Molecular Biology of Cancer

Telomere length as a predictor of therapy response and survival in patients diagnosed with ovarian carcinoma

In collaboration with the National Institute of Public Health, we investigated the regulation of telomere length (TL) in 209 ovarian cancer patients. TL in leukocytes and tumors was measured by multiplex qPCR. Methylation profiles and gene expression of shelterin and telomerase were analyzed by Illumina microarrays and RNA-Seq. Patients sensitive to platinum-based therapy had shorter leukocyte TL. Transcriptomic analysis showed peroxisome proliferator-activated receptor (PPAR) signaling pathway alterations in patients with differing therapy responses. Tumor TL below the median predicted better overall survival.

Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer

We characterised colorectal cancer liver metastases (CRCLMs) and addressed molecular profi les in Synchronous (SmCRC) and Metachronous (MmCRC) colorectal cancer. The most frequent somatic mutations were in APC, SYNE1, TP53, and TTN genes. The differently methylated and expressed genes comprised those in cell adhesion, extracellular matrix organisation and degradation, neuroactive ligand-receptor interaction. MmCRC patients had higher mutational burden, more duplications and deletions, and a higher heterogeneous mutational signature than SmCRC. The combined analysis resulted in 107 deregulated genes related to relaxin, estrogen, PI3K-Akt, WNT signalling pathways, and intracellular second messenger signalling. Our data contribute to molecular distinctions between SmCRC and MmCRC.

Publication:

Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer. Horak J, Kubecek O, Siskova A, Honkova K, Chvojkova I, Krupova M, Manethova M, Vodenkova S, García-Mulero S, John S, Cecka F, Vodickova L, Petera J, Filip S, Vymetalkova V. Frontiers Oncol. 2023 Apr 27:13:1133598. doi: 10.3389/fonc.2023.1133598.

Mutational analysis of driver genes defines the colorectal adenoma: in situ carcinoma transition

To dissect the genetics in the evolvement of colorectal adenomas into colorectal carcinomas (CRC) we have analyzed the mutation spectrum of genes involved in CRC (APC, BRAF, EGFR, NRAS, KRAS, PIK3CA, POLE, POLD1, SMAD4, PTEN, TP53) in 96 adenomas and in situ carcinomas by a high-throughput genotyping technique. We found a high frequency of pathogenic variants in these genes. The APC, KRAS and TP53 mutation frequencies were lower in adenomas than in in situ carcinoma samples. The frequency distribution of mutations was as follows: low-grade adenomas-high-grade adenomas-in situ carcinoma: APC gene 42.9-56.0-54.5%; KRAS gene 32.7-32.0-45.5%; TP53 gene 8.2-20.0-18.2%. KRAS mutations occurred mainly in villous histology, APC promoter methylation associated with POLE genetic variations. There is a multistep model of gradual accumulation of mutations in the driver genes.

Publication:

Jungwirth, J., Urbanová, M., Boot, A., Hošek, P., Bendová, P., Šišková, A., Švec, J., Kment, M., Tůmová, D., Summerová, S., Beneš, Z., Buchler, T., Kohout, P., Hucl, T., Matěj, R., Vodičková, L., van Wezel, T., Vodička, P., Vymetálková, V.: (2022) Mutational analysis of driver genes defines the colorectal adenoma: in situ carcinoma transition. Scientific Reports. 12(1): 2570. doi: 10.1038/s41598-022-06498-9.

Analysis of microRNA expression changes during the course of therapy in rectal cancer patients

MicroRNAs (miR) regulate gene expression in a tissue-specific manner. However, little is known about the miR expression changes during the therapy in rectal cancer (RC) patients. Here the expression levels of miR-122-5p and miR-142-5p were significantly different between RC patients and controls (p < 0.001). A year after diagnosis, miR expression profiles were no longer different in patients responding to treatment from those measured in cancer-free individuals. On the other hand, patients not responding to therapy maintained low expression levels in their second sampling. Overexpression of miR-122-5p and miR-142-5p in RC cell lines inhibited cell growth and survival. This study shows the usefulness of circulating miR-122-5p and miR-142-5p screening for the assessment of patients’ outcomes and the effectiveness of the treatment schedule.

Publication:

Červená, K., Novosadová, V., Pardini, B., Naccarati, A., Opattová, A., Horák, J., Vodenková, S., Buchler, T., Skrobanek, P., Levy, M., Vodička, P., Vymetálková, V.: (2021) Analysis of MicroRNA Expression Changes During the Course of Therapy In Rectal Cancer Patients. Frontiers in Oncology. 11: 702258. doi: 10.3389/fonc.2021.702258. eCollection 2021