https://doi.org/10.1136/gutjnl-2016-311403.
  16. 16.
    Moller P, Seppala TT, Bernstein I, Holinski-Feder E, Sala P, Gareth Evans D, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the prospective Lynch syndrome database. Gut. 2017.  https://doi.org/10.1136/gutjnl-2017-314057.
  17. 17.
    Stuckless S, Parfrey PS, Woods MO, Cox J, Fitzgerald GW, Green JS, et al. The phenotypic expression of three MSH2 mutations in large Newfoundland families with Lynch syndrome. Fam Cancer. 2007;6(1):1–12.  https://doi.org/10.1007/s10689-006-0014-8.
  18. 18.
    Kamiza AB, Hsieh LL, Tang R, Chien HT, Lai CH, Chiu LL, et al. Risk factors associated with colorectal cancer in a subset of patients with mutations in MLH1 and MSH2 in Taiwan fulfilling the Amsterdam II criteria for Lynch syndrome. PLoS One. 2015;10(6):e0130018.  https://doi.org/10.1371/journal.pone.0130018.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Park J-G, Park YJ, Wijnen JT, Vasen HFA. Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing. Int J Cancer. 1999;82(4):516–9. https://doi.org/10.1002/(SICI)1097-0215(19990812)82:4<516::AID-IJC8>3.0.CO;2-U.
  20. 20.
    Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9(10):749–58.  https://doi.org/10.1038/nrc2723.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323–31. https://doi.org/10.1016/S0092-8674(00)81871-1.
  22. 22.
    Jones JS, Chi X, Gu X, Lynch PM, Amos CI, Frazier ML. p53 polymorphism and age of onset of hereditary nonpolyposis colorectal cancer in a Caucasian population. Clin Cancer Res. 2004;10(17):5845–9.  https://doi.org/10.1158/1078-0432.ccr-03-0590.CrossRefPubMedGoogle Scholar
  23. 23.
    Kruger S, Engel C, Bier A, Silber AS, Gorgens H, Mangold E, et al. The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in Lynch syndrome patients with pathogenic germline mutations in MSH2 or MLH1. Cancer Lett. 2007;252(1):55–64. https://doi.org/10.1016/j.canlet.2006.12.006.Google Scholar
  24. 24.
    Kruger S, Silber AS, Engel C, Gorgens H, Mangold E, Pagenstecher C, et al. Arg462Gln sequence variation in the prostate-cancer-susceptibility gene RNASEL and age of onset of hereditary non-polyposis colorectal cancer: a case-control study. Lancet Oncol. 2005;6(8):566–72.  https://doi.org/10.1016/s1470-2045(05)70253-9.CrossRefPubMedGoogle Scholar
  25. 25.
    Sotamaa K, Liyanarachchi S, Mecklin JP, Jarvinen H, Aaltonen LA, Peltomaki P, et al. p53 codon 72 and MDM2 SNP309 polymorphisms and age of colorectal cancer onset in Lynch syndrome. Clin Cancer Res. 2005;11(19 Pt 1):6840–4.  https://doi.org/10.1158/1078-0432.ccr-05-1139.CrossRefPubMedGoogle Scholar
  26. 26.
    Talseth BA, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott RJ. Age of diagnosis of colorectal cancer in HNPCC patients is more complex than that predicted by R72P polymorphism in TP53. Int J Cancer. 2006;118(10):2479–84.  https://doi.org/10.1002/ijc.21661.CrossRefPubMedGoogle Scholar
  27. 27.
    Kong S, Amos CI, Luthra R, Lynch PM, Levin B, Frazier ML. Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer. Cancer Res. 2000;60(2):249–52.PubMedGoogle Scholar
  28. 28.
    Bala S, Peltomaki P. CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer. Cancer Res. 2001;61(16):6042–5.PubMedGoogle Scholar
  29. 29.
    Kruger S, Engel C, Bier A, Mangold E, Pagenstecher C, Doeberitz M, et al. Absence of association between cyclin D1 (CCND1) G870A polymorphism and age of onset in hereditary nonpolyposis colorectal cancer. Cancer Lett. 2006;236(2):191–7. https://doi.org/10.1016/j.canlet.2005.05.013.Google Scholar
  30. 30.
    Talseth BA, Ashton KA, Meldrum C, Suchy J, Kurzawski G, Lubinski J, et al. Aurora-A and Cyclin D1 polymorphisms and the age of onset of colorectal cancer in hereditary nonpolyposis colorectal cancer. Int J Cancer. 2008;122(6):1273–7.  https://doi.org/10.1002/ijc.23177.CrossRefPubMedGoogle Scholar
  31. 31.
    Chen J, Sen S, Amos CI, Wei C, Jones JS, Lynch P, et al. Association between Aurora-A kinase polymorphisms and age of onset of hereditary nonpolyposis colorectal cancer in a Caucasian population. Mol Carcinog. 2007;46(4):249–56.  https://doi.org/10.1002/mc.20283.CrossRefPubMedGoogle Scholar
  32. 32.
    Chen J, Pande M, Huang YJ, Wei C, Amos CI, Talseth-Palmer BA, et al. Cell cycle-related genes as modifiers of age of onset of colorectal cancer in Lynch syndrome: a large-scale study in non-Hispanic white patients. Carcinogenesis. 2013;34(2):299–306.  https://doi.org/10.1093/carcin/bgs344.CrossRefPubMedGoogle Scholar
  33. 33.
    Talseth BA, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott RJ. MDM2 SNP309 T>G alone or in combination with the TP53 R72P polymorphism does not appear to influence disease expression and age of diagnosis of colorectal cancer in HNPCC patients. Int J Cancer. 2007;120(3):563–5.  https://doi.org/10.1002/ijc.22339.CrossRefPubMedGoogle Scholar
  34. 34.
    Zecevic M, Amos CI, Gu X, Campos IM, Jones JS, Lynch PM, et al. IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer. J Natl Cancer Inst. 2006;98(2):139–43.  https://doi.org/10.1093/jnci/djj016.CrossRefPubMedGoogle Scholar
  35. 35.
    Reeves SG, Rich D, Meldrum CJ, Colyvas K, Kurzawski G, Suchy J, et al. IGF1 is a modifier of disease risk in hereditary non-polyposis colorectal cancer. Int J Cancer. 2008;123(6):1339–43. https://doi.org/10.1002/ijc.23668.Google Scholar
  36. 36.
    Houlle S, Charbonnier F, Houivet E, Tinat J, Buisine MP, Caron O, et al. Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers. Eur J Hum Genet. 2011;19(8):887–92. https://doi.org/10.1038/ejhg.2011.44.Google Scholar
  37. 37.
    Chen J, Etzel CJ, Amos CI, Zhang Q, Viscofsky N, Lindor NM, et al. Genetic variants in the cell cycle control pathways contribute to early onset colorectal cancer in Lynch syndrome. Cancer Causes Control. 2009;20(9):1769–77.  https://doi.org/10.1007/s10552-009-9416-x.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Wood NJ, Quinton NA, Burdall S, Sheridan E, Duffy SR. Exploring the potential chemopreventative effect of aspirin and rofecoxib on hereditary nonpolyposis colorectal cancer-like endometrial cancer cells in vitro through mechanisms involving apoptosis, the cell cycle, and mismatch repair gene expression. Int J Gynecol Cancer. 2007;17(2):447–54. https://doi.org/10.1111/j.1525-1438.2007.00867.xGoogle Scholar
  39. 39.
    Kunkel TA, Erie DA. DNA mismatch repair. Annu Rev Biochem. 2005;74:681–710.  https://doi.org/10.1146/annurev.biochem.74.082803.133243.CrossRefPubMedGoogle Scholar
  40. 40.
    David SS, O’Shea VL, Kundu S. Base-excision repair of oxidative DNA damage. Nature. 2007;447(7147):941–50. https://doi.org/10.1038/nature05978.Google Scholar
  41. 41.
    Maillet P, Chappuis PO, Vaudan G, Dobbie Z, Muller H, Hutter P, et al. A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer. Int J Cancer. 2000;88(6):928–31. https://doi.org/10.1002/1097-0215(20001215)88:6<928::AID-IJC14>3.0.CO;2-P.
  42. 42.
    Jones JS, Gu X, Lynch PM, Rodriguez-Bigas M, Amos CI, Frazier ML. ATM polymorphism and hereditary nonpolyposis colorectal cancer (HNPCC) age of onset (United States). Cancer Causes Control. 2005;16(6):749–53.  https://doi.org/10.1007/s10552-005-1540-7.CrossRefPubMedGoogle Scholar
  43. 43.
    Kim IJ, Ku JL, Kang HC, Park JH, Yoon KA, Shin Y, et al. Mutational analysis of OGG1, MYH, MTH1 in FAP, HNPCC and sporadic colorectal cancer patients: R154H OGG1 polymorphism is associated with sporadic colorectal cancer patients. Hum Genet. 2004;115(6):498–503. https://doi.org/10.1007/s00439-004-1186-7.
  44. 44.
    Reeves SG, Meldrum C, Groombridge C, Spigelman A, Suchy J, Kurzawski G, et al. DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome. Cancer Epidemiol. 2012;36(2):183–9.  https://doi.org/10.1016/j.canep.2011.09.003.CrossRefPubMedGoogle Scholar
  45. 45.
    Meeker AK, Argani P. Telomere shortening occurs early during breast tumorigenesis: a cause of chromosome destabilization underlying malignant transformation? J Mammary Gland Biol Neoplasia. 2004;9(3):285–96.  https://doi.org/10.1023/B:JOMG.0000048775.04140.92.CrossRefPubMedGoogle Scholar
  46. 46.
    Londono-Vallejo JA, Der-Sarkissian H, Cazes L, Bacchetti S, Reddel RR. Alternative lengthening of telomeres is characterized by high rates of telomeric exchange. Cancer Res. 2004;64(7):2324–7. https://doi.org/10.1158/0008-5472.CAN-03-4035.Google Scholar
  47. 47.
    Bellido F, Guino E, Jagmohan-Changur S, Segui N, Pineda M, Navarro M, et al. Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome. Eur J Hum Genet. 2013;21(5):511–6.  https://doi.org/10.1038/ejhg.2012.204.CrossRefPubMedGoogle Scholar
  48. 48.
    Djojosubroto MW, Choi YS, Lee HW, Rudolph KL. Telomeres and telomerase in aging, regeneration and cancer. Mol Cells. 2003;15(2):164–75.PubMedGoogle Scholar
  49. 49.
    Win AK, Clendenning M, Crawford W, Rosty C, Preston SG, Southey MC, et al. Genetic variants within the hTERT gene and the risk of colorectal cancer in Lynch syndrome. Genes Cancer. 2015;6(11–12):445–51. https://doi.org/10.18632/genesandcancer.85.Google Scholar
  50. 50.
    Smith G, Stanley LA, Sim E, Strange RC, Wolf CR. Metabolic polymorphisms and cancer susceptibility. Cancer Surv. 1995;25:27–65.PubMedGoogle Scholar
  51. 51.
    Slattery ML, Potter JD, Samowitz W, Bigler J, Caan B, Leppert M. NAT2, GSTM-1, cigarette smoking, and risk of colon cancer. Cancer Epidemiol Biomark Prev. 1998;7(12):1079–84.Google Scholar
  52. 52.
    Brockton N, Little J, Sharp L, Cotton SC. N-acetyltransferase polymorphisms and colorectal cancer: a HuGE review. Am J Epidemiol. 2000;151(9):846–61.CrossRefGoogle Scholar
  53. 53.
    Loktionov A, Watson MA, Gunter M, Stebbings WS, Speakman CT, Bingham SA. Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor. Carcinogenesis. 2001;22(7):1053–60. https://doi.org/10.1093/carcin/22.7.1053.Google Scholar
  54. 54.
    Ye Z, Parry JM. Genetic polymorphisms in the cytochrome P450 1A1, glutathione S-transferase M1 and T1, and susceptibility to colon cancer. Teratog Carcinog Mutagen. 2002;22(5):385–92.  https://doi.org/10.1002/tcm.10035.CrossRefPubMedGoogle Scholar
  55. 55.
    He LJ, Yu YM, Qiao F, Liu JS, Sun XF, Jiang LL. Genetic polymorphisms of N-acetyltransferase 2 and colorectal cancer risk. World J Gastroenterol. 2005;11(27):4268–71. https://doi.org/10.3748/wjg.v11.i27.4268.Google Scholar
  56. 56.
    Heinimann K, Scott RJ, Chappuis P, Weber W, Muller H, Dobbie Z, et al. N-acetyltransferase 2 influences cancer prevalence in hMLH1/hMSH2 mutation carriers. Cancer Res. 1999;59(13):3038–40.PubMedGoogle Scholar
  57. 57.
    Frazier ML, O'Donnell FT, Kong S, Gu X, Campos I, Luthra R, et al. Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes. Cancer Res. 2001;61(4):1269–71.PubMedGoogle Scholar
  58. 58.
    Talseth BA, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott RJ. Genetic polymorphisms in xenobiotic clearance genes and their influence on disease expression in hereditary nonpolyposis colorectal cancer patients. Cancer Epidemiol Biomark Prev. 2006;15(11):2307–10. https://doi.org/10.1158/1055-9965.EPI-06-0040.Google Scholar
  59. 59.
    Pistorius S, Gorgens H, Kruger S, Engel C, Mangold E, Pagenstecher C, et al. N-acetyltransferase (NAT) 2 acetylator status and age of onset in patients with hereditary nonpolyposis colorectal cancer (HNPCC). Cancer Lett. 2006;241(1):150–7.  https://doi.org/10.1016/j.canlet.2005.10.018.CrossRefPubMedGoogle Scholar
  60. 60.
    Felix R, Bodmer W, Fearnhead NS, van der Merwe L, Goldberg P, Ramesar RS. GSTM1 and GSTT1 polymorphisms as modifiers of age at diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) in a homogeneous cohort of individuals carrying a single predisposing mutation. Mutat Res. 2006;602(1–2):175–81. https://doi.org/10.1016/j.mrfmmm.2006.09.004.
  61. 61.
    Pande M, Amos CI, Osterwisch DR, Chen J, Lynch PM, Broaddus R, et al. Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome. Cancer Epidemiol Biomark Prev. 2008;17(9):2393–401. https://doi.org/10.1158/1055-9965.EPI-08-0326.Google Scholar
  62. 62.
    Moisio AL, Sistonen P, Mecklin JP, Jarvinen H, Peltomaki P. Genetic polymorphisms in carcinogen metabolism and their association to hereditary nonpolyposis colon cancer. Gastroenterology. 1998;115(6):1387–94.Google Scholar
  63. 63.
    Jones JS, Gu X, Campos IM, Lynch PM, Amos CI, Frazier ML. GSTM1 polymorphism does not affect hereditary nonpolyposis colorectal cancer age of onset. Cancer Epidemiol Biomark Prev. 2004;13(4):676–8.Google Scholar
  64. 64.
    Campbell PT, Edwards L, McLaughlin JR, Green J, Younghusband HB, Woods MO. Cytochrome P450 17A1 and catechol O-methyltransferase polymorphisms and age at Lynch syndrome colon cancer onset in Newfoundland. Clin Cancer Res. 2007;13(13):3783–8. https://doi.org/10.1158/1078-0432.CCR-06-2987.Google Scholar
  65. 65.
    Pande M, Chen J, Amos CI, Lynch PM, Broaddus R, Frazier ML. Influence of methylenetetrahydrofolate reductase gene polymorphisms C677T and A1298C on age-associated risk for colorectal cancer in a caucasian Lynch syndrome population. Cancer Epidemiol Biomark Prev. 2007;16(9):1753–9.  https://doi.org/10.1158/1055-9965.epi-07-0384.CrossRefGoogle Scholar
  66. 66.
    Shin JH, JL K, Shin KH, Shin YK, Kang SB, Park JG. Glutathione S-transferase M1 associated with cancer occurrence in Korean HNPCC families carrying the hMLH1/hMSH2 mutation. Oncol Rep. 2003;10(2):483–6. https://doi.org/10.3892/or.10.2.483.Google Scholar
  67. 67.
    Tomlinson I, Webb E, Carvajal-Carmona L, Broderick P, Kemp Z, Spain S, et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet. 2007;39(8):984–8. https://doi.org/10.1038/ng2085.
  68. 68.
    Broderick P, Carvajal-Carmona L, Pittman AM, Webb E, Howarth K, Rowan A, et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet. 2007;39(11):1315–7. https://doi.org/10.1038/ng.2007.18.Google Scholar
  69. 69.
    Zanke BW, Greenwood CMT, Rangrej J, Kustra R, Tenesa A, Farrington SM, et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet. 2007;39(8):989–94. https://doi.org/10.1038/ng2089.Google Scholar
  70. 70.
    Tomlinson IPM, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, Pittman AM, et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet. 2008;40(5):623–30. https://doi.org/10.1038/ng.111.Google Scholar
  71. 71.
    Houlston RS, Webb E, Broderick P, Pittman AM, Di Bernardo MC, Lubbe S, et al. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet. 2008;40(12):1426–35. https://doi.org/10.1038/ng.262.Google Scholar
  72. 72.
    Tenesa A, Farrington SM, Prendergast JGD, Porteous ME, Walker M, Haq N, et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet. 2008;40(5):631–7. https://doi.org/10.1038/ng.133.Google Scholar
  73. 73.
    Houlston RS, Cheadle J, Dobbins SE, Tenesa A, Jones AM, Howarth K, et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat Genet. 2010;42(11):973–7. https://doi.org/10.1038/ng.670.Google Scholar
  74. 74.
    Dunlop MG, Dobbins SE, Farrington SM, Jones AM, Palles C, Whiffin N, et al. Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat Genet. 2012;44(7):770–6.  https://doi.org/10.1038/ng.2293.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Peters U, Jiao S, Schumacher FR, Hutter CM, Aragaki AK, Baron JA, et al. Identification of genetic susceptibility loci for colorectal tumors in a genome-wide meta-analysis. Gastroenterology. 2013;144(4):799–807.e24.  https://doi.org/10.1053/j.gastro.2012.12.020.CrossRefPubMedGoogle Scholar
  76. 76.
    Jia WH, Zhang B, Matsuo K, Shin A, Xiang YB, Jee SH, et al. Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer. Nat Genet. 2013;45(2):191–6.  https://doi.org/10.1038/ng.2505.CrossRefPubMedGoogle Scholar
  77. 77.
    Whiffin N, Hosking FJ, Farrington SM, Palles C, Dobbins SE, Zgaga L, et al. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum Mol Genet. 2014;23(17):4729–37.  https://doi.org/10.1093/hmg/ddu177.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Real LM, Ruiz A, Gayan J, Gonzalez-Perez A, Saez ME, Ramirez-Lorca R, et al. A colorectal cancer susceptibility new variant at 4q26 in the Spanish population identified by genome-wide association analysis. PLoS One. 2014;9(6):e101178.  https://doi.org/10.1371/journal.pone.0101178.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Schmit SL, Schumacher FR, Edlund CK, Conti DV, Raskin L, Lejbkowicz F, et al. A novel colorectal cancer risk locus at 4q32.2 identified from an international genome-wide association study. Carcinogenesis. 2014;35(11):2512–9.  https://doi.org/10.1093/carcin/bgu148.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Schumacher FR, Schmit SL, Jiao S, Edlund CK, Wang H, Zhang B, et al. Genome-wide association study of colorectal cancer identifies six new susceptibility loci. Nat Commun. 2015;6:7138.  https://doi.org/10.1038/ncomms8138.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Peters U, Hutter CM, Hsu L, Schumacher FR, Conti DV, Carlson CS, et al. Meta-analysis of new genome-wide association studies of colorectal cancer risk. Hum Genet. 2012;131(2):217–34.  https://doi.org/10.1007/s00439-011-1055-0.CrossRefPubMedGoogle Scholar
  82. 82.
    Wijnen JT, Brohet RM, van Eijk R, Jagmohan-Changur S, Middeldorp A, Tops CM, et al. Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome. Gastroenterology. 2009;136(1):131–7. https://doi.org/10.1053/j.gastro.2008.09.033.Google Scholar
  83. 83.
    Talseth-Palmer BA, Brenne IS, Ashton KA, Evans TJ, McPhillips M, Groombridge C, et al. Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in Lynch syndrome. J Med Genet. 2011;48(4):279–84. https://doi.org/10.1136/jmg.2010.079962.Google Scholar
  84. 84.
    Talseth-Palmer BA, Wijnen JT, Brenne IS, Jagmohan-Changur S, Barker D, Ashton KA, et al. Combined analysis of three Lynch syndrome cohorts confirms the modifying effects of 8q23.3 and 11q23.1 in MLH1 mutation carriers. Int J Cancer. 2013;132(7):1556–64. https://doi.org/10.1002/ijc.27843.Google Scholar
  85. 85.
    Carvajal-Carmona LG, Cazier JB, Jones AM, Howarth K, Broderick P, Pittman A, et al. Fine-mapping of colorectal cancer susceptibility loci at 8q23.3, 16q22.1 and 19q13.11: refinement of association signals and use of in silico analysis to suggest functional variation and unexpected candidate target genes. Hum Mol Genet. 2011;20(14):2879–88. https://doi.org/10.1093/hmg/ddr190.Google Scholar
  86. 86.
    Win AK, Hopper JL, Buchanan DD, Young JP, Tenesa A, Dowty JG, et al. Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers? Eur J Cancer. 2013;49(7):1578–87. https://doi.org/10.1016/j.ejca.2013.01.029.Google Scholar
  87. 87.
    ten Broeke SW, Elsayed FA, Pagan L, Olderode-Berends MJW, Garcia EG, Gille HJP et al. SNP association study in PMS2-associated Lynch syndrome. Fam Cancer. 2017.  https://doi.org/10.1007/s10689-017-0061-3.
  88. 88.
    Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB, et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet. 2013;9(3):e1003212.  https://doi.org/10.1371/journal.pgen.1003212.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Win AK, Dowty JG, English DR, Campbell PT, Young JP, Winship I, et al. Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes. Br J Cancer. 2011;105(1):162–9. https://doi.org/10.1038/bjc.2011.172.Google Scholar
  90. 90.
    Pande M, Lynch PM, Hopper JL, Jenkins MA, Gallinger S, Haile RW, et al. Smoking and colorectal cancer in Lynch syndrome: results from the colon cancer family registry and The University of Texas M.D. Anderson Cancer Center. Clin Cancer Res. 2010;16(4):1331–9.  https://doi.org/10.1158/1078-0432.ccr-09-1877.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Dashti SG, Buchanan DD, Jayasekara H, Ait Ouakrim D, Clendenning M, Rosty C, et al. Alcohol consumption and the risk of colorectal cancer for mismatch repair gene mutation carriers. Cancer Epidemiol Biomark Prev. 2017;26(3):366–75.  https://doi.org/10.1158/1055-9965.epi-16-0496.CrossRefGoogle Scholar
  92. 92.
    Ait Ouakrim D, Dashti SG, Chau R, Buchanan DD, Clendenning M, Rosty C, et al. Aspirin, ibuprofen, and the risk of colorectal cancer in Lynch syndrome. J Natl Cancer Inst. 2015;107(9):djv170.  https://doi.org/10.1093/jnci/djv170.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Chau R, Dashti SG, Ait Ouakrim D, Buchanan DD, Clendenning M, Rosty C, et al. Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome. Int J Epidemiol. 2016;45(3):940–53.  https://doi.org/10.1093/ije/dyw036.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Win AK, Dowty JG, Antill YC, English DR, Baron JA, Young JP, et al. Body mass index in early adulthood and endometrial cancer risk for mismatch repair gene mutation carriers. Obstet Gynecol. 2011;117(4):899–905.  https://doi.org/10.1097/AOG.0b013e3182110ea3.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Dashti SG, Chau R, Ouakrim DA, Buchanan DD, Clendenning M, Young JP, et al. Female hormonal factors and the risk of endometrial cancer in Lynch syndrome. JAMA. 2015;314(1):61–71.  https://doi.org/10.1001/jama.2015.6789.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Botma A, Nagengast FM, Braem MGM, Hendriks JCM, Kleibeuker JH, Vasen HFA, et al. Body mass index increases risk of colorectal adenomas in men with Lynch syndrome: the GEOLynch cohort study. J Clin Oncol. 2010;28(28):4346–53.  https://doi.org/10.1200/jco.2010.28.0453.CrossRefPubMedGoogle Scholar
  97. 97.
    Winkels RM, Botma A, Van Duijnhoven FJ, Nagengast FM, Kleibeuker JH, Vasen HF, et al. Smoking increases the risk for colorectal adenomas in patients with Lynch syndrome. Gastroenterology. 2012;142(2):241–7.  https://doi.org/10.1053/j.gastro.2011.10.033.CrossRefPubMedGoogle Scholar
  98. 98.
    Heine-Broring RC, Winkels RM, Botma A, van Duijnhoven FJ, Jung AY, Kleibeuker JH, et al. Dietary supplement use and colorectal adenoma risk in individuals with Lynch syndrome: the GEOLynch cohort study. PLoS One. 2013;8(6):e66819.  https://doi.org/10.1371/journal.pone.0066819.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Botma A, Vasen HF, van Duijnhoven FJ, Kleibeuker JH, Nagengast FM, Kampman E. Dietary patterns and colorectal adenomas in Lynch syndrome: the GEOLynch cohort study. Cancer. 2013;119(3):512–21.  https://doi.org/10.1002/cncr.27726.CrossRefPubMedGoogle Scholar
  100. 100.
    Movahedi M, Bishop DT, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al. Obesity, aspirin, and risk of colorectal cancer in carriers of hereditary colorectal cancer: a prospective investigation in the CAPP2 study. J Clin Oncol. 2015;33(31):3591–7.  https://doi.org/10.1200/jco.2014.58.9952.CrossRefPubMedGoogle Scholar
  101. 101.
    Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378(9809):2081–7. https://doi.org/10.1016/S0140-6736(11)61049-0.Google Scholar
  102. 102.
    Campbell PT, Cotterchio M, Dicks E, Parfrey P, Gallinger S, McLaughlin JR. Excess body weight and colorectal cancer risk in Canada: associations in subgroups of clinically defined familial risk of cancer. Cancer Epidemiol Biomark Prev. 2007;16(9):1735–44.  https://doi.org/10.1158/1055-9965.epi-06-1059.CrossRefGoogle Scholar
  103. 103.
    Diergaarde B, Braam H, Vasen HF, Nagengast FM, GNPv M, Kok FJ, et al. Environmental factors and colorectal tumor risk in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol. 2007;5(6):736–42. https://doi.org/10.1016/j.cgh.2007.02.019.Google Scholar
  104. 104.
    Watson P, Ashwathnarayan R, Lynch HT, Roy HK. Tobacco use and increased colorectal cancer risk in patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome). Arch Intern Med. 2004;164(22):2429–31.  https://doi.org/10.1001/archinte.164.22.2429.CrossRefPubMedGoogle Scholar
  105. 105.
    Brand RM, Jones DD, Lynch HT, Brand RE, Watson P, Ashwathnayaran R, et al. Risk of colon cancer in hereditary non-polyposis colorectal cancer patients as predicted by fuzzy modeling: influence of smoking. World J Gastroenterol. 2006;12(28):4485–91. https://doi.org/10.3748/wjg.v12.i28.4485.Google Scholar
  106. 106.
    Staff S, Aaltonen M, Huhtala H, Pylvanainen K, Mecklin JP, Maenpaa J. Endometrial cancer risk factors among Lynch syndrome women: a retrospective cohort study. Br J Cancer. 2016;115(3):375–81.  https://doi.org/10.1038/bjc.2016.193.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Tanakaya K, Furukawa Y, Nakamura Y, Hirata K, Tomita N, Tamura K, et al. Relationship between smoking and multiple colorectal cancers in patients with Japanese Lynch syndrome: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum. Jpn J Clin Oncol. 2015. 2015;45(3):307–10.  https://doi.org/10.1093/jjco/hyu218.
  108. 108.
    Milne RL, Antoniou AC. Modifiers of breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers. Endocr Relat Cancer. 2016;23(10):T69–84.  https://doi.org/10.1530/erc-16-0277.CrossRefPubMedGoogle Scholar
  109. 109.
    Antoniou AC, Goldgar DE, Andrieu N, Chang-Claude J, Brohet R, Rookus MA, et al. A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol. 2005;29(1):1–11. https://doi.org/10.1002/gepi.20074.Google Scholar
  110. 110.
    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(5):424–5. http://dx.doi.org/10.1007/BF02053699.Google Scholar
  111. 111.
    Vasen HFA, 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(6):1453–6. https://doi.org/10.1016/S0016-5085(99)70510-X.Google Scholar
  112. 112.
    Umar A, Boland CR, Terdiman JP, Syngal S, Adl C, Ruschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261–8.  https://doi.org/10.1093/jnci/djh034.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Burn J, Bishop DT, Mecklin J-P, Macrae F, Moslein G, Olschwang S, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med. 2008;359(24):2567–78.  https://doi.org/10.1056/NEJMoa0801297.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Lu KH, Loose DS, Yates MS, Nogueras-Gonzalez GM, Munsell MF, Chen LM, et al. Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome. Cancer Prev Res (Phila). 2013;6(8):774–81.  https://doi.org/10.1158/1940-6207.capr-13-0020.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneMelbourneAustralia
  2. 2.Genetic Medicine and Familial Cancer Centre, The Royal Melbourne HospitalParkvilleAustralia
  3. 3.School of Biomedical Sciences and Pharmacy, University of NewcastleNewcastleAustralia
  4. 4.Department of Molecular MedicineNSW Health PathologyNewcastleAustralia

Personalised recommendations