A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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-tekijät tai -toimittajat

Julkaisun tiedot

Julkaisun kaikki tekijät tai toimittajat: Martin, Samantha; Katainen, Riku; Taira, Aurora; Välimäki, Niko; Ristimäki, Ari; Seppälä, Toni; Renkonen-Sinisalo, Laura; Lepistö, Anna; Tahkola, Kyösti; Mattila, Anne; et al.

Lehti tai sarja: Human Molecular Genetics

ISSN: 0964-6906

eISSN: 1460-2083

Julkaisuvuosi: 2024

Ilmestymispäivä: 24.08.2024

Volyymi: 33

Lehden numero: 21

Artikkelin sivunumerot: 1858–1872

Kustantaja: Oxford University Press

Julkaisumaa: Britannia

Julkaisun kieli: englanti

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

Julkaisun avoin saatavuus: Avoimesti saatavilla

Julkaisukanavan avoin saatavuus: Osittain avoin julkaisukanava

Julkaisu on rinnakkaistallennettu (JYX): https://jyx.jyu.fi/handle/123456789/96837

Tiivistelmä

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.

YSO-asiasanat: paksusuolisyöpä; kasvaimet; mutaatiot; Lynchin oireyhtymä; syöpägeenit; mikrosatelliitit; genomiikka; RNA-sekvensointi

Vapaat asiasanat: colorectal cancer; microsatellite instability; Lynch syndrome; whole genome sequencing; RNA sequencing

Liittyvät organisaatiot

OKM-raportointi: Kyllä

VIRTA-lähetysvuosi: 2024

Alustava JUFO-taso: 2