Familial Cancer

, Volume 15, Issue 2, pp 253–260 | Cite as

Mismatch repair deficiency concordance between primary colorectal cancer and corresponding metastasis

  • Sigurdis Haraldsdottir
  • Rachel Roth
  • Rachel Pearlman
  • Heather Hampel
  • Christina A. Arnold
  • Wendy L. Frankel
Original Article


Universal screening for mismatch repair deficiency (dMMR) in cancer is increasingly being implemented to detect Lynch syndrome and aid in treatment decisions. The mismatch repair (MMR) immunohistochemistry (IHC) concordance rate between primary colorectal cancer (CRC) and metastasis is unknown. At times, only metastatic tumor is available for screening (lymph node, liver, lung etc.) rather than the primary tumor. Therefore, it is important to confirm that tissue from metastases can be used for screening for dMMR. We tested dMMR primary and metastatic tumor to assess concordance between the two. We identified dMMR CRC resected at Ohio State University from 1999 to 2013 and stained a corresponding metastasis for all four MMR proteins (MLH1, MSH2, MSH6, PMS2) with IHC. A total of 50 primary CRC with dMMR and available regional lymph nodes (LN; 26 cases) or other metastatic tissue (24 cases) were identified. Thirteen cases were explained by MLH1 hypermethylation and 10 cases had Lynch syndrome. Two cases had somatic MMR mutations and the etiology for dMMR was unknown in 25 cases. All cases showed concordance in IHC staining between the primary tumor and corresponding metastatic tissue. In 36 cases, metastatic LN/other site was resected at the same time as the primary tumor. In 14 cases, time lapsed [median 16.5 months; quartile (Q)1 8.0; Q3 25; range 3–69] from the primary resection until metastatic resection. Metastatic tissue can be used to screen for Lynch syndrome and dMMR.


Deficient mismatch repair system Lynch syndrome Immunohistochemistry Metastatic cancer Colorectal cancer Concordance 


  1. 1.
    Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561CrossRefPubMedGoogle Scholar
  2. 2.
    Risinger JI, Berchuck A, Kohler MF, Watson P, Lynch HT, Boyd J (1993) Genetic instability of microsatellites in endometrial carcinoma. Cancer Res 53(21):5100–5103PubMedGoogle Scholar
  3. 3.
    Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch Syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352(18):1851–1860CrossRefPubMedGoogle Scholar
  4. 4.
    Kane MF, Loda M, Gaida GM et al (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57:808–811PubMedGoogle Scholar
  5. 5.
    Haraldsdottir S, Hampel H, Tomsic J et al (2014) Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology 147(6):1308–1316CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Mensenkamp AR, Vogelaar IP, van Zelst-Stams WAG et al (2014) Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146(3):643–646CrossRefPubMedGoogle Scholar
  7. 7.
    Rodríguez-Soler M, Pérez-Carbonell L, Guarinos C et al (2013) Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology 144(5):926–932CrossRefPubMedGoogle Scholar
  8. 8.
    Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN (2009) EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med 11(1):42–65CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Network NCC (2014) NCCN genetic/familial high-risk assessment: colorectal. Version 1.2014. Accessed 30 April 2014Google Scholar
  10. 10.
    Giardiello FM, Allen JI, Axilbund JE et al (2014) Guidelines on genetic evaluation and management of lynch syndrome: a consensus statement by the US multi-society task force on colorectal cancer. Gastroenterology 147(2):502–526CrossRefPubMedGoogle Scholar
  11. 11.
    Ribic CM, Sargent DJ, Moore MJ et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Sargent DJ, Marsoni S, Monges G et al (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28(20):3219–3226CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Network NCC (2015) NCCN clinical practice guidelines in oncology: thyroid carcinoma. Version 3.2015. Accessed 24 July 2015Google Scholar
  14. 14.
    Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520CrossRefPubMedGoogle Scholar
  15. 15.
    Leach FS, Polyak K, Burrell M et al (1996) Expression of the human mismatch repair gene hMSH2 in normal and neoplastic tissues. Cancer Res 56(2):235–240PubMedGoogle Scholar
  16. 16.
    Aaltonen L, Peltomaki P, Leach F et al (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260(5109):812–816CrossRefPubMedGoogle Scholar
  17. 17.
    Salahshor S, Koelble K, Rubio C, Lindblom A (2001) Microsatellite Instability and hMLH1 and hMSH2 expression analysis in familial and sporadic colorectal cancer. Lab Investig J Tech Methods Pathol 81(4):535–541CrossRefGoogle Scholar
  18. 18.
    Shia J (2008) Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: part I. The utility of immunohistochemistry. J Mol Diagn 10(4):293–300CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kumarasinghe AP, de Boer B, Bateman AC, Kumarasinghe MP (2010) DNA mismatch repair enzyme immunohistochemistry in colorectal cancer: a comparison of biopsy and resection material. Pathology 42(5):414–420CrossRefPubMedGoogle Scholar
  20. 20.
    Shia J, Stadler Z, Weiser MR et al (2011) Immunohistochemical staining for DNA mismatch repair proteins in intestinal tract carcinoma: how reliable are biopsy samples? Am J Surg Pathol 35(3):447–454CrossRefPubMedGoogle Scholar
  21. 21.
    Warrier SK, Trainer AH, Lynch AC et al (2011) Preoperative diagnosis of Lynch syndrome with DNA mismatch repair immunohistochemistry on a diagnostic biopsy. Dis Colon Rectum 54(12):1480–1487CrossRefPubMedGoogle Scholar
  22. 22.
    Kononen J, Bubendorf L, Kallioniemi A et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7):844–847CrossRefPubMedGoogle Scholar
  23. 23.
    Hendriks Y, Franken P, Dierssen JW et al (2003) Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors. Am J Pathol 162:469–477CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    ClinicalTrials.gov. Ohio Colorectal Cancer Prevention Initiative (OCCPI). http://clinicaltrials.gov/show/NCT01850654. Accessed 04 Oct 2014
  25. 25.
    Hampel H, Frankel WL, Martin E et al (2008) Feasibility of screening for lynch syndrome among patients with colorectal cancer. J Clin Oncol 26(35):5783–5788CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    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(12):6870–6875CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Larsen NB, HeibergEngel PJ, Rasmussen M, Rasmussen LJ (2009) Differential expression of hMLH1 in sporadic human colorectal cancer tumors and distant metastases. APMIS 117(11):839–848CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Sigurdis Haraldsdottir
    • 1
  • Rachel Roth
    • 2
  • Rachel Pearlman
    • 3
  • Heather Hampel
    • 3
  • Christina A. Arnold
    • 2
  • Wendy L. Frankel
    • 2
  1. 1.Division of Medical Oncology, Department of Internal MedicineStanford UniversityStanfordUSA
  2. 2.Department of PathologyOhio State University Medical CenterColumbusUSA
  3. 3.Division of Human Genetics, Department of Internal MedicineOhio State University Medical CenterColumbusUSA

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