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Patterns of chromosomal copy-number alterations in intrahepatic cholangiocarcinoma.

Dalmasso C, Carpentier W, Guettier C, Camilleri-Broët S, Borelli WV, Campos Dos Santos CR, Castaing D, Duclos-Vallée JC, Broët P - BMC Cancer (2015)

Bottom Line: This study describes the spectrum of chromosomal aberrations across the whole genome.Some of the recurrent exclusive CNAs harbor candidate target genes.Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), Université d'Evry Val d'Essonne, UMR CNRS 8071, USC INRA, Evry, France. cyril.dalmasso@genopole.cnrs.fr.

ABSTRACT

Background: Intrahepatic cholangiocarcinomas (ICC) are relatively rare malignant tumors associated with a poor prognosis. Recent studies using genome-wide sequencing technologies have mainly focused on identifying new driver mutations. There is nevertheless a need to investigate the spectrum of copy number aberrations in order to identify potential target genes in the altered chromosomal regions. The aim of this study was to characterize the patterns of chromosomal copy-number alterations (CNAs) in ICC.

Methods: 53 patients having ICC with frozen material were selected. In 47 cases, DNA hybridization has been performed on a genomewide SNP array. A procedure with a segmentation step and a calling step classified genomic regions into copy-number aberration states. We identified the exclusively amplified and deleted recurrent genomic areas. These areas are those showing the highest estimated propensity level for copy loss (resp. copy gain) together with the lowest level for copy gain (resp. copy loss). We investigated ICC clustering. We analyzed the relationships between CNAs and clinico-pathological characteristics.

Results: The overall genomic profile of ICC showed many alterations with higher rates for the deletions. Exclusively deleted genomic areas were 1p, 3p and 14q. The main exclusively amplified genomic areas were 1q, 7p, 7q and 8q. Based on the exclusively deleted/amplified genomic areas, a clustering analysis identified three tumors groups: the first group characterized by copy loss of 1p and copy gain of 7p, the second group characterized by 1p and 3p copy losses without 7p copy gain, the last group characterized mainly by very few CNAs. From univariate analyses, the number of tumors, the size of the largest tumor and the stage were significantly associated with shorter time recurrence. We found no relationship between the number of altered cytobands or tumor groups and time to recurrence.

Conclusion: This study describes the spectrum of chromosomal aberrations across the whole genome. Some of the recurrent exclusive CNAs harbor candidate target genes. Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies.

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Related in: MedlinePlus

Flowchart of the calling algorithm used to classify each segment. Steps (1) and (2) are based on the BAF values while the final calling (steps (3), (3’) and (3")) is based on the LRR values.
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Fig1: Flowchart of the calling algorithm used to classify each segment. Steps (1) and (2) are based on the BAF values while the final calling (steps (3), (3’) and (3")) is based on the LRR values.

Mentions: The basic two consecutive steps of the procedure are the segmentation step (identification of the breakpoints in the data) and the calling step (allocation of the segments to one of the CNA states). For the segmentation step, the data were processed using a joint segmentation of the bivariate signal (LRR and BAF) [34]. Broadly speaking, a recursive binary segmentation [35] has been used to identify a list of candidate breakpoints and the final segmentation has been obtained from a pruning step using dynamic programming [36]. For the calling step, we considered a tree-based algorithm (summarized in Figure 1) with five decision nodes allowed to assign each segment a CNA state. The BAF values were used at two decision nodes (labeled (1) and (2)) to distinguish segments with a loss of heterozygosity (LOH), segments with an even number of copies for both alleles or segments with an odd number of copies. The LRR values were used at three decision nodes (labeled (3), (3’) and (3”)) to classify segments as copy loss, copy neutral or copy gain. The decision nodes are described in more details below.Figure 1


Patterns of chromosomal copy-number alterations in intrahepatic cholangiocarcinoma.

Dalmasso C, Carpentier W, Guettier C, Camilleri-Broët S, Borelli WV, Campos Dos Santos CR, Castaing D, Duclos-Vallée JC, Broët P - BMC Cancer (2015)

Flowchart of the calling algorithm used to classify each segment. Steps (1) and (2) are based on the BAF values while the final calling (steps (3), (3’) and (3")) is based on the LRR values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4373066&req=5

Fig1: Flowchart of the calling algorithm used to classify each segment. Steps (1) and (2) are based on the BAF values while the final calling (steps (3), (3’) and (3")) is based on the LRR values.
Mentions: The basic two consecutive steps of the procedure are the segmentation step (identification of the breakpoints in the data) and the calling step (allocation of the segments to one of the CNA states). For the segmentation step, the data were processed using a joint segmentation of the bivariate signal (LRR and BAF) [34]. Broadly speaking, a recursive binary segmentation [35] has been used to identify a list of candidate breakpoints and the final segmentation has been obtained from a pruning step using dynamic programming [36]. For the calling step, we considered a tree-based algorithm (summarized in Figure 1) with five decision nodes allowed to assign each segment a CNA state. The BAF values were used at two decision nodes (labeled (1) and (2)) to distinguish segments with a loss of heterozygosity (LOH), segments with an even number of copies for both alleles or segments with an odd number of copies. The LRR values were used at three decision nodes (labeled (3), (3’) and (3”)) to classify segments as copy loss, copy neutral or copy gain. The decision nodes are described in more details below.Figure 1

Bottom Line: This study describes the spectrum of chromosomal aberrations across the whole genome.Some of the recurrent exclusive CNAs harbor candidate target genes.Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), Université d'Evry Val d'Essonne, UMR CNRS 8071, USC INRA, Evry, France. cyril.dalmasso@genopole.cnrs.fr.

ABSTRACT

Background: Intrahepatic cholangiocarcinomas (ICC) are relatively rare malignant tumors associated with a poor prognosis. Recent studies using genome-wide sequencing technologies have mainly focused on identifying new driver mutations. There is nevertheless a need to investigate the spectrum of copy number aberrations in order to identify potential target genes in the altered chromosomal regions. The aim of this study was to characterize the patterns of chromosomal copy-number alterations (CNAs) in ICC.

Methods: 53 patients having ICC with frozen material were selected. In 47 cases, DNA hybridization has been performed on a genomewide SNP array. A procedure with a segmentation step and a calling step classified genomic regions into copy-number aberration states. We identified the exclusively amplified and deleted recurrent genomic areas. These areas are those showing the highest estimated propensity level for copy loss (resp. copy gain) together with the lowest level for copy gain (resp. copy loss). We investigated ICC clustering. We analyzed the relationships between CNAs and clinico-pathological characteristics.

Results: The overall genomic profile of ICC showed many alterations with higher rates for the deletions. Exclusively deleted genomic areas were 1p, 3p and 14q. The main exclusively amplified genomic areas were 1q, 7p, 7q and 8q. Based on the exclusively deleted/amplified genomic areas, a clustering analysis identified three tumors groups: the first group characterized by copy loss of 1p and copy gain of 7p, the second group characterized by 1p and 3p copy losses without 7p copy gain, the last group characterized mainly by very few CNAs. From univariate analyses, the number of tumors, the size of the largest tumor and the stage were significantly associated with shorter time recurrence. We found no relationship between the number of altered cytobands or tumor groups and time to recurrence.

Conclusion: This study describes the spectrum of chromosomal aberrations across the whole genome. Some of the recurrent exclusive CNAs harbor candidate target genes. Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies.

Show MeSH
Related in: MedlinePlus