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Progress Report: New insights into the prevention of CRC by colonoscopic surveillance in Lynch syndrome

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Abstract

Lynch syndrome is the most frequent hereditary colorectal cancer (CRC) syndrome, affecting approximately 1 in 300 in the Western population. It is caused by pathogenic variants in the mismatch repair (MMR) genes including MLH1, MSH2 (EPCAM), MSH6 and PMS2, and is associated with high risks of CRC, endometrial cancer and other cancers. In view of these risks, carriers of such variants are encouraged to participate in colonoscopic surveillance programs that are known to substantially improve their prognosis. In the last decade several important studies have been published that provide detailed cancer risk estimates and prognoses based on large numbers of patients. These studies also provided new insights regarding the pathways of carcinogenesis in CRC, which appear to differ depending on the specific MMR gene defect. In this report, we will discuss the implications of these new findings for the development of new surveillance protocols.

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References

  1. Win AK, Jenkins MA, Dowty JG, Antoniou AC, Lee A, Giles GG et al (2017) Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomark Prev 26(3):404–412

    CAS  Google Scholar 

  2. Biller LH, Syngal S, Yurgelun MB (2019) Recent advances in Lynch syndrome. Fam Cancer 18(2):211–219

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Dominguez-Valentin M, Sampson JR, Seppala TT, Ten Broeke SW, Plazzer JP, Nakken S et al (2020) Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 22(1):15–25

    CAS  PubMed  Google Scholar 

  4. Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM et al (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104(5):1535–1549

    CAS  PubMed  Google Scholar 

  5. Lynch HT, Watson P, Lanspa SJ, Marcus J, Smyrk T, Fitzgibbons RJ Jr et al (1988) Natural history of colorectal cancer in hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). Dis Colon Rectum 31(6):439–444

    CAS  PubMed  Google Scholar 

  6. Vasen HF, Nagengast FM, Khan PM (1995) Interval cancers in hereditary non-polyposis colorectal cancer (Lynch syndrome). Lancet 345(8958):1183–1184

    CAS  PubMed  Google Scholar 

  7. Engel C, Rahner N, Schulmann K, Holinski-Feder E, Goecke TO, Schackert HK et al (2010) Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 8(2):174–182

    PubMed  Google Scholar 

  8. Haanstra JF, Kleibeuker JH, Koornstra JJ (2013) Role of new endoscopic techniques in Lynch syndrome. Fam Cancer 12(2):267–272

    PubMed  Google Scholar 

  9. Mecklin JP, Jarvinen HJ, Aukee S, Elomaa I, Karjalainen K (1987) Screening for colorectal carcinoma in cancer family syndrome kindreds. Scand J Gastroenterol 22(4):449–453

    CAS  PubMed  Google Scholar 

  10. Vasen HF, den Hartog Jager FC, Menko FH, Nagengast FM (1989) Screening for hereditary non-polyposis colorectal cancer: a study of 22 kindreds in The Netherlands. Am J Med 86(3):278–281

    CAS  PubMed  Google Scholar 

  11. Jarvinen HJ, Mecklin JP, Sistonen P (1995) Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 108(5):1405–1411

    CAS  PubMed  Google Scholar 

  12. Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomaki P et al (2000) Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118(5):829–834

    CAS  Google Scholar 

  13. Mecklin JP, Aarnio M, Laara E, Kairaluoma MV, Pylvanainen K, Peltomaki P et al (2007) Development of colorectal tumors in colonoscopic surveillance in Lynch syndrome. Gastroenterology 133(4):1093–1098

    PubMed  Google Scholar 

  14. Vasen HF, Abdirahman M, Brohet R, Langers AM, Kleibeuker JH, van Kouwen M et al (2010) One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome. Gastroenterology 138(7):2300–2306

    PubMed  Google Scholar 

  15. Stupart DA, Goldberg PA, Algar U, Ramesar R (2009) Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation. Colorectal Dis 11(2):126–130

    CAS  PubMed  Google Scholar 

  16. Newton K, Green K, Lalloo F, Evans DG, Hill J (2015) Colonoscopy screening compliance and outcomes in patients with Lynch syndrome. Colorectal Dis 17(1):38–46

    CAS  PubMed  Google Scholar 

  17. Stuckless S, Green JS, Morgenstern M, Kennedy C, Green RC, Woods MO et al (2012) Impact of colonoscopic screening in male and female Lynch syndrome carriers with an MSH2 mutation. Clin Genet 82(5):439–445

    CAS  PubMed  Google Scholar 

  18. Ahadova A, Seppala TT, Engel C, Gallon R, Burn J, Holinski-Feder E et al (2020) The “unnatural” history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance. Int J Cancer. https://doi.org/10.1002/ijc.33224

    Article  PubMed  Google Scholar 

  19. Zhao S, Wang S, Pan P, Xia T, Chang X, Yang X et al (2019) Magnitude, risk factors, and factors associated with adenoma miss rate of tandem colonoscopy: a systematic review and meta-analysis. Gastroenterology 156(6):1661–1674

    PubMed  Google Scholar 

  20. Latchford A (2020) How should colonoscopy surveillance in Lynch syndrome be performed? Gastroenterology 158(4):818–819

    PubMed  Google Scholar 

  21. Haanstra JF, Dekker E, Cats A, Nagengast FM, Hardwick JC, Vanhoutvin SA et al (2019) Effect of chromoendoscopy in the proximal colon on colorectal neoplasia detection in Lynch syndrome: a multicenter randomized controlled trial. Gastrointest Endosc 90(4):624–632

    PubMed  Google Scholar 

  22. Rivero-Sanchez L, Arnau-Collell C, Herrero J, Remedios D, Cubiella J, Garcia-Cougil M et al (2020) White-light endoscopy is adequate for Lynch syndrome surveillance in a randomized and noninferiority study. Gastroenterology 158(4):895–904

    CAS  PubMed  Google Scholar 

  23. Argillander TE, Koornstra JJ, van Kouwen M, Langers AM, Nagengast FM, Vecht J et al (2018) Features of incident colorectal cancer in Lynch syndrome. United Eur Gastroenterol J 6(8):1215–1222

    Google Scholar 

  24. De Jong AE, Morreau H, Van Puijenbroek M, Eilers PH, Wijnen J, Nagengast FM et al (2004) The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. Gastroenterology 126(1):42–48

    PubMed  Google Scholar 

  25. Jass JR, Stewart SM (1992) Evolution of hereditary non-polyposis colorectal cancer. Gut 33(6):783–786

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Love RR (1986) Adenomas are precursor lesions for malignant growth in nonpolyposis hereditary carcinoma of the colon and rectum. Surg Gynecol Obstet 162(1):8–12

    CAS  PubMed  Google Scholar 

  27. Kloor M, Huth C, Voigt AY, Benner A, Schirmacher P, von Knebel DM et al (2012) Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study. Lancet Oncol 13(6):598–606

    CAS  PubMed  Google Scholar 

  28. Pedroni M, Sala E, Scarselli A, Borghi F, Menigatti M, Benatti P et al (2001) Microsatellite instability and mismatch-repair protein expression in hereditary and sporadic colorectal carcinogenesis. Cancer Res 61(3):896–899

    CAS  PubMed  Google Scholar 

  29. Sekine S, Mori T, Ogawa R, Tanaka M, Yoshida H, Taniguchi H et al (2017) Mismatch repair deficiency commonly precedes adenoma formation in Lynch syndrome-associated colorectal tumorigenesis. Mod Pathol 30(8):1144–1151

    CAS  PubMed  Google Scholar 

  30. Ahadova A, Gallon R, Gebert J, Ballhausen A, Endris V, Kirchner M et al (2018) Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int J Cancer 143(1):139–150

    CAS  PubMed  Google Scholar 

  31. Mecklin JP, Sipponen P, Jarvinen HJ (1986) Histopathology of colorectal carcinomas and adenomas in cancer family syndrome. Dis Colon Rectum 29(12):849–853

    CAS  PubMed  Google Scholar 

  32. Rijcken FE, Hollema H, Kleibeuker JH (2002) Proximal adenomas in hereditary non-polyposis colorectal cancer are prone to rapid malignant transformation. Gut 50(3):382–386

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ahadova A, von Knebel DM, Blaker H, Kloor M (2016) CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Fam Cancer 15(4):579–586

    CAS  PubMed  Google Scholar 

  34. Miyaki M, Iijima T, Kimura J, Yasuno M, Mori T, Hayashi Y et al (1999) Frequent mutation of beta-catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer. Cancer Res 59(18):4506–4509

    CAS  PubMed  Google Scholar 

  35. Johnson V, Volikos E, Halford SE, Eftekhar Sadat ET, Popat S, Talbot I et al (2005) Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome. Gut 54(2):264–267

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Huels DJ, Ridgway RA, Radulescu S, Leushacke M, Campbell AD, Biswas S et al (2015) E-cadherin can limit the transforming properties of activating beta-catenin mutations. EMBO J 34(18):2321–2333

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Moller P, Seppala T, Bernstein I, Holinski-Feder E, Sala P, Evans DG et al (2017) Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 66(3):464–472

    PubMed  Google Scholar 

  38. Moller P, Seppala T, Bernstein I, Holinski-Feder E, Sala P, Evans DG et al (2017) 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 66(9):1657–1664

    PubMed  Google Scholar 

  39. Moller P, Seppala TT, Bernstein I, Holinski-Feder E, Sala P, Gareth Evans D et al (2018) 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 67(7):1306–1316

    PubMed  Google Scholar 

  40. Seppala T, Pylvanainen K, Evans DG, Jarvinen H, Renkonen-Sinisalo L, Bernstein I et al (2017) Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a prospective Lynch syndrome database report. Hered Cancer Clin Pract 15:18

    PubMed  PubMed Central  Google Scholar 

  41. Dominguez-Valentin M, Seppala TT, Sampson JR, Macrae F, Winship I, Evans DG et al (2019) Survival by colon cancer stage and screening interval in Lynch syndrome: a prospective Lynch syndrome database report. Hered Cancer Clin Pract 17:28

    PubMed  PubMed Central  Google Scholar 

  42. Seppala TT, Ahadova A, Dominguez-Valentin M, Macrae F, Evans DG, Therkildsen C et al (2019) Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report. Hered Cancer Clin Pract 17:8

    PubMed  PubMed Central  Google Scholar 

  43. ten Broeke SW, Brohet RM, Tops CM, van der Klift HM, Velthuizen ME, Bernstein I et al (2015) Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol 33(4):319–325

    PubMed  Google Scholar 

  44. Ten Broeke SW, van der Klift HM, Tops CMJ, Aretz S, Bernstein I, Buchanan DD et al (2018) Cancer risks for PMS2-associated Lynch syndrome. J Clin Oncol 36:2961

    PubMed  PubMed Central  Google Scholar 

  45. Engel C, Vasen HF, Seppala T, Aretz S, Bigirwamungu-Bargeman M, de Boer SY et al (2018) No difference in colorectal cancer incidence or stage at detection by colonoscopy among 3 countries with different Lynch syndrome surveillance policies. Gastroenterology 155(5):1400–1409

    PubMed  Google Scholar 

  46. Engel C, Ahadova A, Seppala TT, Aretz S, Bigirwamungu-Bargeman M, Blaker H et al (2020) Associations of pathogenic variants in MLH1, MSH2, and MSH6 with risk of colorectal adenomas and tumors and with somatic mutations in patients with Lynch syndrome. Gastroenterology 158(5):1326–1333

    CAS  PubMed  Google Scholar 

  47. Ten Broeke SW, van Bavel TC, Jansen AML, Gomez-Garcia E, Hes FJ, van Hest LP et al (2018) Molecular background of colorectal tumors from patients with Lynch syndrome associated with germline variants in PMS2. Gastroenterology 155(3):844–851

    PubMed  Google Scholar 

  48. 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):988–997

    CAS  PubMed  Google Scholar 

  49. Peltomaki P (2016) Update on Lynch syndrome genomics. Fam Cancer 15(3):385–393

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Yurgelun MB, Goel A, Hornick JL, Sen A, Turgeon DK, Ruffin MTT et al (2012) Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res (Phila) 5(4):574–582

    CAS  Google Scholar 

  51. Walsh MD, Buchanan DD, Pearson SA, Clendenning M, Jenkins MA, Win AK et al (2012) Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry. Mod Pathol 25(5):722–730

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Goverde A, Eikenboom EL, Viskil EL, Bruno MJ, Doukas M, Dinjens WNM et al (2020) Yield of Lynch syndrome surveillance for patients with pathogenic variants in DNA mismatch repair genes. Clin Gastroenterol Hepatol 18(5):1112–1120

    CAS  PubMed  Google Scholar 

  53. Rubenstein JH, Enns R, Heidelbaugh J, Barkun A, Clinical GC (2015) American Gastroenterological Association Institute guideline on the diagnosis and management of Lynch syndrome. Gastroenterology 149(3):777–782

    PubMed  Google Scholar 

  54. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW et al (2015) ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 110(2):223–262

    PubMed  PubMed Central  Google Scholar 

  55. van Leerdam ME, Roos VH, van Hooft JE, Balaguer F, Dekker E, Kaminski MF et al (2019) Endoscopic management of Lynch syndrome and of familial risk of colorectal cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 51(11):1082–1093

    PubMed  Google Scholar 

  56. Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE et al (2020) Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG). Gut 69(3):411–444

    CAS  PubMed  Google Scholar 

  57. Seppala TT, Latchford A, Negoi I, Sampaio Soares A, Jimenez-Rodriguez R, Sanchez-Guillen L et al (2020) European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender. Br J Surg. https://doi.org/10.1002/bjs.11902

  58. Vasen HF, Tomlinson I, Castells A (2015) Clinical management of hereditary colorectal cancer syndromes. Nat Rev Gastroenterol Hepatol 12(2):88–97

    PubMed  Google Scholar 

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Acknowledgements

I am very gratefull for all scientific discussions with Aysel Ahadova, Christoph Engel, Juul Wijnen, Wouter de Vos tot Nederveen Cappel and Matthias Kloor, that greatly improved the manuscript.

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  1. Department of Gastroenterology & Hepatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands

    Hans F. A. Vasen

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Correspondence to Hans F. A. Vasen.

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I want to dedicate this report to Henry Lynch, who passed away on June the 2nd, 2019 at the age of 91. Henry spent practically his whole life researching hereditary cancer and in doing so saved the lives of countless individuals genetically predisposed to cancer. As Henry and I had the same goals in research, we successfully collaborated as colleagues and friends for more than 30 years. He is still sorely missed.

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Vasen, H.F.A. Progress Report: New insights into the prevention of CRC by colonoscopic surveillance in Lynch syndrome. Familial Cancer 21, 49–56 (2022). https://doi.org/10.1007/s10689-020-00225-x

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