Skip to main content

Advertisement

SpringerLink
Log in

Usefulness of genotyping APC gene for individualizing management of patients with familial adenomatous polyposis

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Colorectal polyp burden is crucial for the management of patients with familial adenomatous polyposis (FAP). However, accurate evaluation of polyp burden is difficult to standardize. This study aimed to examine the possible utility of genotype-oriented management of colorectal neoplasms in patients with FAP.

Methods

Clinicopathological data from genetically proven patients with FAP was analyzed using the database of a nationwide retrospective Japanese multicenter study. The cumulative incidence of CRC was evaluated between different genotype groups. Genotype-1 were defined as germline variants on attenuated FAP-associated regions (codons 1–177, alternative splice site of exon 10 (codon 312), 1581–2843) and Genotype-2 as the other variants. Weibull and Joinpoint analyses were performed to determine the annual percentage changes in CRC risk.

Results

Overall, 69 men and 102 women were included. Forty-eight patients underwent colorectal resection for the first CRC, and five patients underwent resection for first cancer in the remnant anorectal segment after prophylactic surgery. The 70-year cumulative incidence of CRC in all patients was 59.3%. Patients with Genotype-1 (n = 23) demonstrated a lower risk of CRC stages II–IV than those with Genotype-2 (n = 148, P = 0.04). The risk of stage II–IV CRC was estimated to increase markedly at the age of 49 years in the Genotype-1 patients and 34 years in the Genotype-2 patients, respectively.

Conclusions

Different interventional strategies based on genotypes may be proposed for the clinical management of patients with FAP. This policy needs to be validated in further prospective studies focusing on long-term endoscopic intervention and optimal age at prophylactic (procto)colectomy.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Yen T, Stanich PP, Axell L et al (2022) APC-associated polyposis conditions. 1998 Dec 18. GeneReviews® [Internet]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. University of Washington, Seattle, pp 1993–2022

  2. Tomita N, Ishida H, Tanakaya K et al (2021) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2020 for the Clinical Practice of Hereditary Colorectal Cancer. Int J Clin Oncol 26:1353–1419

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mori Y, Amano K, Chikatani K et al (2022) Recent trends in the morbidity and mortality in patients with familial adenomatous polyposis: a retrospective single institutional study in Japan. Int J Clin Oncol 27:1034–1042

    Article  PubMed  Google Scholar 

  4. Ishikawa H, Mutoh M, Iwama T et al (2016) Endoscopic management of familial adenomatous polyposis in patients refusing colectomy. Endoscopy 48:51–55

    PubMed  Google Scholar 

  5. Matsubara T, Beppu N, Ikeda M et al (2022) Current clinical practice for familial adenomatous polyposis in Japan: a nationwide multicenter study. Ann Gastroenterol Surg 6:778–787

    Article  PubMed  PubMed Central  Google Scholar 

  6. Vasen HFA, Ghorbanoghli Z, de Ruijter B et al (2019) Optimizing the timing of colorectal surgery in patients with familial adenomatous polyposis in clinical practice. Scand J Gastroenterol 54:733–739

    Article  PubMed  Google Scholar 

  7. Lynch PM, Morris JS, Wen S et al (2016) A proposed staging system and stage-specific interventions for familial adenomatous polyposis. Gastrointest Endosc 84:115-125.e4

    Article  PubMed  PubMed Central  Google Scholar 

  8. Campos FG (2014) Surgical treatment of familial adenomatous polyposis: dilemmas and current recommendations. World J Gastroenterol 20:16620–16629

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kartheuser A, Stangherlin P, Brandt D et al (2006) Restorative proctocolectomy and ileal pouch-anal anastomosis for familial adenomatous polyposis revisited. Fam Cancer 5:241–260

    Article  PubMed  Google Scholar 

  10. Wallace MH, Frayling IM, Clark SK et al (1999) Attenuated adenomatous polyposis coli: the role of ascertainment bias through failure to dye-spray at colonoscopy. Dis Colon Rectum 42:1078–1080

    Article  CAS  PubMed  Google Scholar 

  11. Young J, Simms LA, Tarish J et al (1998) A family with attenuated familial adenomatous polyposis due to a mutation in the alternatively spliced region of APC exon 9. Hum Mutat 11:450–455

    Article  CAS  PubMed  Google Scholar 

  12. Cheah PY, Wong YH, Koh PK et al (2014) A novel indel in exon 9 of APC upregulates a ‘skip exon 9’ isoform and causes very severe familial adenomatous polyposis. Eur J Hum Genet 22:833–836

    Article  CAS  PubMed  Google Scholar 

  13. Su LK, Barnes CJ, Yao W et al (2000) Inactivation of germline mutant APC alleles by attenuated somatic mutations: a molecular genetic mechanism for attenuated familial adenomatous polyposis. Am J Hum Genet 67:582–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jansen AML, Goel A (2020) Mosaicism in patients with colorectal cancer or polyposis syndromes: a systematic review. Clin Gastroenterol Hepatol 18:1949–1960

    Article  CAS  PubMed  Google Scholar 

  15. Takao M, Yamaguchi T, Eguchi H et al (2021) APC germline variant analysis in the adenomatous polyposis phenotype in Japanese patients. Int J Clin Oncol 26:1661–1670

    Article  CAS  PubMed  Google Scholar 

  16. Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424

    Article  PubMed  PubMed Central  Google Scholar 

  17. James DB (editor) (2016) M.K.G.E. In: Wittekind C editor, TNM classification of malignant tumours, 8th ed. Willey, Oxford

  18. Sieber OM, Segditsas S, Knudsen AL et al (2006) Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation. Gut 55:1440–1448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim HJ, Fay MP, Feuer EJ et al (2000) Permutation tests for joinpoint regression with applications to cancer rates. Stat Med 19:335–351

    Article  CAS  PubMed  Google Scholar 

  20. Iwama T, Mishima Y, Utsunomiya J (1993) The impact of familial adenomatous polyposis on the tumorigenesis and mortality at the several organs. Its rational treatment. Ann Surg 217:101–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Iwama T, Tamura K, Morita T et al (2004) A clinical overview of familial adenomatous polyposis derived from the database of the polyposis registry of Japan. Int J Clin Oncol 9:308–316

    Article  PubMed  Google Scholar 

  22. Hanson CA, Miller JR (2005) Non-traditional roles for the adenomatous polyposis coli (APC) tumor suppressor protein. Gene 361:1–12

    Article  CAS  PubMed  Google Scholar 

  23. Spirio L, Olschwang S, Groden J et al (1993) Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75:951–957

    Article  CAS  PubMed  Google Scholar 

  24. Sulekova Z, Reina-Sanchez J, Ballhausen WG (1995) Multiple APC messenger RNA isoforms encoding exon 15 short open reading frames are expressed in the context of a novel exon 10A-derived sequence. Int J Cancer 63:435–441

    Article  CAS  PubMed  Google Scholar 

  25. Rozen P, Samuel Z, Shomrat R et al (1999) Notable intrafamilial phenotypic variability in a kindred with familial adenomatous polyposis and an APC mutation in exon 9. Gut 45:829–833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ishikawa H, Yamada M, Sato Y et al (2022) Intensive endoscopic resection for downstaging of polyp burden in patients with familial adenomatous polyposis (J-FAPP Study III): a multicenter prospective interventional study. Endoscopy. https://doi.org/10.1055/a-1945-9120

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to express our gratitude to Dr. Takeo Iwama and Dr. Kazushige Kawai for their useful advice.

Funding

The authors did not received support from any organization for the submitted work.

Author information

Authors and Affiliations

  1. Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan

    Yoshiko Mori, Hideyuki Ishida, Noriyasu Chika, Tetsuya Ito, Kunihiko Amano & Kenichi Chikatani

  2. The Committee of Hereditary Colorectal Cancer, Japanese Society for Cancer of the Colon and Rectum, Tokyo, Japan

    Hideyuki Ishida, Yoji Takeuchi, Akiko Chino, Toshiya Nagasaki, Akinari Takao, Kazuhito Sasaki, Kiwamu Akagi, Tatsuro Yamaguchi, Kohji Tanakaya, Tomita Naohiro & Yoichi Ajioka

  3. Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan

    Yoji Takeuchi, Mitsuhiro Kono & Satoki Shichijo

  4. Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan

    Akiko Chino & Toshiya Nagasaki

  5. Department of Gastroenterology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan

    Akinari Takao

  6. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan

    Misato Takao & Sakiko Nakamori

  7. Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Kazuhito Sasaki

  8. Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan

    Kiwamu Akagi

  9. Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22, Bunkyo-ku, Honkomagome, Tokyo, 113-8677, Japan

    Tatsuro Yamaguchi

  10. Department of Surgery, National Hospital Organization Iwakuni Clinical Center, Iwakuni, Japan

    Kohji Tanakaya

  11. Department of Surgery, Toyonaka Municipal Hospital, Toyonaka, Japan

    Tomita Naohiro

  12. Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Yoichi Ajioka

Authors
  1. Yoshiko Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideyuki Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noriyasu Chika
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tetsuya Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kunihiko Amano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kenichi Chikatani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoji Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mitsuhiro Kono
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Satoki Shichijo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akiko Chino
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Toshiya Nagasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Akinari Takao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Misato Takao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Sakiko Nakamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kazuhito Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kiwamu Akagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Tatsuro Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kohji Tanakaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Tomita Naohiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Yoichi Ajioka
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HI, AC, NT, AT, KS, KA, KT, TN, and YA designed and conceptualized the study. YM, NC, TI, KA, KC, YT, MK, SS, MT, and SN collected data. YM, HI, and TY analyzed the data. HI, YM, and TY interpreted data and drafted the manuscript. TY, YM, and HI revised the APC variants. All the authors have read and approved the final manuscript.

Corresponding author

Correspondence to Tatsuro Yamaguchi.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare.

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.

Supplementary file1 (PPTX 91 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mori, Y., Ishida, H., Chika, N. et al. Usefulness of genotyping APC gene for individualizing management of patients with familial adenomatous polyposis. Int J Clin Oncol 28, 1641–1650 (2023). https://doi.org/10.1007/s10147-023-02419-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-023-02419-6

Keywords

Search

Navigation