Dataset Information

Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma.

ABSTRACT: Genetic changes during tumorigenesis are usually acquired sequentially. However, a recent study showed that in 2% to 3% of all cancers a single catastrophic event, termed chromothripsis, can lead to massive genomic rearrangements confined to one or a few chromosomes. To explore whether the degree of genomic instability and chromothripsis influences prognosis in cancer, we retrospectively applied array-comparative genomic hybridization (aCGH) to 20 malignant melanomas that showed, despite comparable conventional clinical and pathologic parameters, a profoundly different clinical course. We compared 10 patients who died of malignant melanoma 3.7 years (median, range 0.9-7.6 years) after diagnosis with 10 patients who survived malignant melanoma and had a median disease-free survival of 14.8 years (range 12.5-16.7 years; P = 0.00001). We observed a striking association between the degree of chromosomal instability, both numerical and structural, and outcome. Malignant melanomas associated with good prognosis showed only few chromosomal imbalances (mean 1.6 alterations per case), predominantly whole chromosome or chromosome arm gains and losses, whereas malignant melanomas with poor prognosis harbored significantly more chromosomal aberrations (13.9 per case; P = 0.008). Array-based CGH showed that these aberrations were mostly focal events, culminating in two cases in a pattern consistent with the phenomenon of chromothripsis, which was confirmed by paired-end sequencing. This is the first description of chromothripsis in primary malignant melanomas. Our study therefore links focal copy number alterations and chromothripsis with poor outcome in patients with malignant melanomas (P = 0.0002) and provides a genetic approach to predict outcome in malignant melanomas.

SUBMITTER: Hirsch D

PROVIDER: S-EPMC4535704 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma.

Hirsch Daniela D Kemmerling Ralf R Davis Sean S Camps Jordi J Meltzer Paul S PS Ried Thomas T Gaiser Timo T

Cancer research 20121227 5

Genetic changes during tumorigenesis are usually acquired sequentially. However, a recent study showed that in 2% to 3% of all cancers a single catastrophic event, termed chromothripsis, can lead to massive genomic rearrangements confined to one or a few chromosomes. To explore whether the degree of genomic instability and chromothripsis influences prognosis in cancer, we retrospectively applied array-comparative genomic hybridization (aCGH) to 20 malignant melanomas that showed, despite compara ...[more]

PMID: 23271725

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Project description:BACKGROUND:Detection of DNA copy number alterations (CNAs) is critical to understand genetic diversity, genome evolution and pathological conditions such as cancer. Cancer genomes are plagued with widespread multi-level structural aberrations of chromosomes that pose challenges to discover CNAs of different length scales, and distinct biological origins and functions. Although several computational tools are available to identify CNAs using read depth (RD) signal, they fail to distinguish between large-scale and focal alterations due to inaccurate modeling of the RD signal of cancer genomes. Additionally, RD signal is affected by overdispersion-driven biases at low coverage, which significantly inflate false detection of CNA regions. RESULTS:We have developed CNAtra framework to hierarchically discover and classify 'large-scale' and 'focal' copy number gain/loss from a single whole-genome sequencing (WGS) sample. CNAtra first utilizes a multimodal-based distribution to estimate the copy number (CN) reference from the complex RD profile of the cancer genome. We implemented Savitzky-Golay smoothing filter and Modified Varri segmentation to capture the change points of the RD signal. We then developed a CN state-driven merging algorithm to identify the large segments with distinct copy numbers. Next, we identified focal alterations in each large segment using coverage-based thresholding to mitigate the adverse effects of signal variations. Using cancer cell lines and patient datasets, we confirmed CNAtra's ability to detect and distinguish the segmental aneuploidies and focal alterations. We used realistic simulated data for benchmarking the performance of CNAtra against other single-sample detection tools, where we artificially introduced CNAs in the original cancer profiles. We found that CNAtra is superior in terms of precision, recall and f-measure. CNAtra shows the highest sensitivity of 93 and 97% for detecting large-scale and focal alterations respectively. Visual inspection of CNAs revealed that CNAtra is the most robust detection tool for low-coverage cancer data. CONCLUSIONS:CNAtra is a single-sample CNA detection tool that provides an analytical and visualization framework for CNA profiling without relying on any reference control. It can detect chromosome-level segmental aneuploidies and high-confidence focal alterations, even from low-coverage data. CNAtra is an open-source software implemented in MATLAB®. It is freely available at https://github.com/AISKhalil/CNAtra.

Dataset Information

Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma.

Publications

Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma.

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