SpringerLink
Log in

Clinicopathological characteristics of Lynch-like syndrome

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

Abstract

Background

Lynch-like syndrome (LLS) has recently been proposed as a third type of microsatellite instability (MSI) tumor after Lynch syndrome (LS) and sporadic MSI colorectal cancer (CRC) without either a germline variant of mismatch repair (MMR) genes or hypermethylation of the MLH1 gene. The present study aimed to clarify and compare the clinicopathological characteristics of LLS with those of the other MSI CRC subtypes.

Methods

In total, 2634 consecutive patients with CRC who underwent surgical resection and subsequently received universal tumor screening (UTS), including MSI analysis were enrolled between January 2008 and November 2019. Genetic testing was performed in patients suspected of having Lynch syndrome.

Results

UTS of the cohort found 146 patients with MSI CRC (5.5%). Of these, excluding sporadic MSI CRC, 30 (1.1%) had a diagnosis of LS, and 19 (0.7%) had no germline pathogenic variants of the MMR gene. The CRC type in the latter group was identified as LLS. LLS occurred significantly more often in young patients, was left-sided, involved a KRAS variant and BRAF wild-type, and had a higher concordance rate with the Revised Bethesda Guidelines than sporadic MSI CRC. No significant differences were observed in terms of the clinicopathological factors between LLS and LS-associated MSI CRC; however, LLS had a lower frequency of LS-related neoplasms compared with LS.

Conclusions

Distinguishing clinically between LS and LLS was challenging, but the incidence of neoplasms was higher in LS than in LLS, suggesting the need for different screening and surveillance methods for the two subtypes.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532

    Article  CAS  PubMed  Google Scholar 

  2. Miyaki M, Seki M, Okamoto M et al (1990) Genetic changes and histopathological types in colorectal tumors from patients with familial adenomatous polyposis. Cancer Res 50:7166–7173

    CAS  PubMed  Google Scholar 

  3. Herman JG, Umar A, Polyak K et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95:6870–6875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Esteller M, Levine R, Baylin SB et al (1998) MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene 17:2413–2417

    Article  CAS  PubMed  Google Scholar 

  5. Kambara T, Simms LA, Whitehall VL et al (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53:1137–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yamaguchi T, Iijima T, Mori T et al (2006) Accumulation profile of frameshift mutations during development and progression of colorectal cancer from patients with hereditary nonpolyposis colorectal cancer. Dis Colon Rectum 49:399–406

    Article  PubMed  Google Scholar 

  7. Rodriguez-Soler M, Perez-Carbonell L, Guarinos C et al (2013) Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology 144:926–932 (e921; quiz e913–924)

    Article  CAS  PubMed  Google Scholar 

  8. Kang SY, Park CK, Chang DK et al (2015) Lynch-like syndrome: characterization and comparison with EPCAM deletion carriers. Int J Cancer 136:1568–1578

    Article  CAS  PubMed  Google Scholar 

  9. Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA et al (2014) Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146:643-646.e648

    Article  CAS  PubMed  Google Scholar 

  10. Chika N, Eguchi H, Kumamoto K et al (2017) Prevalence of Lynch syndrome and Lynch-like syndrome among patients with colorectal cancer in a Japanese hospital-based population. Jpn J Clin Oncol 47:108–117

    Article  PubMed  Google Scholar 

  11. Provenzale D, Gupta S, Ahnen DJ et al (2016) Genetic/familial high-risk assessment: colorectal version 1.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 14:1010–1030

    Article  CAS  PubMed  Google Scholar 

  12. Kang YJ, Killen J, Caruana M et al (2020) The predicted impact and cost-effectiveness of systematic testing of people with incident colorectal cancer for Lynch syndrome. Med J Aust 212:72–81

    Article  PubMed  Google Scholar 

  13. Ladabaum U, Wang G, Terdiman J et al (2011) Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med 155:69–79

    Article  PubMed  PubMed Central  Google Scholar 

  14. Win AK, Jenkins MA, Dowty JG et al (2017) Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev 26:404–412

    Article  CAS  PubMed  Google Scholar 

  15. Fujita M, Liu X, Iwasaki Y et al (2022) Population-based Screening for Hereditary Colorectal Cancer Variants in Japan. Clin Gastroenterol Hepatol 20:2132-2141.e2139

    Article  CAS  PubMed  Google Scholar 

  16. Golubicki M, Diaz-Gay M, Bonjoch L et al (2021) Comprehensive genomic characterization of fifteen early-onset lynch-like syndrome colorectal cancers. Cancers (Basel) 13:1259

    Article  CAS  PubMed  Google Scholar 

  17. Xu HX, Zhu P, Zheng YY et al (2020) Molecular screening and clinicopathologic characteristics of Lynch-like syndrome in a Chinese colorectal cancer cohort. Am J Cancer Res 10:3920–3934

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352:1851–1860

    Article  CAS  PubMed  Google Scholar 

  19. Golubicki M, Bonjoch L, Acuna-Ochoa JG, et al (2020) Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome. JCI Insight 5

  20. **cola RM, Clark JR, Carroll T et al (2019) Implication of DNA repair genes in Lynch-like syndrome. Fam Cancer 18:331–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Antelo M, Golubicki M, Roca E et al (2019) Lynch-like syndrome is as frequent as Lynch syndrome in early-onset nonfamilial nonpolyposis colorectal cancer. Int J Cancer 145:705–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mas-Moya J, Dudley B, Brand RE et al (2015) Clinicopathological comparison of colorectal and endometrial carcinomas in patients with Lynch-like syndrome versus patients with Lynch syndrome. Hum Pathol 46:1616–1625

    Article  PubMed  Google Scholar 

  23. Overbeek LI, Kets CM, Hebeda KM et al (2007) Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer. Br J Cancer 96:1605–1612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xu Y, Huang Z, Li C et al (2020) Comparison of molecular, clinicopathological, and pedigree differences between lynch-like and lynch syndromes. Front Genet 11:991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Venderbosch S, Nagtegaal ID, Maughan TS et al (2014) Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res 20:5322–5330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bucksch K, Zachariae S, Aretz S et al (2020) Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study. BMC Cancer 20:460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pico MD, Sanchez-Heras AB, Castillejo A et al (2020) Risk of cancer in family members of patients with lynch-like syndrome. Cancers (Basel) 12:2225

    Article  CAS  PubMed  Google Scholar 

  28. Pearlman R, Haraldsdottir S, de la Chapelle A et al (2019) Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome. J Med Genet 56:462–470

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all the patients and their families and Mr. James R. Valera for his assistance with editing this manuscript.

Funding

This work was funded by Japan Society for the Promotion of Science (Grant nos. 21K07187 ,18K07314, 21K16437).

Author information

Authors and Affiliations

  1. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-Ku, Tokyo, 113-8677, Japan

    Sakiko Nakamori, Misato Takao, Soichiro Natsume, Daisuke Nakano & Kazushige Kawai

  2. Department of Gastroenterology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-Ku, Tokyo, 113-8677, Japan

    Akinari Takao & Tatsuro Yamaguchi

  3. Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-Ku, Tokyo, 113-8677, Japan

    Takeru Iijima, Ekumi Kojika, Takuhiko Inokuchi, Ai Fujimoto & Makiko Urushibara

  4. Hereditary Tumor Research Project, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-Ku, Tokyo, 113-8677, Japan

    Takeru Iijima & Ekumi Kojika

  5. Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-Ku, Tokyo, 113-8677, Japan

    Shin-ichiro Horiguchi

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

    Hideyuki Ishida & Tatsuro Yamaguchi

Authors
  1. Sakiko Nakamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Misato Takao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akinari Takao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Soichiro Natsume
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takeru Iijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ekumi Kojika
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daisuke Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazushige Kawai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Takuhiko Inokuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ai Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Makiko Urushibara
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shin-ichiro Horiguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hideyuki Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Tatsuro Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Sakiko Nakamori: Acquisition of data, analysis and interpretation of data, drafting the article, final approval of the version to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Misato Takao, Akinari Takao, Soichiro Natsume, Daisiuke Nakano, Kazushige Kawai, Takuhiko Inokuchi, Makiko Urushibara, Shin-ichiro Horiguchi, and Hideyuki Ishida: Acquisition of data, critically revising the article, final approval of the version to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Takeru Iijima and Ekumi Kojika: Analysis and interpretation of data, critically revising the article, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Tatsuro Yamaguchi: Conception and design, acquisition of date, drafting the article, final approval of the version to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Tatsuro Yamaguchi.

Ethics declarations

Conflicts of interest

The authors have no conflict of interest.

Ethics statement

Approval of the research protocol by an Institutional Reviewer Board: The present study was approved by the ethical review board at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital.

Informed consent

N/A.

Registry and the Registration No. of the study/trial

Approval number: 612, 1202, 1433, and 2001.

Animal studies

N/A.

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 (DOCX 21 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakamori, S., Takao, M., Takao, A. et al. Clinicopathological characteristics of Lynch-like syndrome. Int J Clin Oncol 29, 944–952 (2024). https://doi.org/10.1007/s10147-024-02527-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-024-02527-x

Keywords

Search

Navigation