Skip to main content

Advertisement

SpringerLink
Log in

Mutation analysis of POLE gene in patients with early-onset colorectal cancer revealed a rare silent variant within the endonuclease domain with potential effect on splicing

  • Original Article
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

The colorectal cancer harbor germline, somatic or epimutations in mismatch repair genes, MUTYH or POLE gene, which lead to the hypermutated and ultramutator phenotypes with increased immune response. The mutations in POLE gene were reported to occur more frequently in early-onset colorectal cancer (EOCRC), and the patients are strong candidates for checkpoint inhibitor therapy. Here, we report mutation analysis within the endonuclease domain of the POLE gene in the cohort of patients with EOCRC in order to identify recurrent or new mutations and evaluate their association with the presence of tumor-infiltrating lymphocytes (TILs) and peritumoral lymphoid reaction. We have shown a significant association between MSI tumors and TILs (p = 0.004). Using sensitive single-tube nested PCR with subsequent Sanger sequencing, we have found in one female patient diagnosed at age 48 with rectal adenocarcinoma with mucinous elements staged pT3pN2pM1 a silent variant within the exon 9 NM_006231.3 c.849 C > T, NP_00622.2 p.Leu283 = recorded in dSNP as rs1232888774 with MAF = 0.00002. In silico prediction, result showed possible involvement into splicing; therefore, this rare variant can be involved into EOCRC pathogenesis. In the time of precise medicine, it is important to develop screening strategies also for less common conditions such as EOCRC allowing to predict tailored therapy for younger patients suffering from CRC that harbor mutations in the POLE gene.

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. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  2. Network Cancer Genome Atlas. Comprehensive molecular characterization of human and rectal cancer. Nature. 2012;18:330–7.

    Article  CAS  Google Scholar 

  3. Mahasneh A, Al-Shaheri F, Jamal E. Molecular biomarkers for an early diagnosis, effective treatment and prognosis of colorectal cancer: current updates. Exp Mol Pathol. 2017;102:475–83.

    Article  CAS  PubMed  Google Scholar 

  4. Pilati C, Shinde J, Alexandrov LB, et al. Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas. J Pathol. 2017;242:10–5.

    Article  CAS  PubMed  Google Scholar 

  5. Cohen R, Sroussi M, Pilati C, Houry S, Laurent-Puig P, André T. Unresectable metastatic colorectal cancer patient cured with cetuxomab-based chemotherapy: a case report with new molecular insights. Gastrointest Oncol. 2018;9:E23–7.

    Article  Google Scholar 

  6. Palles C, Cazier JB, Howarth KM, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45:136–44.

    Article  CAS  PubMed  Google Scholar 

  7. Bellido F, Pineda M, Aiza G, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med. 2016;18:325–32.

    Article  CAS  PubMed  Google Scholar 

  8. Church DN, Briggs SE, Palles C, Collaborators NSECG, Kaur K, Taylor J, Tomlinson IP, et al. DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer. Hum Mol Genet. 2013;22:2820–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. The Cancer Genome Atlas Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.

    Article  CAS  Google Scholar 

  10. Song Z, Cheng G, Xu C, Wang W, Shao Y, Zhang Y. Clinicopathological characteristics of POLE mutation in patients with non-small cell lung cancer. Lung Cancer. 2018;118:57–61.

    Article  PubMed  Google Scholar 

  11. Rayner E, van Gool IC, Palles C, et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer. 2016;16:71–81.

    Article  CAS  PubMed  Google Scholar 

  12. Domingo E, Freeman-Mills L, Rayner E, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol. 2016;1:207–16.

    Article  PubMed  Google Scholar 

  13. Guerra J, Pinto C, Pinto D, et al. POLE somatic mutations in advanced colorectal cancer. Cancer Med. 2017;6:2966–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Howitt BE, Shukla SA, Sholl LM, et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 2015;1:1319–23.

    Article  PubMed  Google Scholar 

  15. Le DT, Durham JN, Smith KN, et al. PD-1 blockade in tumors in tumors with mismatch—repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gong J, Wang C, Lee PP, Chu P, Fakih M. Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a POLE mutations. J Natl Canc Netw. 2017;15:142–7.

    Article  Google Scholar 

  17. Ahn SM, Ansari AA, Kim J, et al. The somatic POLE P286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy. Oncotarget. 2017;7:68638–49.

    Google Scholar 

  18. Connell LC, Mota JM, Braghiroli MI, Hoff PM. The rising incidence of younger patients with colorectal cancer: questions about screening, biology, and treatment. Curr Treat Options Oncol. 2017;18:23.

    Article  PubMed  Google Scholar 

  19. Schellerer VS, Merkel S, Schumann SC, et al. Despite aggressive histopathology survival is not impaired in young patients with colorectal cancer: CRC in patietns under 50 years of age. Int J Colorectal Dis. 2012;27:71–9.

    Article  PubMed  Google Scholar 

  20. Murphy CC, Singal AG. Establishing a research agenda for early-onset colorectal cancer. PLOS Med. 2018;15:e1002577.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Temko D, Van Gool IC, Rayner E, et al. Somatic POLE exonuclease domain mutation are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response. J Pathol. 2018;245:283–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kašubová I, Kalman M, Jašek K, et al. Stratification of patients with colorectal cancer without the recorded family history. Oncol Lett. 2019;17:3649–56.

    PubMed  PubMed Central  Google Scholar 

  23. Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. 7th ed. New York: Wiley; 2009.

    Google Scholar 

  24. Edge SB, Byrd SR, Compton CC. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.

    Google Scholar 

  25. Jenkins MA, Hayashi S, O’Shea AM, et al. Colon Cancer Family Registry. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population—based study. Gastroenterology. 2007;133:48–56.

    Article  CAS  PubMed  Google Scholar 

  26. Hyde A, Fontaine D, Stuckless S, et al. A histology-based model for predicting microsatellite instability in colorectal cancers. Am J Surg Pathol. 2010;34:1820–9.

    Article  PubMed  Google Scholar 

  27. Malicherova B, Burjanivova T, Grendar M, et al. Droplet digital PCR for detection of BRAF V600E mutation in formalin-fixed, paraffin-embedded melanoma tissues: a comparison with Cobas 4800, Sanger sequencing, and allele-specific PCR. Am J Transl Res. 2018;10:3773–81.

    PubMed  PubMed Central  Google Scholar 

  28. Jasek K, Buzalkova V, Minarik G, et al. Detection of mutations in the BRAF gene in patients with KIT and PDGFRA wild-type gastrointestinal stromal tunors. Virchows Arch. 2017;470:29–36.

    Article  CAS  PubMed  Google Scholar 

  29. Esteban-Jurado C, Giménez-Zaragoza D, Muñoz J, et al. POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. Oncotarget. 2017;8:26732–43.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Wang C, Gong J, Tu TY, Lee PP, Fakih M. Immune profiling of microsatellite instability-high and polymerase ε (POLE)- mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy. J Gastrointest Oncol. 2018;9:404–15.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Grasso CS, Giannakis M, Wells DK, et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov. 2018;8:730–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the Biomedical center Martin (ITMS 26220220187), which is co-financed from EU sources, by Government of Russian Federation, Grant 08-08, and by the projects of the Slovak Research and development Agency APVV Grant APVV-16-0066, and VEGA Grants 1/0199/17 and 1/0380/18.

Author information

Author notes

  1. Zora Lasabová and Michal Kalman: co-first/co-equal authorship.

Authors and Affiliations

  1. Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Maláhora 4C, 03601, Martin, Slovakia

    Zora Lasabová, Veronika Holubeková, Ivana Kašubová, Karin Jašek, Sandra Meršaková & Bibiana Malicherová

  2. Department of Molecular Biology and Genomics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia

    Zora Lasabová

  3. Department of Pathological Anatomy, Jessenius Faculty of Medicine University Hospital in Martin, Comenius University in Bratislava, Martin, Slovakia

    Michal Kalman & Lukáš Plank

  4. Department of Bioinformatics, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia

    Marián Grendár

  5. International Research Centre “Biotechnologies of the Third Millennium”, ITMO University, Saint-Petersburg, Russian Federation

    Denis Baranenko

  6. Department of Thoracic Surgery, Faculty of Medicine and Dentistry, Medical University of Silesia, Katowice, Poland

    Mariusz Adamek

  7. Department of Internal Medicine, Brothers of Mercy Hospital, Brno, Czech Republic

    Peter Kruzliak

Authors
  1. Zora Lasabová
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michal Kalman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Veronika Holubeková
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marián Grendár
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ivana Kašubová
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karin Jašek
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sandra Meršaková
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bibiana Malicherová
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Denis Baranenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mariusz Adamek
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Peter Kruzliak
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Lukáš Plank
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zora Lasabová or Peter Kruzliak.

Ethics declarations

Conflict of interest

All authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lasabová, Z., Kalman, M., Holubeková, V. et al. Mutation analysis of POLE gene in patients with early-onset colorectal cancer revealed a rare silent variant within the endonuclease domain with potential effect on splicing. Clin Exp Med 19, 393–400 (2019). https://doi.org/10.1007/s10238-019-00558-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-019-00558-7

Keywords

Search

Navigation