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Genetics and Genomics

Somatic hits in mismatch repair genes in colorectal cancer among non-seminoma testicular cancer survivors

Abstract

Background

Non-seminoma testicular cancer survivors (TCS) have an increased risk of developing colorectal cancer (CRC) when they have been treated with platinum-based chemotherapy. Previously we demonstrated that among Hodgkin lymphoma survivors (HLS) there is enrichment of rare mismatch repair (MMR) deficient (MMRd) CRCs with somatic hits in MMR genes. We speculate that this phenomenon could also occur among other cancer survivors. We therefore aim to determine the MMR status and its underlying mechanism in CRC among TCS (TCS-CRC).

Methods

Thirty TCS-CRC, identified through the Dutch pathology registry, were analysed for MMR proteins by immunohistochemistry. Next-generation sequencing was performed in MMRd CRCs without MLH1 promoter hypermethylation (n = 4). Data were compared with a male cohort with primary CRC (P-CRC, n = 629).

Results

MMRd was found in 17% of TCS-CRCs vs. 9% in P-CRC (p = 0.13). MMRd was more often caused by somatic double or single hit in MMR genes by mutation or loss of heterozygosity in TCS-CRCs (3/30 (10%) vs. 11/629 (2%) in P-CRCs (p < 0.01)).

Conclusions

MMRd CRCs with somatic double or single hit are more frequent in this small cohort of TCS compared with P-CRC. Exposure to anticancer treatments appears to be associated with the development of these rare MMRd CRC among cancer survivors.

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Fig. 1: Study flowchart.

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Data availability

Data are available upon request from the corresponding author.

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Acknowledgements

The authors thank the registration team of the Netherlands Comprehensive Cancer Organisation (IKNL) for the collection of data for the Netherlands Cancer Registry. We would like to acknowledge PALGA (Dutch Pathology Registry) for providing data and collection of specimens. We would like to acknowledge the NCI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NCI-AVL Biobank material and lab support. We also thank the Sacha Swarttouw Stichting for funding this study.

Funding

This study received a grant from the Dutch Digestive Foundation (Maag-, lever-, darmstichting, MLDS) and Sacha Swarttouw-Hijmans Foundation.

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Contributions

All authors contributed to the study concept and design. BLMY performed acquisition of the data. PS contributed to histopathological evaluation of tissue samples and TvW performed NGS. BLMY, PS and MEvL wrote the manuscript and all authors reviewed and approved the manuscript. PS and MEvL supervised the study.

Corresponding author

Correspondence to Monique E. van Leerdam.

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The authors declare no competing interests.

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This study was approved by the Institutional Review Board of the Netherlands Cancer Institute (CFMPB703). Collection, storage and use of patient-derived tissue and data were performed in compliance with the ‘Code of conduct for responsible use’, Dutch Federation of Dutch Scientific Societies, the Netherlands.

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Ykema, B.L.M., Breekveldt, E.C.H., Carvalho, B. et al. Somatic hits in mismatch repair genes in colorectal cancer among non-seminoma testicular cancer survivors. Br J Cancer 127, 1991–1996 (2022). https://doi.org/10.1038/s41416-022-01972-7

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