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.
- COLORECTAL CANCER
- MICROSATELLITE INSTABILITY
- RADIATION THERAPY
- DNA DAMAGE
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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.
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