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Original article
Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment
  1. Lisanne S Rigter1,
  2. Petur Snaebjornsson2,
  3. Efraim H Rosenberg2,
  4. Peggy N Atmodimedjo3,
  5. Berthe M Aleman4,
  6. Jelle ten Hoeve5,
  7. Willemina R Geurts-Giele3,
  8. PALGA group,
  9. Thomas W van Ravesteyn6,
  10. Johan Hoeksel6,
  11. Gerrit A Meijer2,
  12. Hein te Riele6,
  13. Flora E van Leeuwen7,
  14. Winand N Dinjens3,
  15. Monique E van Leerdam1
    1. 1Department of Gastroenterology, Netherlands Cancer Institute, Amsterdam, The Netherlands
    2. 2Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
    3. 3Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
    4. 4Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
    5. 5Division of Computational Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands
    6. 6Division of Biological Stress Response, Netherlands Cancer Institute, Amsterdam, The Netherlands
    7. 7Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
    1. Correspondence to Dr Monique E van Leerdam, Department of Gastroenterology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; m.v.leerdam{at}


    Objective Hodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics.

    Design 54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS/BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111).

    Results KRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, p<0.001). Loss of MLH1/PMS2 staining and MLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome.

    Conclusions We have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment.


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    • Contributors Study concept and design: LSR, BMA, GAM, FEvL, MEvL, PS. Acquisition of data: LSR, PS, PNA, TWvR and JH. Analysis and interpretation of data: LSR, PS, WND, EHR, JtH, PNA, WRG-G, GAM, HtR, TWvR, JH, FEvL and MEvL. Drafting of the manuscript: LSR and PS. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: LSR, FEvL and MEvL. Obtained funding: MEvL, MLDS funding project FP14-04. Administrative, technical or material support: PALGA group. Study supervision: GAM, HtR, FEvL and MEvL.

    • Collaborators PALGA collaborators; K Schelfout, HADM van Herk, ID Nagtegaal, JWR Meijer.

    • Funding Dutch Society of Gastroenterology and Hepatology (Maag Lever Darm Stichting (MLDS) (FP14-04).

    • Competing interests MEvL obtained funding from the Dutch Society of Gastroenterology and Hepatology (Maag Lever Darm Stichting (MLDS) funding project FP14-04).

    • Ethics approval Translational Research Board of the Netherlands Cancer Institute (study number CFMPB208).

    • Provenance and peer review Not commissioned; externally peer reviewed.