Wever, in that study genomic instability was based on the average

Wever, in that study genomic instability was based on the average expression of 70 genes that correlated with “total 76932-56-4 web functional aneuploidy”. The presented study is based on the analysis of high-resolution DNA copy number data and the application of a robust and easily interpretable measure of genomic instability (TAI). TAI assesses the deviation of the estimated copy number curve from the zeroline (Figure S1), and thus represents a numeric measure of the abundance and genomic size of copy number changes in a tumour. Low-grade ovarian tumours usually carry few genomic aberrations [43]; however, a small number of short aberrations in vital genes may be essential for JW-74 initiating tumour development and progression. Such short aberrations have low impact on TAI making the index less suitable for studying initial steps in tumour development, but rather for quantifying the wide-spread genomic disorganization that may occur at a later stage of tumour progression. In the current work, we are considering advanced ovarian cancer with the aim of examining the importance of broad aberrations on survival and for this purpose TAI appears as a suitable way of obtaining numerical quantifications to be used in statistical analysis. Genomic instability causes disturbed mitoses, segregation, and spindle assembly (see reviews by [44?6]). In ovarian cancer, as in other cancer types, genomic instability and copy number alterations have been associated with poor prognosis. However, recent publications have stated that high levels of genomic instability may be beneficial for the survival and prognosis of patients in some tumour types [28?0]. Furthermore, elevating the frequency of genomic instability has been proposed as a strategy to kill cancer cells [26]. It is thus possible that the initial growth advantage of cancer cells, based on the transforming effect of genomic instability, becomes a net disadvantage for the cancer cells, when the wellorganized regulatory system is devastated. The capability for DNA repair may be reduced, leading to an increased sensitivity to DNA damaging agents, including chemotherapeutic drugs, such as cisplatin (see review by [47]). However, most patients are usually treated with adjuvant chemotherapy making it difficult to determine whether the observed association of genomic instability to patient survival is a result of intrinsically less fit cancer cells or the inability of the tumour cells to repair DNA damages caused by chemotherapeutic drugs. Thus, it is an interesting observation that in the Norwegian cohort the patients with a high degree of genomic instability showed a significantly better response to platinum-based chemotherapy. SOC patients with germline mutations in BRCA1 and BRCA2 are more sensitive to chemotherapy and have improved survival [39,41,42]. In addition, an even higher fraction of ovarian cancer patients have somatic aberrations in the BRCA genes or the BRCApathway, characterising the phenotype called BRCA-ness [48]. A number of patients (n = 35) in the Australian cohort were analysed for germline BRCA-mutations. No significant difference in theGenomic Instability in Ovarian CancerTAI-index was observed between the BRCA-mutated samples and others, a finding that is consistent with the TCGA analysis of BRCA1/2 mutation and ploidy in a large series of SOC [39,41,42]. Germline status may only be represented in a fraction of the total homologous recombination dysfunction observed in the entire cohort, theref.Wever, in that study genomic instability was based on the average expression of 70 genes that correlated with “total functional aneuploidy”. The presented study is based on the analysis of high-resolution DNA copy number data and the application of a robust and easily interpretable measure of genomic instability (TAI). TAI assesses the deviation of the estimated copy number curve from the zeroline (Figure S1), and thus represents a numeric measure of the abundance and genomic size of copy number changes in a tumour. Low-grade ovarian tumours usually carry few genomic aberrations [43]; however, a small number of short aberrations in vital genes may be essential for initiating tumour development and progression. Such short aberrations have low impact on TAI making the index less suitable for studying initial steps in tumour development, but rather for quantifying the wide-spread genomic disorganization that may occur at a later stage of tumour progression. In the current work, we are considering advanced ovarian cancer with the aim of examining the importance of broad aberrations on survival and for this purpose TAI appears as a suitable way of obtaining numerical quantifications to be used in statistical analysis. Genomic instability causes disturbed mitoses, segregation, and spindle assembly (see reviews by [44?6]). In ovarian cancer, as in other cancer types, genomic instability and copy number alterations have been associated with poor prognosis. However, recent publications have stated that high levels of genomic instability may be beneficial for the survival and prognosis of patients in some tumour types [28?0]. Furthermore, elevating the frequency of genomic instability has been proposed as a strategy to kill cancer cells [26]. It is thus possible that the initial growth advantage of cancer cells, based on the transforming effect of genomic instability, becomes a net disadvantage for the cancer cells, when the wellorganized regulatory system is devastated. The capability for DNA repair may be reduced, leading to an increased sensitivity to DNA damaging agents, including chemotherapeutic drugs, such as cisplatin (see review by [47]). However, most patients are usually treated with adjuvant chemotherapy making it difficult to determine whether the observed association of genomic instability to patient survival is a result of intrinsically less fit cancer cells or the inability of the tumour cells to repair DNA damages caused by chemotherapeutic drugs. Thus, it is an interesting observation that in the Norwegian cohort the patients with a high degree of genomic instability showed a significantly better response to platinum-based chemotherapy. SOC patients with germline mutations in BRCA1 and BRCA2 are more sensitive to chemotherapy and have improved survival [39,41,42]. In addition, an even higher fraction of ovarian cancer patients have somatic aberrations in the BRCA genes or the BRCApathway, characterising the phenotype called BRCA-ness [48]. A number of patients (n = 35) in the Australian cohort were analysed for germline BRCA-mutations. No significant difference in theGenomic Instability in Ovarian CancerTAI-index was observed between the BRCA-mutated samples and others, a finding that is consistent with the TCGA analysis of BRCA1/2 mutation and ploidy in a large series of SOC [39,41,42]. Germline status may only be represented in a fraction of the total homologous recombination dysfunction observed in the entire cohort, theref.