High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint

Iina Niittymäki, Alexandra Gylfe, Leena Laine, Marko Laakso, Heli J. Lehtonen, Johanna Kondelin, Jaana Tolvanen, Kari Nousiainen, Jeroen Pouwels, Heikki Järvinen, Kyösti Nuorva, Jukka-Pekka Mecklin, Markus Mäkinen, Ari Ristimäki, Torben F. Ørntoft, Sampsa Hautaniemi, Auli Karhu, Marko Kallio, Lauri A. Aaltonen

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9 Citations (Scopus)

Abstract

Frameshift mutations frequently accumulate in microsatellite-unstable colorectal cancers (MSI CRCs) typically leading to downregulation of the target genes due to nonsense-mediated messenger RNA decay. However, frameshift mutations that occur in the 3′ end of the coding regions can escape decay, which has largely been ignored in previous works. In this study, we characterized nonsense-mediated decay-escaping frameshift mutations in MSI CRC in an unbiased, genome wide manner. Combining bioinformatic search with expression profiling, we identified genes that were predicted to escape decay after a deletion in a microsatellite repeat. These repeats, located in 258 genes, were initially sequenced in 30 MSI CRC samples. The mitotic checkpoint kinase TTK was found to harbor decay-escaping heterozygous mutations in exon 22 in 59% (105/179) of MSI CRCs, which is notably more than previously reported. Additional novel deletions were found in exon 5, raising the mutation frequency to 66%. The exon 22 of TTK contains an A 9 –G 4 –A 7 locus, in which the most common mutation was a mononucleotide deletion in the A 9 (c.2560delA). When compared with identical non-coding repeats, TTK was found to be mutated significantly more often than expected without selective advantage. Since TTK inhibition is known to induce override of the mitotic spindle assembly checkpoint (SAC), we challenged mutated cancer cells with the microtubule-stabilizing drug paclitaxel. No evidence of checkpoint weakening was observed. As a conclusion, heterozygous TTK mutations occur at a high frequency in MSI CRCs. Unexpectedly, the plausible selective advantage in tumourigenesis does not appear to be related to SAC.
Original languageEnglish
Pages (from-to)305-311
JournalCarcinogenesis
Volume32
Issue number3
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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M Phase Cell Cycle Checkpoints
Mutation Rate
Microsatellite Repeats
Colorectal Neoplasms
Frameshift Mutation
Exons
Mutation
RNA Stability
Gene Expression Profiling
Paclitaxel
Computational Biology
Microtubules
Genes
Phosphotransferases
Down-Regulation
Genome
Messenger RNA
Pharmaceutical Preparations
Neoplasms

Keywords

  • cancer

Cite this

Niittymäki, I., Gylfe, A., Laine, L., Laakso, M., Lehtonen, H. J., Kondelin, J., ... Aaltonen, L. A. (2011). High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint. Carcinogenesis, 32(3), 305-311. https://doi.org/10.1093/carcin/bgq272
Niittymäki, Iina ; Gylfe, Alexandra ; Laine, Leena ; Laakso, Marko ; Lehtonen, Heli J. ; Kondelin, Johanna ; Tolvanen, Jaana ; Nousiainen, Kari ; Pouwels, Jeroen ; Järvinen, Heikki ; Nuorva, Kyösti ; Mecklin, Jukka-Pekka ; Mäkinen, Markus ; Ristimäki, Ari ; Ørntoft, Torben F. ; Hautaniemi, Sampsa ; Karhu, Auli ; Kallio, Marko ; Aaltonen, Lauri A. / High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint. In: Carcinogenesis. 2011 ; Vol. 32, No. 3. pp. 305-311.
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abstract = "Frameshift mutations frequently accumulate in microsatellite-unstable colorectal cancers (MSI CRCs) typically leading to downregulation of the target genes due to nonsense-mediated messenger RNA decay. However, frameshift mutations that occur in the 3′ end of the coding regions can escape decay, which has largely been ignored in previous works. In this study, we characterized nonsense-mediated decay-escaping frameshift mutations in MSI CRC in an unbiased, genome wide manner. Combining bioinformatic search with expression profiling, we identified genes that were predicted to escape decay after a deletion in a microsatellite repeat. These repeats, located in 258 genes, were initially sequenced in 30 MSI CRC samples. The mitotic checkpoint kinase TTK was found to harbor decay-escaping heterozygous mutations in exon 22 in 59{\%} (105/179) of MSI CRCs, which is notably more than previously reported. Additional novel deletions were found in exon 5, raising the mutation frequency to 66{\%}. The exon 22 of TTK contains an A 9 –G 4 –A 7 locus, in which the most common mutation was a mononucleotide deletion in the A 9 (c.2560delA). When compared with identical non-coding repeats, TTK was found to be mutated significantly more often than expected without selective advantage. Since TTK inhibition is known to induce override of the mitotic spindle assembly checkpoint (SAC), we challenged mutated cancer cells with the microtubule-stabilizing drug paclitaxel. No evidence of checkpoint weakening was observed. As a conclusion, heterozygous TTK mutations occur at a high frequency in MSI CRCs. Unexpectedly, the plausible selective advantage in tumourigenesis does not appear to be related to SAC.",
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Niittymäki, I, Gylfe, A, Laine, L, Laakso, M, Lehtonen, HJ, Kondelin, J, Tolvanen, J, Nousiainen, K, Pouwels, J, Järvinen, H, Nuorva, K, Mecklin, J-P, Mäkinen, M, Ristimäki, A, Ørntoft, TF, Hautaniemi, S, Karhu, A, Kallio, M & Aaltonen, LA 2011, 'High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint', Carcinogenesis, vol. 32, no. 3, pp. 305-311. https://doi.org/10.1093/carcin/bgq272

High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint. / Niittymäki, Iina; Gylfe, Alexandra; Laine, Leena; Laakso, Marko; Lehtonen, Heli J.; Kondelin, Johanna; Tolvanen, Jaana; Nousiainen, Kari; Pouwels, Jeroen; Järvinen, Heikki; Nuorva, Kyösti; Mecklin, Jukka-Pekka; Mäkinen, Markus; Ristimäki, Ari; Ørntoft, Torben F.; Hautaniemi, Sampsa; Karhu, Auli; Kallio, Marko; Aaltonen, Lauri A.

In: Carcinogenesis, Vol. 32, No. 3, 2011, p. 305-311.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint

AU - Niittymäki, Iina

AU - Gylfe, Alexandra

AU - Laine, Leena

AU - Laakso, Marko

AU - Lehtonen, Heli J.

AU - Kondelin, Johanna

AU - Tolvanen, Jaana

AU - Nousiainen, Kari

AU - Pouwels, Jeroen

AU - Järvinen, Heikki

AU - Nuorva, Kyösti

AU - Mecklin, Jukka-Pekka

AU - Mäkinen, Markus

AU - Ristimäki, Ari

AU - Ørntoft, Torben F.

AU - Hautaniemi, Sampsa

AU - Karhu, Auli

AU - Kallio, Marko

AU - Aaltonen, Lauri A.

PY - 2011

Y1 - 2011

N2 - Frameshift mutations frequently accumulate in microsatellite-unstable colorectal cancers (MSI CRCs) typically leading to downregulation of the target genes due to nonsense-mediated messenger RNA decay. However, frameshift mutations that occur in the 3′ end of the coding regions can escape decay, which has largely been ignored in previous works. In this study, we characterized nonsense-mediated decay-escaping frameshift mutations in MSI CRC in an unbiased, genome wide manner. Combining bioinformatic search with expression profiling, we identified genes that were predicted to escape decay after a deletion in a microsatellite repeat. These repeats, located in 258 genes, were initially sequenced in 30 MSI CRC samples. The mitotic checkpoint kinase TTK was found to harbor decay-escaping heterozygous mutations in exon 22 in 59% (105/179) of MSI CRCs, which is notably more than previously reported. Additional novel deletions were found in exon 5, raising the mutation frequency to 66%. The exon 22 of TTK contains an A 9 –G 4 –A 7 locus, in which the most common mutation was a mononucleotide deletion in the A 9 (c.2560delA). When compared with identical non-coding repeats, TTK was found to be mutated significantly more often than expected without selective advantage. Since TTK inhibition is known to induce override of the mitotic spindle assembly checkpoint (SAC), we challenged mutated cancer cells with the microtubule-stabilizing drug paclitaxel. No evidence of checkpoint weakening was observed. As a conclusion, heterozygous TTK mutations occur at a high frequency in MSI CRCs. Unexpectedly, the plausible selective advantage in tumourigenesis does not appear to be related to SAC.

AB - Frameshift mutations frequently accumulate in microsatellite-unstable colorectal cancers (MSI CRCs) typically leading to downregulation of the target genes due to nonsense-mediated messenger RNA decay. However, frameshift mutations that occur in the 3′ end of the coding regions can escape decay, which has largely been ignored in previous works. In this study, we characterized nonsense-mediated decay-escaping frameshift mutations in MSI CRC in an unbiased, genome wide manner. Combining bioinformatic search with expression profiling, we identified genes that were predicted to escape decay after a deletion in a microsatellite repeat. These repeats, located in 258 genes, were initially sequenced in 30 MSI CRC samples. The mitotic checkpoint kinase TTK was found to harbor decay-escaping heterozygous mutations in exon 22 in 59% (105/179) of MSI CRCs, which is notably more than previously reported. Additional novel deletions were found in exon 5, raising the mutation frequency to 66%. The exon 22 of TTK contains an A 9 –G 4 –A 7 locus, in which the most common mutation was a mononucleotide deletion in the A 9 (c.2560delA). When compared with identical non-coding repeats, TTK was found to be mutated significantly more often than expected without selective advantage. Since TTK inhibition is known to induce override of the mitotic spindle assembly checkpoint (SAC), we challenged mutated cancer cells with the microtubule-stabilizing drug paclitaxel. No evidence of checkpoint weakening was observed. As a conclusion, heterozygous TTK mutations occur at a high frequency in MSI CRCs. Unexpectedly, the plausible selective advantage in tumourigenesis does not appear to be related to SAC.

KW - cancer

U2 - 10.1093/carcin/bgq272

DO - 10.1093/carcin/bgq272

M3 - Article

VL - 32

SP - 305

EP - 311

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 3

ER -