A1 Journal article (refereed)
Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers : different patterns of clonal evolution yield highly similar tumours (2024)

Martin, S., Katainen, R., Taira, A., Välimäki, N., Ristimäki, A., Seppälä, T., Renkonen-Sinisalo, L., Lepistö, A., Tahkola, K., Mattila, A., Koskensalo, S., Mecklin, J.-P., Rajamäki, K., Palin, K., & Aaltonen, L. A. (2024). Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers : different patterns of clonal evolution yield highly similar tumours. Human Molecular Genetics, 33(21), 1858-1872. https://doi.org/10.1093/hmg/ddae124

JYU authors or editors

Publication details

All authors or editors: Martin, Samantha; Katainen, Riku; Taira, Aurora; Välimäki, Niko; Ristimäki, Ari; Seppälä, Toni; Renkonen-Sinisalo, Laura; Lepistö, Anna; Tahkola, Kyösti; Mattila, Anne; et al.

Journal or series: Human Molecular Genetics

ISSN: 0964-6906

eISSN: 1460-2083

Publication year: 2024

Publication date: 24/08/2024

Volume: 33

Issue number: 21

Pages range: 1858–1872

Publisher: Oxford University Press

Publication country: United Kingdom

Publication language: English

DOI: https://doi.org/10.1093/hmg/ddae124

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/96837

Abstract

Microsatellite unstable colorectal cancer (MSI-CRC) can arise through germline mutations in mismatch repair (MMR) genes in individuals with Lynch syndrome (LS), or sporadically through promoter methylation of the MMR gene MLH1. Despite the different origins of hereditary and sporadic MSI tumours, their genomic features have not been extensively compared. A prominent feature of MMR-deficient genomes is the occurrence of many indels in short repeat sequences, an understudied mutation type due to the technical challenges of variant calling in these regions. In this study, we performed whole genome sequencing and RNA-sequencing on 29 sporadic and 14 hereditary MSI-CRCs. We compared the tumour groups by analysing genome-wide mutation densities, microsatellite repeat indels, recurrent protein-coding variants, signatures of single base, doublet base, and indel mutations, and changes in gene expression. We show that the mutational landscapes of hereditary and sporadic MSI-CRCs, including mutational signatures and mutation densities genome-wide and in microsatellites, are highly similar. Only a low number of differentially expressed genes were found, enriched to interferon-γ regulated immune response pathways. Analysis of the variance in allelic fractions of somatic variants in each tumour group revealed higher clonal heterogeneity in sporadic MSI-CRCs. Our results suggest that the differing molecular origins of MMR deficiency in hereditary and sporadic MSI-CRCs do not result in substantial differences in the mutational landscapes of these tumours. The divergent patterns of clonal evolution between the tumour groups may have clinical implications, as high clonal heterogeneity has been associated with decreased tumour immunosurveillance and reduced responsiveness to immunotherapy.

Keywords: cancer of the large intestine; tumours; mutations; Lynch syndrome; oncogenes; microsatellites; genomics; RNA sequencing

Free keywords: colorectal cancer; microsatellite instability; Lynch syndrome; whole genome sequencing; RNA sequencing

Contributing organizations

Ministry reporting: Yes

VIRTA submission year: 2024

Preliminary JUFO rating: 2