Genome Alteration Print (GAP): a tool to visualize and mine complex cancer genomic profiles obtained by SNP arrays

GAP, a method for analyzing complex cancer genome profiles from SNP arrays, performs well even with poor quality data and rearranged genome

Analysis of Somatic Alterations in Cancer Genome: From SNP Arrays to Next Generation Sequencing

International audienceIn this chapter we consider basic hypothesis, problem statements and technological and computa- tional solutions for analysis of copy number alterations in tumor genomes. We provide a data mining tech- nique (based on the GAP method described in (Popova et al., 2009)) which allows extraction of absolute copy numbers and allelic contents from the whole genome copy number variation and allelic imbalance profiles obtained by SNP arrays or NGS

Analysis of Somatic Alterations in Cancer Genome: From SNP Arrays to Next Generation Sequencing

International audienceIn this chapter we consider basic hypothesis, problem statements and technological and computa- tional solutions for analysis of copy number alterations in tumor genomes. We provide a data mining tech- nique (based on the GAP method described in (Popova et al., 2009)) which allows extraction of absolute copy numbers and allelic contents from the whole genome copy number variation and allelic imbalance profiles obtained by SNP arrays or NGS

Lack of evidence for CDK12 as an ovarian cancer predisposing gene

International audienceCDK12 variants were investigated as a genetic susceptibility to ovarian cancer in a series of 416 unrelated and consecutive patients with ovarian carcinoma and who carry neither germline BRCA1 nor BRCA2 pathogenic variant. The presence of CDK12 variants was searched in germline DNA by massive parallel sequencing on pooled DNAs. The lack of detection of deleterious variants and the observed proportion of missense variants in the series of ovarian carcinoma patients as compared with all human populations strongly suggests that CDK12 is not an ovarian cancer predisposing gene

ShallowHRD: detection of homologous recombination deficiency from shallow whole genome sequencing

International audienceWe introduce shallowHRD, a software tool to evaluate tumor homologous recombination deficiency (HRD) based on whole genome sequencing (WGS) at low coverage (shallow WGS or sWGS; $1X coverage). The tool, based on mining copy number alterations profile, implements a fast and straightforward procedure that shows 87.5% sensitivity and 90.5% specificity for HRD detection. shallowHRD could be instrumental in predicting response to poly(ADP-ribose) polymerase inhibitors, to which HRD tumors are selectively sensitive. shallowHRD displays efficiency comparable to most state-of-art approaches, is cost-effective, generates low-storable outputs and is also suitable for fixed-formalin paraffin embedded tissues

Genetic heterogeneity versus molecular analysis of prion susceptibility in neuroblasma N2a sublines

The neuroblastoma-derived cell line N2a is permissive to certain prion strains but resistant sublines unable to accumulate the pathological proteinase-K resistant form of the prion protein can be isolated. We compared for gene expression and phenotypes different N2a sublines that were susceptible or resistant to the 22L prion strain. Karyotypes and comparative genomic hybridization arrays revealed chromosomal imbalances but did not demonstrate a characteristic profile of genomic alterations linked to prion susceptibility. Likewise, we showed that this phenotype was not dependent on the binding of PrPres, the expression of the prion protein gene, or on its primary sequence. We completed this analysis by looking using real-time quantitative PCR at the expression of a set of genes encoding proteins linked to prion biology. None of the candidates could account by itself for the infection phenotype, nevertheless sublines had distinct transcriptional profiles. Taken together, our results do not support a role for specific genomic abnormalities and possible candidate proteins in N2a prion susceptibility. They also reveal genetic heterogeneity among the sublines and serve as a guidance for further investigation into the molecular mechanisms of prion infection

BAC array CGH distinguishes mutually exclusive alterations that define clinicogenetic subtypes of gliomas.

International audienceThe pathological classification of gliomas constitutes a critical step of the clinical management of patients, yet it is frequently challenging. To assess the relationship between genetic abnormalities and clinicopathological characteristics, we have performed a genetic and clinical analysis of a series of gliomas. A total of 112 gliomas were analyzed by comparative genomic hybridization on a BAC array with a 1 megabase resolution. Altered regions were identified and correlation analysis enabled to retrieve significant associations and exclusions. Whole chromosomes (chrs) 1p and 19q losses with centromeric breakpoints and EGFR high level amplification were found to be mutually exclusive, permitting identification of 3 distinct, nonoverlapping groups of tumors with striking clinicopathological differences. Type A tumors with chrs 1p and 19q co-deletion exhibited an oligodendroglial phenotype and a longer patient survival. Type B tumors were characterized by EGFR amplification. They harbored a WHO high grade of malignancy and a short patient survival. Finally, type C tumors displayed none of the previous patterns but the presence of chr 7 gain, chr 9p deletion and/or chr 10 loss. It included astrocytic tumors in patients younger than in type B and whose prognosis was highly dependent upon the number of alterations. A multivariate analysis based on a Cox model shows that age, WHO grade and genomic type provide complementary prognostic informations. Finally, our results highlight the potential of a whole-genome analysis as an additional diagnostic in cases of unclear conventional genetic findings

Syntenic Relationships between Genomic Profiles of Fiber-Induced Murine and Human Malignant Mesothelioma

Malignant mesothelioma (MM) is an aggressive tumor with a poor prognosis mainly linked to past asbestos exposure. Murine models of MM based on fiber exposure have been developed to elucidate the mechanism of mesothelioma formation. Genomic alterations in murine MM have now been partially characterized. To gain insight into the pathophysiology of mesothelioma, 16 murine and 35 human mesotheliomas were characterized by array-comparative genomic hybridization and were screened for common genomic alterations. Alteration of the 9p21 human region, often by biallelic deletion, was the most frequent alteration in both species, in agreement with the CDKN2A/CDKN2B locus deletion in human disease and murine models. Other shared aberrations were losses of 1p36.3–p35 and 13q14–q33 and gains of 5p15.3–p13 regions. However, some differences were noted, such as absence of recurrent alterations in mouse regions corresponding to human chromosome 22. Comparison between altered recurrent regions in asbestos-exposed and non–asbestos-exposed patients showed a significant difference in the 14q11.2–q21 region, which was also lost in fiber-induced murine mesothelioma. A correlation was also demonstrated between genomic instability and tumorigenicity of human mesothelioma xenografts in nude mice. Overall, these data show similarities between murine and human disease, and contribute to the understanding of the influence of fibers in the pathogenesis of mesothelioma and validation of the murine model for preclinical testing