Skip to main content

Advertisement

SpringerLink
Log in

Colorectal carcinoma occurring via the adenoma–carcinoma pathway in patients with serrated polyposis syndrome

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Although serrated polyposis syndrome (SPS) is associated with an increased colorectal cancer (CRC) risk, the carcinogenic mechanisms remain unknown. We investigated clinicopathological characteristics and genetic abnormalities in colorectal polyps and CRC to elucidate carcinogenic mechanisms in SPS.

Methods

We retrospectively analyzed clinicopathological features of colorectal polyps in 44 SPS patients, and examined mutations of genes including APC, RAS, BRAF, and TP53, and microsatellite instability (MSI) in CRC tissues.

Results

Of the 44 patients, 25 (56%) fulfilled WHO criterion 1, 11 (25%) fulfilled criterion 2, and 8 (18%) fulfilled both. A total of 956 polyps were observed; 642 (67%) hyperplastic polyps (HP), 204 (21%) sessile serrated lesions (SSL), 10 (1%) traditional serrated adenoma (TSA), and 100 (11%) adenomas. The median numbers of polyps (/patient) were 10.5 (IQR 2.75–23) HPs, 4.0 (2.0–6.0) SSLs, 0 (0–0) TSA, and 1 (0–3.3) adenoma. SSL and HP located preferentially in the proximal and distal colon, respectively. Twenty-two CRCs were found in 18 patients. Based on the histological coexistence of SSL/TSA, BRAF mutation and MSI, 5 CRCs (26%) were classified as serrated-neoplasia pathway. Conversely, based on the coexistence of adenoma, APC/RAS and TP53 mutations, 11 CRCs (58%) were classified as adenoma–carcinoma pathway. The remaining three were unclassifiable. Most CRCs through adenoma–carcinoma pathway were located in the left-side colorectum and patients bearing those met criterion 2, characterized by many HP and advanced adenomas. Adenoma was a significant risk factor for CRC.

Conclusions

Our results suggest that more than half of the CRCs, particularly those in the left-side colorectum, developed through the adenoma–carcinoma pathway in SPS patients. Adenoma was a risk factor for CRCs, suggesting its importance in colorectal carcinogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Pai RK (Rish) MM, Rosty C. Colorectal serrated lesions and polyps. In: the WHO Classification of Tumours Editorial Board, editor. WHO classification of tumours of the digestive system. 5th ed. Lyon: IARC press; 2019. pp. 163–9.

    Google Scholar 

  2. Carballal S, Rodríguez-Alcalde D, Moreira L, et al. Colorectal cancer risk factors in patients with serrated polyposis syndrome: a large multicentre study. Gut. 2016;65:1829–37.

    PubMed  Google Scholar 

  3. Ijspeert JEG, Rana SAQ, Atkinson NSS, et al. Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis. Gut. 2017;66:278–84.

    CAS  PubMed  Google Scholar 

  4. Quintana I, Mejías-Luque R, Terradas M, et al. Evidence suggests that germline RNF43 mutations are a rare cause of serrated polyposis. Gut. 2018;67:2230–2.

    CAS  PubMed  Google Scholar 

  5. Buchanan DD, Clendenning M, Zhuoer L, et al. Lack of evidence for germline RNF43 mutations in patients with serrated polyposis syndrome from a large multinational study. Gut. 2017;66:1170–2.

    CAS  PubMed  Google Scholar 

  6. Rosty CBL, Dekker E, Nagtegaal ID. Serrated polyposis. In: the WHO Classification of Tumours Editorial Board, editor. WHO classification of tumours of the digestive system. 5th ed. Lyon: IARC press; 2019. pp. 532–4.

    Google Scholar 

  7. Rosty C, Buchanan DD, Walsh MD, et al. Phenotype and polyp landscape in serrated polyposis syndrome: a series of 100 patients from genetics clinics. Am J Surg Pathol. 2012;36:876–82.

    PubMed  PubMed Central  Google Scholar 

  8. Bleijenberg AG, JE IJ, van Herwaarden YJ, et al. Personalised surveillance for serrated polyposis syndrome: results from a prospective 5-year international cohort study. Gut. 2020;69:112–21.

    PubMed  Google Scholar 

  9. Boparai KS, Mathus-Vliegen EM, Koornstra JJ, et al. Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study. Gut. 2010;59:1094–100.

    PubMed  Google Scholar 

  10. Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.

    CAS  PubMed  Google Scholar 

  11. Rosty C, Hewett DG, Brown IS, et al. Serrated polyps of the large intestine: current understanding of diagnosis, pathogenesis, and clinical management. J Gastroenterol. 2013;48:287–302.

    PubMed  Google Scholar 

  12. Crockett SD, Nagtegaal ID. Terminology, molecular features, epidemiology, and management of serrated colorectal neoplasia. Gastroenterology. 2019;157:949–66.

    PubMed  Google Scholar 

  13. He EY, Wyld L, Sloane MA, et al. The molecular characteristics of colonic neoplasms in serrated polyposis: a systematic review and meta-analysis. J Pathol Clin Res. 2016;2:127–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Boparai KS, Dekker E, Polak MM, et al. A serrated colorectal cancer pathway predominates over the classic WNT pathway in patients with hyperplastic polyposis syndrome. Am J Pathol. 2011;178:2700–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Nagtegaal AM, Odze RD, Lam AK. Tumours of the colon and rectum. In: the WHO Classification of Tumours Editorial Board, editor. WHO classification of tumours of the digestive system. 5th ed. Lyon: IARC press; 2019. pp. 157–91.

    Google Scholar 

  16. Hashiguchi Y, Muro K, Saito Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol. 2020;25:1–42.

    PubMed  Google Scholar 

  17. Taniguchi H, Okamoto W, Muro K, et al. Clinical validation of newly developed multiplex kit using luminex xMAP technology for detecting simultaneous RAS and BRAF mutations in colorectal cancer: results of the RASKET-B Study. Neoplasia. 2018;20:1219–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Nagasaka T, Sasamoto H, Notohara K, et al. Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J Clin Oncol. 2004;22:4584–94.

    CAS  PubMed  Google Scholar 

  19. Miyoshi Y, Ando H, Nagase H, et al. Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A. 1992;89:4452–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Song G, Yuan Y, Zheng F, et al. Novel insertion mutation p.Asp610GlyfsX23 in APC gene causes familial adenomatous polyposis in Chinese families. Gene. 2013;516:204–8.

    CAS  PubMed  Google Scholar 

  21. Chang XY, Wu Y, Jiang Y, et al. RNF43 Mutations in IPMN Cases: A Potential Prognostic Factor. Gastroenterol Res Pract. 2020. https://doi.org/10.1155/2020/1457452.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Murphy KM, Zhang S, Geiger T, et al. Comparison of the microsatellite instability analysis system and the Bethesda panel for the determination of microsatellite instability in colorectal cancers. J Mol Diagn. 2006;8:305–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Miyamoto Y, Muguruma N, Fujimoto S, et al. Epidermal growth factor receptor-targeted molecular imaging of colorectal tumors: Detection and treatment evaluation of tumors in animal models. Cancer Sci. 2019;110:1921–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.

    CAS  PubMed  Google Scholar 

  25. Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–90.

    CAS  PubMed  Google Scholar 

  26. Takayama T, Miyanishi K, Hayashi T, et al. Colorectal cancer: genetics of development and metastasis. J Gastroenterol. 2006;41:185–92.

    CAS  PubMed  Google Scholar 

  27. Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology. 2010;138:2088–100.

    CAS  PubMed  Google Scholar 

  28. Bettington M, Walker N, Rosty C, et al. Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma. Gut. 2017;66:97–106.

    CAS  PubMed  Google Scholar 

  29. Bettington ML, Walker NI, Rosty C, et al. A clinicopathological and molecular analysis of 200 traditional serrated adenomas. Mod Pathol. 2015;28:414–27.

    PubMed  Google Scholar 

  30. Tanaka Y, Eizuka M, Uesugi N, et al. Traditional serrated adenoma has two distinct genetic pathways for molecular tumorigenesis with potential neoplastic progression. J Gastroenterol. 2020;55:846–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ikeda Y, Mori M, Yoshizumi T, et al. Cancer and adenomatous polyp distribution in the colorectum. Am J Gastroenterol. 1999;94:191–3.

    CAS  PubMed  Google Scholar 

  32. Bai Y, Gao J, Zou DW, et al. Distribution trends of colorectal adenoma and cancer: a colonoscopy database analysis of 11,025 Chinese patients. J Gastroenterol Hepatol. 2010;25:1668–73.

    PubMed  Google Scholar 

  33. Yokota T, Ura T, Shibata N, et al. BRAF mutation is a powerful prognostic factor in advanced and recurrent colorectal cancer. Br J Cancer. 2011;104:856–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Asaka S, Arai Y, Nishimura Y, et al. Microsatellite instability-low colorectal cancer acquires a KRAS mutation during the progression from Dukes’ A to Dukes’ B. Carcinogenesis. 2009;30:494–9.

    CAS  PubMed  Google Scholar 

  35. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998;338:1481–7.

    CAS  PubMed  Google Scholar 

  36. Peltomäki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21:1174–9.

    PubMed  Google Scholar 

  37. Yoshino T, Muro K, Yamaguchi K, et al. Clinical validation of a multiplex kit for RAS mutations in colorectal cancer: results of the RASKET (RAS KEy testing) prospective. Multicent Study EBioMed. 2015;2:317–23.

    Google Scholar 

  38. Hashimoto T, Yamashita S, Yoshida H, et al. WNT pathway gene mutations are associated with the presence of dysplasia in colorectal sessile serrated adenoma/polyps. Am J Surg Pathol. 2017;41:1188–97.

    PubMed  Google Scholar 

  39. Lee GH, Malietzis G, Askari A, et al. Is right-sided colon cancer different to left-sided colorectal cancer? a systematic review. Eur J Surg Oncol. 2015;41:300–8.

    CAS  PubMed  Google Scholar 

  40. Sugai T, Habano W, Jiao YF, et al. Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis: proposal for new molecular profile of colorectal carcinomas. J Mol Diagn. 2006;8:193–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Buchanan DD, Sweet K, Drini M, et al. Risk factors for colorectal cancer in patients with multiple serrated polyps: a cross-sectional case series from genetics clinics. PLoS ONE. 2010;5:e11636.

    PubMed  PubMed Central  Google Scholar 

  42. East JE, Atkin WS, Bateman AC, et al. British society of gastroenterology position statement on serrated polyps in the colon and rectum. Gut. 2017;66:1181–96.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Misato Hirata and Masahiro Bando (Department of Gastroenterology and Oncology, Tokushima University, Tokushima) for their technical assistance. We also appreciate professor Yoshimi Bando (Division of Pathology, Tokushima University Hospital, Tokushima) for helping us by consultation for pathological diagnosis.

Funding

This work was partly supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS; grant number 19K08471).

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Fumika Nakamura, Yasushi Sato, Koichi Okamoto, Yasuteru Fujino, Yasuhiro Mitsui, Kaizo Kagemoto, Tomoyuki Kawaguchi, Hiroshi Miyamoto, Naoki Muguruma & Tetsuji Takayama

  2. Department of Public Health, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Hokkaido, 060-8556, Japan

    Tomoko Sonoda

  3. Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Koichi Tsuneyama

Authors
  1. Fumika Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasushi Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koichi Okamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuteru Fujino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasuhiro Mitsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kaizo Kagemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomoyuki Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroshi Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Naoki Muguruma
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tomoko Sonoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Koichi Tsuneyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tetsuji Takayama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tetsuji Takayama.

Ethics declarations

Competing interests

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

535_2022_1858_MOESM1_ESM.pptx

Flow diagram. SSA/P, sessile serrated adenoma/polyp; IBD, inflammatory bowel disease; FAP, familial adenomatous polyposis; GAPPS, gastric adenocarcinoma and proximal polyposis syndrome mentary

Supplementary file2 (DOCX 17 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakamura, F., Sato, Y., Okamoto, K. et al. Colorectal carcinoma occurring via the adenoma–carcinoma pathway in patients with serrated polyposis syndrome. J Gastroenterol 57, 286–299 (2022). https://doi.org/10.1007/s00535-022-01858-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-022-01858-8

Keywords

Search

Navigation