Browsing by Subject "INSTABILITY"

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  • Kondelin, Johanna; Tuupanen, Sari; Gylfe, Alexandra E.; Aavikko, Mervi; Renkonen-Sinisalo, Laura; Järvinen, Heikki; Bohm, Jan; Mecklin, Jukka-Pekka; Andersen, Claus L.; Vahteristo, Pia; Pitkanen, Esa; Aaltonen, Lauri A. (2015)
    Approximately 15 % of colorectal cancers exhibit instability of short nucleotide repeat regions, microsatellites. These tumors display a unique clinicopathologic profile and the microsatellite instability status is increasingly used to guide clinical management as it is known to predict better prognosis as well as resistance to certain chemotherapeutics. A panel of five repeats determined by the National Cancer Institute, the Bethesda panel, is currently the standard for determining the microsatellite instability status in colorectal cancer. Recently, a quasimonomorphic mononucleotide repeat 16T/U at the 3' untranslated region of the Ewing sarcoma breakpoint region 1 gene was reported to show perfect sensitivity and specificity in detecting mismatch repair deficient colorectal, endometrial, and gastric cancers in two independent populations. To confirm this finding, we replicated the analysis in 213 microsatellite unstable colorectal cancers from two independent populations, 148 microsatellite stable colorectal cancers, and the respective normal samples by PCR and fragment analysis. The repeat showed nearly perfect sensitivity for microsatellite unstable colorectal cancer as it was altered in 212 of the 213 microsatellite unstable (99.5 %) and none of the microsatellite stable colorectal tumors. This repeat thus represents the first potential single marker for detecting microsatellite instability.
  • German HNPCC Consortium; Dutch Lynch Syndrome Collaborative; Finnish Lynch Syndrome Registry; Engel, Christoph; Ahadova, Aysel; Seppälä, Toni T.; Lepistö, Anna; Renkonen-Sinisalo, Laura; Vasen, Hans F. (2020)
    BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P <.001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.
  • Gu, Yuexi; Helenius, Mikko; Vaananen, Kristiina; Bulanova, Daria; Saarela, Jani; Sokolenko, Anna; Martens, John; Imyanitov, Evgeny; Kuznetsov, Sergey (2016)
    Germ-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four BRCA1-wild-type (MDA-MB-231, SUM229PE, MCF10A, and MCF7) breast cancer cell lines. We found that all BRCA1-mutant cell lines were insensitive to inhibitors of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) Selumetinib and Pimasertib in contrast to BRCA1-wildtype control cell lines. However, unexpectedly, only two BRCA1-mutant cell lines, HCC1937 and MDA-MB-436, were hypersensitive to a nucleotide analogue 6-thioguanine (6-TG). SUM149PT cells readily formed radiation-induced RAD51-positive nuclear foci indicating a functional homologous recombination, which may explain their resistance to 6-TG. However, the reason underlying 6-TG resistance of SUM1315MO2 cells remains unclear. Our data reveal a remarkable heterogeneity among BRCA1-mutant cell lines and provide a reference for future studies.
  • Kondelin, Johanna; Gylfe, Alexandra E.; Lundgren, Sofie; Tanskanen, Tomas; Hamberg, Jiri; Aavikko, Mervi; Palin, Kimmo; Ristolainen, Heikki; Katainen, Riku; Kaasinen, Eevi; Taipale, Minna; Taipale, Jussi; Renkonen-Sinisalo, Laura; Jarvinen, Heikki; Bohm, Jan; Mecklin, Jukka-Pekka; Vahteristo, Pia; Tuupanen, Sari; Aaltonen, Lauri A.; Pitkanen, Esa (2017)
    Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in micro-satellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8. Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. (C) 2017 AACR.
  • Rendo, Veronica; Kundu, Snehangshu; Rameika, Natallia; Ljungstrom, Viktor; Svensson, Richard; Palin, Kimmo; Aaltonen, Lauri; Stoimenov, Ivaylo; Sjöblom, Tobias (2020)
    Therapies targeting somatic bystander genetic events represent a new avenue for cancer treatment. We recently identified a subset of colorectal cancer (CRC) patients who are heterozygous for a wild-type and a low activity allele (NAT2*6) but lack the wild-type allele in their tumors due to loss of heterozygosity (LOH) at 8p22. These tumors were sensitive to treatment with a cytotoxic substrate of NAT2 (6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine, APA), and pointed to NAT2 loss being a therapeutically exploitable vulnerability of CRC tumors. To better estimate the total number of treatable CRC patients, we here determined whether tumor cells retaining also other NAT2 low activity variants after LOH respond to APA treatment. The prevalent low activity alleles NAT2*5 and NAT2*14, but not NAT2*7, were found to be low metabolizers with high sensitivity to APA. By analysis of two different CRC patient cohorts, we detected heterozygosity for NAT2 alleles targetable by APA, along with allelic imbalances pointing to LOH, in similar to 24% of tumors. Finally, to haplotype the NAT2 locus in tumor and patient-matched normal samples in a clinical setting, we develop and demonstrate a long-read sequencing based assay. In total,>79.000 CRC patients per year fulfil genetic criteria for high sensitivity to a NAT2 LOH therapy and their eligibility can be assessed by clinical sequencing.
  • Ertoprak, A.; Cederwall, B.; Qi, C.; Aktas, O.; Doncel, M.; Hadinia, B.; Liotta, R.; Sandzelius, M.; Scholey, C.; Andgren, K.; Back, T.; Badran, H.; Braunroth, T.; Calverley, T.; Cox, D. M.; Cullen, D. M.; Fang, Y. D.; Ganioglu, E.; Giles, M.; Gomez Hornillos, M. B.; Grahn, T.; Greenlees, P. T.; Hilton, J.; Hodge, D.; Ideguchi, E.; Jakobsson, U.; Johnson, A.; Jones, P. M.; Julin, R.; Juutinen, S.; Ketelhut, S.; Khaplanov, A.; Kumar Raju, M.; Leino, M.; Li, H.; Liu, H.; Matta, S.; Modamio, V.; Nara Singh, B. S.; Niikura, M.; Nyman, M.; Ozgur, I.; Page, R. D.; Pakarinen, J.; Papadakis, P.; Partanen, J.; Paul, E. S.; Petrache, C. M.; Peura, P.; Rahkila, P.; Ruotsalainen, P.; Saren, J.; Sorri, J.; Stolze, S.; Subramaniam, P.; Taylor, M. J.; Uusitalo, J.; Valiente-Dobon, J. J.; Wyss, R. (2020)
    Excited states in the extremely neutron-deficient nucleus Pt-172 were populated via Ru-96(Kr-78, 2p) and Mo-92(Kr-83, 3n) reactions. The level scheme has been extended up to an excitation energy of approximate to 5MeV and tentative spin-parity assignments up to I-pi = 18(+). Linear polarization and angular distribution measurements were used to determine the electromagnetic E1 character of the dipole transitions connecting the positive-parity ground-state band with an excited side-band, firmly establishing it as a negativeparity band. The lowestmember of this negative-parity structure was firmly assigned spin-parity 3(-). In addition, we observed an E3 transition from this 3(-) state to the ground state, providing direct evidence for octupole collectivity in Pt-172. Large-scale shell model (LSSM) and total Routhian surface (TRS) calculations have been performed, supporting the interpretation of the 3(-) state as a collective octupole-vibrational state.
  • Välimäki, Niko; Schalin-Jäntti, Camilla; Karppinen, Atte; Paetau, Anders; Kivipelto, Leena; Aaltonen, Lauri A.; Karhu, Auli (2019)
    Somatic driver mechanisms of pituitary adenoma pathogenesis have remained incompletely characterized; apart from mutations in the stimulatory G alpha protein (G alpha(s) encoded by GNAS) causing activated cAMP synthesis, pathogenic variants are rarely found in growth hormone-secreting pituitary tumors (somatotropinomas). The purpose of the current work was to clarify how genetic and epigenetic alterations contribute to the development of somatotropinomas by conducting an integrated copy number alteration, whole-genome and bisulfite sequencing, and transcriptome analysis of 21 tumors. Somatic mutation burden was low, but somatotropinomas formed two subtypes associated with distinct aneuploidy rates and unique transcription profiles. Tumors with recurrent chromosome aneuploidy (CA) were GNAS mutation negative (Gsp(-)). The chromosome stable (CS) -group contained Gsp(+) somatotropinomas and two totally aneuploidy-free Gsp(-) tumors. Genes related to the mitotic G(1)-S-checkpoint transition were differentially expressed in CA- and CS-tumors, indicating difference in mitotic progression. Also, pituitary tumor transforming gene 1 (PTTG1), a regulator of sister chromatid segregation, showed abundant expression in CA-tumors. Moreover, somatotropinomas displayed distinct Gsp genotypespecific methylation profiles and expression quantitative methylation (eQTM) analysis revealed that inhibitory G alpha (G alpha(i)) signaling is activated in Gsp(+) tumors. These findings suggest that aneuploidy through modulated driver pathways may be a causative mechanism for tumorigenesis in Gsp(-) somatotropinomas, whereas Gsp(+) tumors with constitutively activated cAMP synthesis seem to be characterized by DNA methylation activated G alpha(i) signaling.
  • Kuisma, Heli; Bramante, Simona; Rajamäki, Kristiina; Sipilä, Lauri J.; Kaasinen, Eevi; Kaukomaa, Jaana; Palin, Kimmo; Mäkinen, Netta; Sjöberg, Jari; Sarvilinna, Nanna; Taipale, Jussi; Kauppi, Liisa; Tumiati, Manuela; Hassinen, Antti; Pitkäniemi, Janne; Jalkanen, Jyrki; Heikkinen, Sanna; Pasanen, Annukka; Heikinheimo, Oskari; Bützow, Ralf; Välimäki, Niko; Aaltonen, Lauri A. (2021)
    Mechanical forces in a constrained cellular environment were recently established as a facilitator of chromosomal damage. Whether this could contribute to tumorigenesis is not known. Uterine leiomyomas are common neoplasms that display relatively few chromosomal aberrations. We hypothesized that if mechanical forces contribute to chromosomal damage, signs of this could be seen in uterine leiomyomas from parous women. We examined the karyotypes of 1946 tumors, and found a striking overrepresentation of chromosomal damage associated with parity. We then subjected myometrial cells to physiological forces similar to those encountered during pregnancy, and found this to cause DNA breaks and a DNA repair response. While mechanical forces acting in constrained cellular environments may thus contribute to neoplastic degeneration, and genesis of uterine leiomyoma, further studies are needed to prove possible causality of the observed association. No evidence for progression to malignancy was found. Many factors have been associated with chromosomal damage, including mechanical forces in a constrained cellular environment. Here the authors reveal an association between parity and chromosomal damage by analysing karyotypes of 1946 uterine leiomyomas.
  • Dubart, Maxime; Ganse, Urs; Osmane, Adnane; Johlander, Andreas; Battarbee, Markus; Grandin, Maxime; Pfau-Kempf, Yann; Turc, Lucile; Palmroth, Minna (2020)
    Kinetically driven plasma waves are fundamental for a description of the thermodynamical properties of the Earth's magnetosheath. The most commonly observed ion-scale instabilities are generated by temperature anisotropy of the ions, such as the mirror and proton cyclotron instabilities. We investigate here the spatial resolution dependence of the mirror and proton cyclotron instabilities in a global hybrid-Vlasov simulation using the Vlasiator model; we do this in order to find optimal resolutions and help future global hybrid-Vlasov simulations to save resources when investigating those instabilities in the magnetosheath. We compare the proton velocity distribution functions, power spectra and growth rates of the instabilities in a set of simulations with three different spatial resolutions but otherwise identical setup. We find that the proton cyclotron instability is absent at the lowest resolution and that only the mirror instability remains, which leads to an increased temperature anisotropy in the simulation. We conclude that the proton cyclotron instability, its saturation and the reduction of the anisotropy to marginal levels are resolved at the highest spatial resolution. A further increase in resolution does not lead to a better description of the instability to an extent that would justify this increase at the cost of numerical resources in future simulations. We also find that spatial resolutions between 1.32 and 2.64 times the inertial length in the solar wind present acceptable limits for the resolution within which the velocity distribution functions resulting from the proton cyclotron instability are still bi-Maxwellian and reach marginal stability levels. Our results allow us to determine a range of spatial resolutions suitable for the modelling of the proton cyclotron and mirror instabilities and should be taken into consideration regarding the optimal grid spacing for the modelling of these two instabilities, within available computational resources.
  • Kavaja, L.; Malmivaara, A.; Lähdeoja, T.; Remes, V.; Sund, R.; Paavola, M. (2018)
    Background and Aims: Shoulder capsular surgery is nowadays usually performed arthroscopically, and the proportion of arthroscopic method has rapidly increased during the last two decades. We assessed the incidence of shoulder capsular surgery procedures in Finland between 1999 and 2008. Material and Methods: We gathered the shoulder capsular surgery procedures for all kinds of shoulder instability in Finland between 1999 and 2008 from National Hospital Discharge Register and limited the patient material to include only certain diagnosis (International Classification of Diseases, 10th Edition) and Nordic Medico-Statistical Committee procedure code combinations. We analyzed the data in the whole country, between different age groups, and in university hospital districts. Results: The total incidence of shoulder capsular surgery procedures in Finland increased from 17 to 33 per 100,000 person-years. The incidence of arthroscopic procedures increased from 11 to 30 per 100,000 person-years and the proportion of arthroscopic procedures increased from 63% to 92% between years 1999 and 2007. The incidence of shoulder capsular surgery procedures increased on average around 90% in almost all age groups and particularly in the older age groups. We observed no significant geographical variation between university hospital districts. Conclusion: The incidence of shoulder capsular surgery procedures increased on average round 90% in almost all age groups. It seems to be difficult to support the rapidly increased rates of shoulder capsular surgery procedures or the arthroscopic method based on scientific evidence. While also older patients are treated with shoulder capsular surgery, well-defined indications for surgical intervention are needed so that the operations are conducted for the symptomatic patients benefitting most regardless of patients' age.
  • Aska, Elli-Mari; Dermadi, Denis; Kauppi, Liisa (2020)
    DNA mismatch repair (MMR) corrects replication errors and is recruited by the histone mark H3K36me3, enriched in exons of transcriptionally active genes. To dissect in vivo the mutational landscape shaped by these processes, we employed single-cell exome sequencing on T cells of wild-type andMMR-deficient (Mlh1(-/-)) mice. Within active genes, we uncovered a spatial bias in MMR efficiency: 3' exons, often H3K36me3-enriched, acquire significantly fewer MMR-dependent mutations compared with 5' exons. Huwe1 and Mcm7 genes, both active during lymphocyte development, stood out as mutational hotspots in MMR-deficient cells, demonstrating their intrinsic vulnerability to replication error in this cell type. Both genes are H3K36me3-enriched, which can explain MMR-mediated elimination of replication errors in wild-type cells. Thus, H3K36me3 can boost MMR in transcriptionally active regions, both locally and globally. This offers an attractive concept of thriftyMMR targeting, where critical genes in each cell type enjoy preferential shielding against de novo mutations.
  • Margerin, V.; Murphy, A. St. J.; Davinson, T.; Dressler, R.; Fallis, J.; Kankainen, A.; Laird, A. M.; Lotay, G.; Mountford, D. J.; Murphy, C. D.; Seiffert, C.; Schumann, D.; Stowasser, T.; Stora, T.; Wang, C. H. -T.; Woods, P. J. (2014)
  • Ballhausen, Alexej; Przybilla, Moritz Jakob; Jendrusch, Michael; Haupt, Saskia; Pfaffendorf, Elisabeth; Seidler, Florian; Witt, Johannes; Hernandez Sanchez, Alejandro; Urban, Katharina; Draxlbauer, Markus; Krausert, Sonja; Ahadova, Aysel; Kalteis, Martin Simon; Pfuderer, Pauline L.; Heid, Daniel; Stichel, Damian; Gebert, Johannes; Bonsack, Maria; Schott, Sarah; Blaeker, Hendrik; Seppälä, Toni; Mecklin, Jukka-Pekka; Ten Broeke, Sanne; Nielsen, Maartje; Heuveline, Vincent; Krzykalla, Julia; Benner, Axel; Riemer, Angelika Beate; von Knebel Doeberitz, Magnus; Kloor, Matthias (2020)
    The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers. DNA mismatch repair (MMR)-deficient cancers with microsatellite-instability are characterized by a high load of frameshift mutation-derived neoantigens. Here, by mapping the frameshift mutation landscape and predicting the immunogenicity of the resulting peptides, the authors show evidence of immunoediting in MMR-deficient colorectal and endometrial cancers.