A statistical approach for detecting genomic aberrations in heterogeneous tumor samples from single nucleotide polymorphism genotyping data

Yau, Christopher; Mouradov, Dmitri; Jorissen, Robert N.; Colella, Stefano; Mirza, Ghazala; Steers, Graham; Harris, Adrian L.; Ragoussis, Jiannis; Sieber, Oliver M.; Holmes, Connor

doi:10.1186/gb-2010-11-9-r92

Cited by 126 publications

(125 citation statements)

References 42 publications

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“…Two “state of the art” methods for paired SNP array analysis: ASCAT [25] and OncoSNP [26], were also examined for comparison. Similar with GIANT, both methods are featured with automatic calibration for normal cell contamination and tumor aneuploidy.…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Identification of Somatic Aberrations from Paired Normal-Tumor Samples

Liu

Zhao

et al. 2014

PLoS ONE

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Genomic copy number alteration and allelic imbalance are distinct features of cancer cells, and recent advances in the genotyping technology have greatly boosted the research in the cancer genome. However, the complicated nature of tumor usually hampers the dissection of the SNP arrays. In this study, we describe a bioinformatic tool, named GIANT, for genome-wide identification of somatic aberrations from paired normal-tumor samples measured with SNP arrays. By efficiently incorporating genotype information of matched normal sample, it accurately detects different types of aberrations in cancer genome, even for aneuploid tumor samples with severe normal cell contamination. Furthermore, it allows for discovery of recurrent aberrations with critical biological properties in tumorigenesis by using statistical significance test. We demonstrate the superior performance of the proposed method on various datasets including tumor replicate pairs, simulated SNP arrays and dilution series of normal-cancer cell lines. Results show that GIANT has the potential to detect the genomic aberration even when the cancer cell proportion is as low as 5∼10%. Application on a large number of paired tumor samples delivers a genome-wide profile of the statistical significance of the various aberrations, including amplification, deletion and LOH. We believe that GIANT represents a powerful bioinformatic tool for interpreting the complex genomic aberration, and thus assisting both academic study and the clinical treatment of cancer.

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Section: Resultsmentioning

confidence: 99%

Genome-Wide Identification of Somatic Aberrations from Paired Normal-Tumor Samples

Liu

Zhao

et al. 2014

PLoS ONE

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“…88 For quality control, the subset of samples genotyped on HumanOmni 2.5–8v1 BeadChips (as part of whole genome sequencing) were also analyzed for CNVs by using tQN 89 for normalization, followed by OncoSNP v1.2 for characterization of CNVs and loss-of-heterozygosity (LOH) events. 90 Copy number clustering was performed on segmented copy number data. A unified breakpoint profile (region by sample matrix) was derived by combining breakpoints across all samples and determining the minimal common regions of change.…”

Section: Methodsmentioning

confidence: 99%

The mutational landscape of adenoid cystic carcinoma

et al. 2013

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Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here, we determined the ACC mutational landscape and report the exome or whole genome sequences of 60 ACC tumor/normal pairs. These analyses revealed a low exonic somatic mutation rate (0.31 non-silent events/megabase) and wide mutational diversity. Interestingly, mutations selectively involved chromatin state regulators, such as SMARCA2, CREBBP, and KDM6A, suggesting aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to DNA damage and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying these aberrations as critical events. Lastly, we identified recurrent mutations in the FGF/IGF/PI3K pathway that may potentially offer new avenues for therapy (30%). Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.

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“…LOH and copy-number states were determined using OncoSNP software (Isis Innovations, Oxford, UK) (Supplementary Figure 1). 32 …”

Section: Methodsmentioning

confidence: 99%

Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis

et al. 2012

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Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/β-catenin signalling levels ‘just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282–1581) leaving 1–3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5′ to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2–3 intact 20AARs were associated with 5′ mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3′ to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2–3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate ‘fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/β-catenin signalling, with different ‘optimal' thresholds for proximal and distal cancers.

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A statistical approach for detecting genomic aberrations in heterogeneous tumor samples from single nucleotide polymorphism genotyping data

Cited by 126 publications

References 42 publications

Genome-Wide Identification of Somatic Aberrations from Paired Normal-Tumor Samples

Genome-Wide Identification of Somatic Aberrations from Paired Normal-Tumor Samples

The mutational landscape of adenoid cystic carcinoma

Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/β-catenin signalling thresholds for tumourigenesis

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