TY - JOUR AU - Zamborszky, J AU - Szikriszt, B AU - Gervai, J Z AU - Pipek, Orsolya Anna AU - Póti, Ádám AU - Krzystanek, M AU - Ribli, D AU - Szalai-Gindl, J M AU - Csabai, I AU - Szállási, Zoltán AU - Swanton, C AU - Richardson, A L AU - Szüts, Dávid TI - Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions (vol 36, pg 746, 2017) JF - ONCOGENE J2 - ONCOGENE VL - 36 PY - 2017 IS - 35 SP - 5085 EP - 5086 PG - 2 SN - 0950-9232 DO - 10.1038/onc.2017.213 UR - https://m2.mtmt.hu/api/publication/26935896 ID - 26935896 LA - English DB - MTMT ER - TY - JOUR AU - Zámborszky, Judit AU - Szikriszt, Bernadett AU - Gervai, Judit Zsuzsanna AU - Pipek, Orsolya Anna AU - Póti, Ádám AU - Krzystanek, M AU - Ribli, Dezső AU - Szalai-Gindl, János Márk AU - Csabai, István AU - Szállási, Zoltán AU - Swanton, C AU - Richardson, AL AU - Szüts, Dávid TI - Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions JF - ONCOGENE J2 - ONCOGENE VL - 36 PY - 2017 IS - 6 SP - 746 EP - 755 PG - 10 SN - 0950-9232 DO - 10.1038/onc.2016.243 UR - https://m2.mtmt.hu/api/publication/3118171 ID - 3118171 AB - Loss-of-function mutations in the BRCA1 and BRCA2 genes increase the risk of cancer. Owing to their function in homologous recombination repair, much research has focused on the unstable genomic phenotype of BRCA1/2 mutant cells manifest mainly as large-scale rearrangements. We used whole-genome sequencing of multiple isogenic chicken DT40 cell clones to precisely determine the consequences of BRCA1/2 loss on all types of genomic mutagenesis. Spontaneous base substitution mutation rates increased sevenfold upon the disruption of either BRCA1 or BRCA2, and the arising mutation spectra showed strong and specific correlation with a mutation signature associated with BRCA1/2 mutant tumours. To model endogenous alkylating damage, we determined the mutation spectrum caused by methyl methanesulfonate (MMS), and showed that MMS also induces more base substitution mutations in BRCA1/2-deficient cells. Spontaneously arising and MMS-induced insertion/deletion mutations and large rearrangements were also more common in BRCA1/2 mutant cells compared with the wild-type control. A difference in the short deletion phenotypes of BRCA1 and BRCA2 suggested distinct roles for the two proteins in the processing of DNA lesions, as BRCA2 mutants contained more short deletions, with a wider size distribution, which frequently showed microhomology near the breakpoints resembling repair by non-homologous end joining. An increased and prolonged gamma-H2AX signal in MMS-treated BRCA1/2 cells suggested an aberrant processing of stalled replication forks as the cause of increased mutagenesis. The high rate of base substitution mutagenesis demonstrated by our experiments is likely to significantly contribute to the oncogenic effect of the inactivation of BRCA1 or BRCA2.Oncogene advance online publication, 25 July 2016; doi:10.1038/onc.2016.243. © 2016 The Author(s) LA - English DB - MTMT ER - TY - JOUR AU - Telli, ML AU - Timms, KM AU - Reid, J AU - Hennessy, B AU - Mills, GB AU - Jensen, KC AU - Szállási, Zoltán AU - Barry, WT AU - Winer, EP AU - Tung, N AU - Isakoff, SJ AU - Ryan, PD AU - Greene-Colozzi, A AU - Gutin, A AU - Sangale, Z AU - Iliev, D AU - Neff, C AU - Abkevich, V AU - Jones, JT AU - Lanchbury, JS AU - Hartman, AR AU - Garber, JE AU - Ford, JM AU - Silver, DP AU - Richardson, AL TI - Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer JF - CLINICAL CANCER RESEARCH J2 - CLIN CANCER RES VL - 22 PY - 2016 IS - 15 SP - 3764 EP - 3773 PG - 10 SN - 1078-0432 DO - 10.1158/1078-0432.CCR-15-2477 UR - https://m2.mtmt.hu/api/publication/26513282 ID - 26513282 N1 - Funding Agency and Grant Number: Adelson Medical Research Foundation; AstraZenecaAstraZeneca; Critical Outcome Technologies; Komen Research Foundation; Nanostrong; Ambry Genetics; Myriad Genetics; Natera; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P50CA168504, P50CA083639] Funding Source: NIH RePORTER; Novo Nordisk FondenNovo Nordisk Foundation [NNF15OC0016584, NNF14OC0009569] Funding Source: researchfish Funding text: G.B. Mills has ownership interest (including patents) in Catena Pharmaceuticals, PTV Ventures, Spindletop Ventures, and Myriad Genetics, reports receiving speakers bureau honoraria from AstraZeneca, Eli Lilly, ISIS Pharmaceuticals, Nuevolution, and Symphogen, is a consultant/advisory board member for Adventist Health, AstraZeneca, Blend, Catena Pharmaceuticals, Critical Outcome Technologies, HaIaI Bio Korea, ImmunoMET, Millennium Pharmaceuticals, Nuevolution, Precision Medicine, Provista Diagnostics, Signalchem Lifesciences, and Symphogen, and reports receiving commercial research grants from Adelson Medical Research Foundation, AstraZeneca, Critical Outcome Technologies, Komen Research Foundation, and Nanostrong. S.J. Isakoff is a consultant/advisory board member for Myriad Genetics. K.M. Timms, A. Gutin, and V. Abkevich have ownership interest (including patents) in Myriad Genetics Inc. J.E. Garber reports receiving commercial research grants from Ambry Genetics and Myriad Genetics. J.M. Ford reports receiving commercial research grants from Myriad Genetics and Natera. D.P. Silver and A.L. Richardson are listed as co-inventors on a patent on telomeric allelic imbalance, which is owned by the Dana-Farber Cancer Institute and licensed to Myriad Genetics. No potential conflicts of interest were disclosed by the other authors. LA - English DB - MTMT ER - TY - JOUR AU - Favero, F AU - Joshi, T AU - Marquard, A M AU - Birkbak, N J AU - Krzystanek, M AU - Li, Q AU - Szállási, Zoltán AU - Eklund, A C TI - Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data JF - ANNALS OF ONCOLOGY J2 - ANN ONCOL VL - 26 PY - 2015 IS - 1 SP - 64 EP - 70 PG - 7 SN - 0923-7534 DO - 10.1093/annonc/mdu479 UR - https://m2.mtmt.hu/api/publication/31826051 ID - 31826051 AB - Exome or whole-genome deep sequencing of tumor DNA along with paired normal DNA can potentially provide a detailed picture of the somatic mutations that characterize the tumor. However, analysis of such sequence data can be complicated by the presence of normal cells in the tumor specimen, by intratumor heterogeneity, and by the sheer size of the raw data. In particular, determination of copy number variations from exome sequencing data alone has proven difficult; thus, single nucleotide polymorphism (SNP) arrays have often been used for this task. Recently, algorithms to estimate absolute, but not allele-specific, copy number profiles from tumor sequencing data have been described.We developed Sequenza, a software package that uses paired tumor-normal DNA sequencing data to estimate tumor cellularity and ploidy, and to calculate allele-specific copy number profiles and mutation profiles. We applied Sequenza, as well as two previously published algorithms, to exome sequence data from 30 tumors from The Cancer Genome Atlas. We assessed the performance of these algorithms by comparing their results with those generated using matched SNP arrays and processed by the allele-specific copy number analysis of tumors (ASCAT) algorithm.Comparison between Sequenza/exome and SNP/ASCAT revealed strong correlation in cellularity (Pearson's r = 0.90) and ploidy estimates (r = 0.42, or r = 0.94 after manual inspecting alternative solutions). This performance was noticeably superior to previously published algorithms. In addition, in artificial data simulating normal-tumor admixtures, Sequenza detected the correct ploidy in samples with tumor content as low as 30%.The agreement between Sequenza and SNP array-based copy number profiles suggests that exome sequencing alone is sufficient not only for identifying small scale mutations but also for estimating cellularity and inferring DNA copy number aberrations. LA - English DB - MTMT ER - TY - JOUR AU - Birkbak, NJ AU - Wang, ZGC AU - Kim, JY AU - Eklund, AC AU - Li, QY AU - Tian, RY AU - Bowman-Colin, C AU - Li, Y AU - Greene-Colozzi, A AU - Iglehart, JD AU - Tung, N AU - Ryan, PD AU - Garber, JE AU - Silver, DP AU - Szállási, Zoltán AU - Richardson, AL TI - Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents JF - CANCER DISCOVERY J2 - CANCER DISCOV VL - 2 PY - 2012 IS - 4 SP - 366 EP - 375 PG - 10 SN - 2159-8274 DO - 10.1158/2159-8290.CD-11-0206 UR - https://m2.mtmt.hu/api/publication/22539074 ID - 22539074 LA - English DB - MTMT ER -