TCGA Pan-Cancer genomic analysis of Alternative Lengthening of Telomeres (ALT) related genes

Armendariz-Castillo, I.; Lopez-Cortes, A.; Garcia-Cardenas, J.; Guevara-Ramirez, P.; Leone, P. E.; Perez-Villa, A.; Yumiceba, V.; Zambrano, A. K.; Guerrero, S.; Paz-y-Mino, C.

doi:10.1101/2020.04.27.063610

bioRxiv · 10.1101/2020.04.27.063610

TCGA Pan-Cancer genomic analysis of Alternative Lengthening of Telomeres (ALT) related genes

Armendariz-Castillo, I.·Lopez-Cortes, A.·Garcia-Cardenas, J.·Guevara-Ramirez, P.·Leone, P. E.·Perez-Villa, A.·Yumiceba, V.·Zambrano, A. K.·Guerrero, S.·Paz-y-Mino, C.

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Abstract

Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85-90% reactivate telomerase, while 10-15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors have the ability to switch from a telomerase-dependent mechanism to ALT, in fact, the co-existence between telomerase and the ALT pathway have been observed in a variety of cancer types. Despite different elements in the ALT pathway have been uncovered, the molecular mechanism and other factors are still poorly understood, which difficult the detection and treatment of ALT-positive cells, which are known to present poor prognosis. Therefore, with the aim to identify potential molecular markers to be used in the study of ALT, we combined simplistic in silico approaches in 411 telomere maintenance (TM) genes which have been previously validated or predicted to be involved in the ALT pathway. In consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies (n=9,282) from The Cancer Genome Atlas in the cBioPortal and found 325,936 genomic alterations, being mRNA high and low the top alterations with 65.8% and 10.7% respectively. Moreover, we analyzed the highest frequency means of genomics alterations, identified and proposed 20 genes, which are highly mutated and up and down regulated in the cancer studies and could be used for future analysis in the study of ALT. Finally, we made a protein-protein interaction network and enrichment analysis to obtain an insight into the main pathways these genes are involved. We could observe their role in main processes related to the ALT mechanism like homologous recombination, homology directed repair (HDR), HDR through homologous recombination and telomere maintenance and organization.. Overall, due to the lack of understanding of the molecular mechanisms and detection of ALT-positive cancers, we identified and proposed more molecular targets that can be used for expression analysis and additional ex vivo assays to validate them as new potential therapeutic markers in the study of the ALT mechanism.

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Armendariz-Castillo, I., Lopez-Cortes, A., Garcia-Cardenas, J., Guevara-Ramirez, P., Leone, P. E., Perez-Villa, A., Yumiceba, V., Zambrano, A. K., Guerrero, S., Paz-y-Mino, C.. 2020-04-29. TCGA Pan-Cancer genomic analysis of Alternative Lengthening of Telomeres (ALT) related genes. https://doi.org/10.1101/2020.04.27.063610

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