Advertisement

Molecular Medicine

, Volume 19, Issue 1, pp 286–293 | Cite as

Influence of Microsatellite Instability and KRAS and BRAF Mutations on Lymph Node Harvest in Stage I–III Colon Cancers

  • Marianne Berg
  • Marianne Guriby
  • Oddmund Nordgård
  • Bjørn S. Nedrebø
  • Terje C. Ahlquist
  • Rune Smaaland
  • Satu Oltedal
  • Jon Arne Søreide
  • Hartwig Kørner
  • Ragnhild A. Lothe
  • Kjetil Søreide
Research Article

Abstract

Lymph node (LN) harvest is influenced by several factors, including tumor genetics. Microsatellite instability (MSI) is associated with improved node harvest, but the association to other genetic factors is largely unknown. Research methods included a prospective series of stage I-III colon cancer patients undergoing ex vivo sentinel-node sampling. The presence of MSI, KRAS mutations in codons 12 and 13, and BRAFV600E mutations was analyzed. Uni- and multivariate regression models for node sampling were adjusted for clinical, pathological and molecular features. Of 204 patients, 67% had an adequate harvest (≥12 nodes). Adequate harvest was highest in patients whose tumors exhibited MSI (79%; odds ratio (OR) 2.5, 95% confidence interval (CI) 1.2–4.9; P = 0.007) or were located in the proximal colon (73%; 2.8, 1.5–5.3; P = 0.002). In multiple linear regression, MSI was a significant predictor of the total LN count (P= 0.02). Total node count was highest for cancers with MSI and no KRAS/BRAF mutations. The independent association between MSI and a high LN count persisted for stage I and II cancers (P= 0.04). Tumor location in the proximal colon was the only significant predictor of an adequate LN harvest (adjusted OR 2.4, 95% CI 1.2–4.9; P = 0.01). An increase in the total number of nodes harvested was not associated with an increase in nodal metastasis. In conclusion, number of nodes harvested is highest for cancers of the proximal colon and with MSI. The nodal harvest associated with MSI is influenced by BRAF and KRAS genotypes, even for cancers of proximal location. Mechanisms behind the molecular diversity and node yield should be further explored.

Notes

Acknowledgments

This study was funded in part by grants from the Folke Hermansens Cancer Foundation (grant 424508 to K Søreide for M Berg as a postdoctoral fellow) and the Mjaaland Cancer Research Fund (grant 424506 to K Søreide). This work was also supported in part by grants from the Norwegian Cancer Society (grants 2008-0151 to RA Lothe for TC Ahlquist as a postdoctoral fellow, 2009-0231 to RA Lothe and T-97452 to O Nordgård) and from the Western Norway Health authorities (grant 911115 to O Nordgård). TC Ahlquist is currently employed by Roche Norway.

References

  1. 1.
    Bilimoria KY, et al. (2008) Adequacy and importance of lymph node evaluation for colon cancer in the elderly. J. Am. Coll. Surg. 206:247–54.CrossRefPubMedGoogle Scholar
  2. 2.
    Chang GJ, Rodriguez-Bigas MA, Skibber JM, Moyer VA.(2007) Lymph node evaluation and survival after curative resection of colon cancer: systematic review. J. Natl. Cancer Inst. 99:433–41.CrossRefPubMedGoogle Scholar
  3. 3.
    Wang J, et al. (2009) Should total number of lymph nodes be used as a quality of care measure for stage III colon cancer? Ann. Surg. 249:559–63.CrossRefPubMedGoogle Scholar
  4. 4.
    Veen T, et al. (2013) Qualitative and quantitative issues of lymph nodes as prognostic factor in colon cancer. Dig. Surg. 30:1–11.CrossRefPubMedGoogle Scholar
  5. 5.
    Cianchi F, et al. (2002) Lymph node recovery from colorectal tumor specimens: recommendation for a minimum number of lymph nodes to be examined. World J. Surg. 26:384–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Nathan H, et al. (2011) Variation in lymph node assessment after colon cancer resection: patient, surgeon, pathologist, or hospital? J. Gastrointest. Surg. 15:471–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Shia J, Wang H, Nash GM, Klimstra DS.(2012) Lymph node staging in colorectal cancer: revisiting the benchmark of at least 12 lymph nodes in r0 resection. J. Am. Coll. Surg. 214:346–55.CrossRefGoogle Scholar
  8. 8.
    Wright FC, Law CH, Berry S, Smith AJ.(2009) Clinically important aspects of lymph node assessment in colon cancer. J. Surg. Oncol. 99:246–55.CrossRefGoogle Scholar
  9. 9.
    Baxter NN. (2009) Is lymph node count an ideal quality indicator for cancer care? J. Surg. Oncol. 99:265–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Nedrebø B, et al. (2013) Risk factors associated with poor lymph node harvest after colon cancer surgery in a national cohort. Colorectal Dis. 15:e301–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Søreide K, Nedrebø BS, Søreide JA, Slewa A, Kørner H. (2009) Lymph node harvest in colon cancer: influence of microsatellite instability and proximal tumor location. World J. Surg. 33:2695–703.CrossRefPubMedGoogle Scholar
  12. 12.
    Belt EJ, et al. (2012) High lymph node yield is related to microsatellite instability in colon cancer. Ann. Surg. Oncol. 19:1222–30.CrossRefPubMedGoogle Scholar
  13. 13.
    Eveno C, et al. (2010) Association between a high number of isolated lymph nodes in T1 to T4 N0M0 colorectal cancer and the microsatellite instability phenotype. Arch. Surg. 145:12–7.PubMedGoogle Scholar
  14. 14.
    Nordgard O, et al. (2009) Quantitative RT-PCR detection of tumor cells in sentinel lymph nodes isolated from colon cancer patients with an ex vivo approach. Ann. Surg. 249:602–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Bjugn R, Dirdal HU.(2001) Colorectal cancer: experiences with the use of standardized forms for reporting pathologic-anatomic data. Tidsskr Nor Laegeforen 121:1697–701.PubMedGoogle Scholar
  16. 16.
    Umar A, et al. (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 96:261–8.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gilje B, Heikkila R, Oltedal S, Tjensvoll K, Nordgård O.(2008) High-fidelity DNA polymerase enhances the sensitivity of a peptide nucleic acid clamp PCR assay for K-ras mutations. J. Mol. Diagn. 10:325–31.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Oltedal S, et al. (2010) Detection of occult metastases in sentinel lymph nodes from colon cancer patients by K-ras mutation peptide nucleic acid clamp PCR. Ann. Surg. 251:1087–91.CrossRefPubMedGoogle Scholar
  19. 19.
    Ahlquist T, et al. (2008) RAS signaling in colorectal carcinomas through alteration of RAS, RAF, NF1, and/or RASSF1A. Neoplasia. 10:680–6.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Pallant J. (2010) Multiple regression. In: SPSS Survival Manual. McGraw-Hill, London, pp. 146–67.Google Scholar
  21. 21.
    Lang TA, Secic M.(2006) Prediciting values from one or more variables: reporting regression analyses. In: How to Report Statistics in Medicine. Annotated Guidelines for Authors, Editors, and Reviewers. Lang TA, Secic M, Eds. American College of Physicians, Philadelphia, pp. 85–107.Google Scholar
  22. 22.
    Merok MA, et al. (2013) Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Ann. Oncol. 24:1274–82.CrossRefPubMedGoogle Scholar
  23. 23.
    Morikawa T, et al. (2012) Predictors of lymph node count in colorectal cancer resections: data from US nationwide prospective cohort studies. Arch. Surg. 8:715–23.Google Scholar
  24. 24.
    Yamauchi M, et al. (2012) Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 61:847–54.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sinicrope FA, Sargent DJ.(2012) Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive and therapeutic implications. Clin. Cancer Res. 18:1506–12.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ogino S, et al. (2012) Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from Intergroup Trial CALGB 89803. Clin. Cancer Res. 18:890–900.CrossRefPubMedGoogle Scholar
  27. 27.
    MacQuarrie E, et al. (2012) Microsatellite instability status does not predict total lymph node or negative lymph node retrieval in stage III colon cancer. Hum. Pathol. 43:1256–64.Google Scholar
  28. 28.
    Yamauchi M, et al. (2012) Colorectal cancer: a tale of two sides or a continuum? Gut. 61:794–7.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Alexander J, et al. (2001) Histopathological identification of colon cancer with microsatellite instability. Am. J. Pathol. 158:527–35.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Phillips SM, et al. (2004) Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br. J. Surg. 91:469–75.CrossRefPubMedGoogle Scholar
  31. 31.
    Deschoolmeester V, Baay M, Lardon F, Pauwels P, Peeters M.(2011) Immune cells in colorectal cancer: prognostic relevance and role of MSI. Cancer Microenviron. 4:377–92.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Nosho K, et al. (2010) Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J. Pathol. 222:350–66.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Parsons HM, et al. (2011) Association between lymph node evaluation for colon cancer and node positivity over the past 20 years. JAMA. 306:1089–97.CrossRefPubMedGoogle Scholar
  34. 34.
    Porter GA, et al. (2012) Improving nodal harvest in colorectal cancer: so what? Ann. Surg. Oncol. 19:1066–73.CrossRefPubMedGoogle Scholar
  35. 35.
    Nash GM, et al. (2011) A predictive model for lymph node yield in colon cancer resection specimens. Ann. Surg. 253:316–22.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2013

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Marianne Berg
    • 1
  • Marianne Guriby
    • 2
    • 3
  • Oddmund Nordgård
    • 4
  • Bjørn S. Nedrebø
    • 1
  • Terje C. Ahlquist
    • 2
    • 3
  • Rune Smaaland
    • 4
  • Satu Oltedal
    • 4
  • Jon Arne Søreide
    • 1
    • 5
  • Hartwig Kørner
    • 1
    • 5
  • Ragnhild A. Lothe
    • 2
    • 3
  • Kjetil Søreide
    • 1
    • 5
  1. 1.Department of Gastrointestinal SurgeryStavanger University HospitalStavangerNorway
  2. 2.Department of Cancer Prevention, Institute for Cancer ResearchOslo University Hospital, Norwegian Radium HospitalOsloNorway
  3. 3.Center for Cancer Biomedicine, Faculty of MedicineUniversity of OsloOsloNorway
  4. 4.Department of Hematology and OncologyStavanger University HospitalStavangerNorway
  5. 5.Department of Clinical MedicineUniversity of BergenBergenNorway

Personalised recommendations