Patterns Of Copy Number Alterations Research Articles

Modeling recurrent DNA copy number alterations in array CGH data

Recurrent DNA copy number alterations (CNA) measured with array comparative genomic hybridization (aCGH) reveal important molecular features of human genetics and disease. Studying aCGH profiles from a phenotypic group of individuals can determine important recurrent CNA patterns that suggest a strong correlation to the phenotype. Computational approaches to detecting recurrent CNAs from a set of aCGH experiments have typically relied on discretizing the noisy log ratios and subsequently inferring patterns. We demonstrate that this can have the effect of filtering out important signals present in the raw data. In this article we develop statistical models that jointly infer CNA patterns and the discrete labels by borrowing statistical strength across samples. We propose extending single sample aCGH HMMs to the multiple sample case in order to infer shared CNAs. We model recurrent CNAs as a profile encoded by a master sequence of states that generates the samples. We show how to improve on two basic models by performing joint inference of the discrete labels and providing sparsity in the output. We demonstrate on synthetic ground truth data and real data from lung cancer cell lines how these two important features of our model improve results over baseline models. We include standard quantitative metrics and a qualitative assessment on which to base our conclusions. http://www.cs.ubc.ca/~sshah/acgh.

High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer

High resolution array-CGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer, and provides a genome-wide list of common copy number alterations associated with aberrant expression and poor prognosis.

Genomic gain of the epidermal growth factor receptor harboring band 7p12 is part of a complex pattern of genomic imbalances in oral squamous cell carcinomas

To determine the association between changes of genomic gene dose and clinical parameters in squamous cell carcinomas of the oral cavity, comparative genomic hybridization seemed suited not only to detect genomic imbalances in these tumors, but also particularly to examine the role of gain of 7p12, the band harboring the epidermal growth factor receptor (EGFR) in this context. Total genomic DNA obtained from 35 oral squamous cell carcinomas was subjected to comparative genomic hybridization (CGH) and detected patterns of genomic imbalances were associated with various clinical parameters. The examined tumors exhibited five and up to 47 DNA copy number alterations (CNAs). Nineteen of these showed a gain of chromosome band 7p12. A highly complex but strikingly consistent pattern of genomic imbalances (average, 32 CNAs per tumor) was associated with this alteration, among which gains clearly dominated over losses of genomic material. Comparable patterns, however, could also be found in a few tumors with a high number of CNAs (average, 26) but without the 7p gain. Low numbers of imbalances always were accompanied by low consistency of CNA patterns and none of these cases showed enh(7p12). No significant differences with respect to pT class or grade of tumors were found between enh(7p)-positive and -negative tumors. Stage IV and lymph node affection were slightly more frequent among enh(7p12)-positive than in -negative cases. Relapse occurred in 63% in 7p12-positive vs. 25% in the negative group. Average disease-free survival of tumors without 7p gain clearly exceeded that of tumors with gain of 7p (36.8 vs. 21.3). However, some of these associations could also be found if comparison was based on number of CNAs. By means of hierarchical cluster analysis, we were able to show that different patterns of CNAs can be separated from each other in tumors with or without 7p alterations, and that these patterns predict short- or long-term survival of patients. Previously described associations of gains of 7p12, the chromosomal band harboring the EGFR gene with clinical parameters can reasonably be estimated only within the context of the pattern and complexity of the genomic imbalances accompanying this chromosomal loss in examined tumors.

Loss of 9p21 is embedded in a complex but consistent pattern of genomic imbalances in oral squamous cell carcinomas

35 oral squamous cell carcinomas examined previously by comparative genomic hybridization (CGH) exhibited 5 up to 47 copy number alterations (CNAs). 13 of those cases showed a loss of parts of the short arm of chromosome 9, band p21 being affected in all of these cases. A highly complex but strikingly consistent pattern of genomic imbalances with an average 31.5 CNAs per tumor was associated with this deletion, and gains clearly dominated over losses of genomic material. Comparable patterns, however, could also be found in tumors with a high number of CNAs (24 CNAs) but without the deletion. Low numbers of imbalances were accompanied by low consistency of the CNA patterns. None of these latter cases showed the deletion 9p21. 66.7% of the dim(9p21)-positive tumors were of class pT4 (vs. 22% in dim(9p21)-negative cases), 77% of stage III or IV (vs. 47% in the group without the deletion), but only 8% of the dim(9p21)-positive tumors were classified as grade 3 (vs. 41% in the negative group). Other clinicopathologic features like prevalence of relapse, or survival time could not be as clearly associated with the deletion. For instance, short relapse-free survival was clearly associated with a high number of CNAs, rather independent of presence or absence of dim(9p21) in the affected tumor. From these findings it is concluded that previously found associations of 9p21 deletion with clinical parameters can reasonably be estimated only in the context of the pattern and complexity of the genomic imbalances accompanying this chromosomal loss in the examined tumors.

Pattern of genomic imbalances in oral squamous cell carcinomas with and without an increased copy number of 11q13.

Among 23 squamous cell carcinomas (SCC) of the oral cavity which were screened for DNA copy number alterations (CNAs) using comparative genomic hybridization, 14 showed a gain of, and 5 of these 14 even an amplification of band 11q13. Amplification of 11q13 was also detected in three of the four studied SCC cell lines and was confirmed by interphase FISH. The number of CNAs in addition to 11q13 varied from 14 to 47 in these carcinomas. All these tumors had seven other specific CNAs in common, i.e. gain on 1p36.3-36.6, 5p15, 9q34, 12p12-13, 14q32, 19 and 20q, all but one showed also an increase of copy number in 7p22, 8q24, 10q26, 12q26, 15q24-25, 16p, 16q23-24, 17q and 22q12-qter. These imbalances were distinctly rarer in the tumors without CNA in 11q13. Loss of material apparently played a minor role in these tumors with gain of 11q13, the most frequent losses (3p12-14 and 5q21) being present in 10 of the 14 cases and loss of 9p13-21 in 5/14 tumors. The three tumors with the highest number of CNAs in addition to 11q13, were histologically classified as pT4, three of the five tumors with 11q13 amplification were highly node-positive (pN 2b-2c). Two of the pT4 tumors shared as many as 23 specific chromosomal segments affected by CNA. Thus, gain of 11q13, though being found at different stages of karyotypic evolution, is apparently associated with a rather specific pattern of other CNAs and involved in progressed stages of malignancy in oral squamous cell carcinoma. In addition, the proportion of patients deceased within one year after diagnosis was clearly higher in the group whose tumors showed an increased 11q13 copy number as compared to the group without this increase. This could point to an association of gain in 11q13 and aggressiveness of the respective tumor.