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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

Heatmap of the tumor samples for exclusively deleted and amplified cytobands. The color coding for the matrix data is: copy loss (light blue), copy neutral (light yellow) and copy gain (pink). Three tumor clusters are indicated on the left side in orange (first class), light green (second class) and gray (third class). Cytoband clusters are shown on the top: dark green (1p), light green (1q), red (2q), purple (3p), blue (dark blue for 7p, light blue for 7q), orange (8q) and gray (14q).
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Fig4: Heatmap of the tumor samples for exclusively deleted and amplified cytobands. The color coding for the matrix data is: copy loss (light blue), copy neutral (light yellow) and copy gain (pink). Three tumor clusters are indicated on the left side in orange (first class), light green (second class) and gray (third class). Cytoband clusters are shown on the top: dark green (1p), light green (1q), red (2q), purple (3p), blue (dark blue for 7p, light blue for 7q), orange (8q) and gray (14q).

Mentions: We also analyzed how the tumor samples could be classified based on the minimal subset of exclusively deleted and amplified cytobands. The aim of this molecular classification was to identify tumor clusters defined by the smallest subset of exclusively deleted and amplified cytobands. The best model (according to the BIC criterion) corresponded to the one that led to three tumor clusters. Figure 4 shows a heatmap of the tumor samples for the exclusively deleted/amplified cytobands. Ten tumors are classified in the first cluster (orange in Figure 4) characterized by copy loss of 1p and copy gain of the short arm of chromosome 7. Twenty tumors are classified in the second cluster (ligth green in Figure 4) characterized by 1p and 3p copy losses and no 7p copy gain. Twelve tumors are classified in the third cluster (gray in Figure 4) characterized by no or very few alterations.Figure 4


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)

Heatmap of the tumor samples for exclusively deleted and amplified cytobands. The color coding for the matrix data is: copy loss (light blue), copy neutral (light yellow) and copy gain (pink). Three tumor clusters are indicated on the left side in orange (first class), light green (second class) and gray (third class). Cytoband clusters are shown on the top: dark green (1p), light green (1q), red (2q), purple (3p), blue (dark blue for 7p, light blue for 7q), orange (8q) and gray (14q).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig4: Heatmap of the tumor samples for exclusively deleted and amplified cytobands. The color coding for the matrix data is: copy loss (light blue), copy neutral (light yellow) and copy gain (pink). Three tumor clusters are indicated on the left side in orange (first class), light green (second class) and gray (third class). Cytoband clusters are shown on the top: dark green (1p), light green (1q), red (2q), purple (3p), blue (dark blue for 7p, light blue for 7q), orange (8q) and gray (14q).
Mentions: We also analyzed how the tumor samples could be classified based on the minimal subset of exclusively deleted and amplified cytobands. The aim of this molecular classification was to identify tumor clusters defined by the smallest subset of exclusively deleted and amplified cytobands. The best model (according to the BIC criterion) corresponded to the one that led to three tumor clusters. Figure 4 shows a heatmap of the tumor samples for the exclusively deleted/amplified cytobands. Ten tumors are classified in the first cluster (orange in Figure 4) characterized by copy loss of 1p and copy gain of the short arm of chromosome 7. Twenty tumors are classified in the second cluster (ligth green in Figure 4) characterized by 1p and 3p copy losses and no 7p copy gain. Twelve tumors are classified in the third cluster (gray in Figure 4) characterized by no or very few alterations.Figure 4

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